Abstracts for the Second International Meeting of the Milan Center for Neuroscience (Neuromi): Prediction and Prevention of Dementia: New Hope (Milan, July 6–8, 2016)

Preserved cognition and Alzheimer pathology in the oldest old

O. Bugiani

Istituto Neurologico Carlo Besta Milano, Fondazione Golgi-Cenci (Abbiategrasso-MI)

People aged over 85, referred to as the oldest old, have been increasing in number faster than any other age group in the population and are expected to triplicate by the end of the century. Luckily, they may feel themselves better than most younger old can do, and even be reasonably autonomous, if not healthy at all. Accordingly, some of them could hold and delay major illnesses, among which the dementia. To focus on the latter and its ageing-related prevalence, it is likely, although debated, that it affects the oldest old less than expected compared to the younger elderly (reviews in Perls 2004, Yang et al 2013), and that the association between dementia and plaques and tangles, the most representative lesions of both normal and pathologic brain ageing and so the most commonly investigated, is stronger in the younger elderly than in the older old (Haroutunian et al 2008, Savva et al 2009, Corrada et al 2012). Longevity-enabling genes, increased adaptation, and lower risk factors for dementia in mid-life have been proposed as an explanation. Interestingly, these data are in agreement with a meta-analysis of prevalence of dementia which showed that, compared with the ageing-based exponential model, logistic models indicated that prevalence rates were higher from age 75 to 95 years and subsequently lower, so originating a plateau after age 95 and suggesting that dementia is related to one age range rather than to ageing (Ritchie & Kildea 1995). Discontinuity in the prevalence of dementia should point to vulnerability of allocortical and neocortical neurons modulated by ontogenetic factors that make them variably sensitive to degeneration, and so mark one difference among individuals (Bugiani 2011). Accordingly, the age-related dementia might be explained in terms of neurons more sensitive to degeneration that survive in the brain after inadequate cell selection during development (Arendt 2005). This theory should apply to Alzheimer pathology due to the crucial role of APP, Abeta and related proteins in brain development. Conversely, privileges of the oldest old might be related to successful cell selection that allows cognitive reserve, neural compensation, and adult neurogenesis to maximise their effects.

Suggestions from epidemiology and clinical epidemiology for prevention and better knowledge of dementia

M. Musicco

Institute of Biomedical Technologies (Segrate- MI)

Population studies on occurrence of neurodegenerative dementias show that in Europe the incidence of these disorders is decreasing over time, despite their progressive increasing prevalence. Actually the number of persons with dementia increases in parallel with the progressive aging of our population, but the number of persons who become demented in the different age strata is decreasing. The reasons of this epochal phenomenon are not completely known but may be searched for in the changing pattern of social characteristics, life habits and access to medical interventions of more recent birth cohorts of population. Better education, healthier life styles and more intense control of disease risk factors characterize contemporary elderly populations with respect to those of the past. This trend of incidence reduction is spontaneous and can be considered an unintended effect of the progressive general improving of the social and health conditions of the European population. It remains to be defined, for the future, what predefined health policies should be implemented with the purpose of controlling and preventing neurodegenerative disorders with clear and evidence based interventions. The results of recent preventive interventions on populations at risk of cognitive decline are more than encouraging for designing public health initiatives targeted to fight against neurodegeneration and dementia. In the field of better understanding the relationship between neurodegeneration and aging there are a number of evidence that dementia in the oldest old presents peculiarities that should be taken into account for future interventions and actions. First neurodegeneration seems to compete with cancer in the complex phenomenon of senescence since a number of studies reported that the occurrence of cancer is less than expected in persons with neurodegenerative disorders and vice-versa. Second, many studies are reporting in the oldest old that many dementias with an Alzheimer phenotype are not sustained by the traditional neuropathological picture of the contemporary presence and amyloid plaques deposition and neuro- phibrillary degeneration. This observations poses the need of reconsidering, at least for the oldest old, our current paradigms about the pathophysiology of dementias.

Ethical Issues on Dementia

V. A. Sironi

Director of the Research Center on the History of Biomedical Thought, University of Milano Bicocca (Milano)

Dementia today is an existential condition which leads, through worsening clinical manifestations, to the inexorable exit from the human through the progressive loss of the possibility of establishing cognitive relations until the complete disintegration of the individual personality. In the medical field, in the early and middle stages of the disease the fundamental task is to prevent possible complications, addressing the behavioural changes and treating the psychological symptoms, while in the terminal stages must lead the patient towards the end of his earthly existence in the most dignified way possible. It must be remembered that in the “therapeutic relationship” with the patient and his family, he will always be considered - although demented - as a person worthy of attention and respect. The communication of the diagnosis to the patient - who has the right to know - is the first ethical knot: we must establish what the subject is able to combine the “right to truth” (diagnostic) with the “right to hope” (existential). A second important aspect concerns the consent to medical procedures, which should be viewed in the context of the patient’s autonomy and decisional aspects of personal identity and the degree of awareness of the subject. This perspective also raises the issue of “Advance treatment statements” relating to future therapy (use of pain medications, access to palliative care, artificial feeding) and a possible “living will” consistent with the system of values and with the beliefs that the patient expressed in the course of its existence. Finally, a fundamental ethical issue concerns the problems of clinical trials on people incapable of expressing a full consensus. Is important that this problem is addressed in a way that it cannot only provide adequate protection in these subjects, but also so that it can be favoured their participation given that testing could result in real benefits to their health.

Synaptopathology of dementia

E. Marcello, M. Di Luca

Department of Pharmacological and Biomolecular Sciences (Milano)

Background: Alzheimer’s disease (AD) is the most prevalent and socially disruptive illness of aging populations. Genetic and pathological evidence strongly supports the amyloid cascade hypothesis, which states that Amyloid β (Aβ) has an early and crucial role in AD. Aβ is liberated from the amyloid precursor protein (APP) by BACE and γ-secretase activity. Alternatively, APP is cleaved within the Aβ domain by ADAM10, which prevents Aβ formation. In addition to Aβ, synapse loss has a central role in AD pathogenesis, rather than just a consequence of cell death. Synapse loss represents an early insult that advances with disease and dendritic spine loss is seen in several AD models.

Aim: We aim at studying the mechanisms underlying the crosstalk between Aβ and synaptic function and failure.

Results: We provide new evidences on local trafficking pathways relevant for AD pathogenesis. We described the mechanisms responsible for ADAM10 forward trafficking and endocytosis, that are important for Aβ production and spine remodelling. We provided a mechanism according to which ADAM10 local trafficking from dendritic Golgi outposts to the postsynaptic density is mediated by SAP97 and is under the control of PKC-dependent phosphorylation of SAP97. On the other hand, activity-regulated association of ADAM10 with the clathrin adaptor AP2 complex mediates ADAM10 endocytosis. Moreover, ADAM10 local trafficking mechanisms are impaired in AD patients at the earlier AD stages.

Conclusions: Taken together these results provide a complete picture of the network of interacting pathways leading to AD that is mandatory for the development of successful therapies.

Lymphatic drainage of the brain and the pathology of cerebral amyloid angiopathy

M. MacGregor-Sharp¹, N. Albargothy¹, A. Morris¹, R.O. Weller¹, A. Verma², R.O. Carare¹

¹University of Southampton, Faculty of Medicine, MP806, South Academic Block, Southampton General Hospital (Southampton- UK)

²Biogen, 14 Cambridge Center (Cambridge-USA)

The brain is an immune privileged organ due to the presence of a blood-brain barrier and the lack of lymphatic vessels. However, it has been clear for several decades that CNS antigens drain into regional lymph nodes. In humans, soluble amyloidβ is produced by neurons and is deposited in the walls of ageing cerebral blood vessels as cerebral amyloid angiopathy (CAA), providing thus a natural tracer for the drainage of solutes. Our anatomical experimental studies using wild-type mice demonstrate that injection of soluble tracers in the gray matter of the brain results in diffusion and drainage of the tracers along the basement membranes of capillaries and the basement membranes surrounding smooth muscle cells of arteries, towards the surface of the brain. This pathway is effectively the lymphatic drainage pathway of the brain and is restricted to solutes, as nanoparticles of 15nm cannot enter the cerebrovascular basement membranes. Ageing, possession of apolipoprotein E4 and vascular immune complexes block this drainage pathway, resulting in CAA. The cerebrovascular basement membranes are also the pathway for convective influx of cerebrospinal fluid (CSF) into the brain. Specifically, the glial-pial basement membranes are the pathways for convective influx of CSF. Using optimally preserved canine brain tissue we have demonstrated that the structure of the wall of arteries is different in gray matter compared to white matter, providing thus a platform for better interpretation of age-related white matter hyperintensities. Our results are significant for the pathology of CAA and for therapeutic delivery of drugs into the brain.

Microglia, neuroinflammation and Alzheimer disease

M. T. Heneka,

Clinical Neuroscience, Dept. Of Neurology, University of Bonn (Bonn-D)

Generation of neurotoxic amyloid-β peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component, which, once initiated in response to neurodegeneration or dysfunction actively contributes to disease progression and chronicity. Microglia is being activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors, which elicit an innate immune response. The latter is characterized by the release of inflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and enzyme systems. Exogenous as well as endogenous factors may promote and facilitate neuroinflammation in the AD brain. Thus, degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may drive inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. Inflammation may not just occur secondary to degeneration, but actively drive amyloid beta aggregation and APP processing. Modulation of the microglia driven innate immune response at key signalling steps may provide protection. Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the pro- into an antiinflammatory phenotype will be reviewed and discussed.

Central and peripheral markers of neuroinflammation: focus on brain Imaging

R. M. Moresco

IBFM-CNR, CIS San Raffaele Scientific Institute and Center for Neurosciences University of Milan Bicocca (Milano)

The 18 k-Da TSPO receptor is part of a multimeric complex whose levels rise in different brain disorders, reflecting macrophage invasion, glial proliferation or both. For this reason, the TSPO antagonist, [11C]PK11195 has been extensively used to image immune system activation during brain infection, inflammation or neuronal injury. The low in vivo signal to noise of [11C]PK11195 –PET images has stimulate the developments of several new chemical class of TSPO radiopharmaceuticals. However, binding of new class of radiopharmaceuticals to TSPO is sensitive to Single nucleotide polymorphism at Rs6971 in human beings increasing data variability. In addition not all reactive microglia/macrophage cells express TSPO receptors, and that their level of expression in different cells are heterogeneous. Finally, microglial cells of TSPO KO animals displayed an impaired mitochondrial metabolism and reduced ATP production. These observation, together with some successful results from TSPO agents used as therapeutics raise the question of the role of this TSPO in immune system and the real meaning of TSPO related images. Despite the low specificity of this target and the large amount of questions remained unsolved, this target represent a unique tool to detect the activation of immune system in human brain. To bypass TSPO limits, several effort of radiochemistry and radiopharmacology are actually focused on the discovery of new ligand selective for specific immune cells phenotype. Radioligand for reactive gliosis ([¹¹C]Deprenyl) or other microglial targets are under current clinical or preclinical evaluation.

Peripheral markers of neuroinflammation

L. Tremolizzo, E. Conti, C. Ferrarese

School of Medicine and NeuroMI, University of Milano-Bicocca (Milano)

Neuroinflammation is a process postulated to be confined to the CNS and to contribute to disease pathogenesis in Alzheimer’s disease (AD), among other neurodegenerative disorders. Albeit microglia cells specifically sustain this process, peripheral monocytes significantly contribute transforming in blood-born macrophages, passing through the blood-brain barrier attracted by increased beta-amyloid (Abeta) production. This interplay between CNS and periphery is further strengthened by the demonstration of the immune reflex, a cholinergic pathway projecting on alpha7- nicotinic receptors expressed by spleen monocytes and blocking the activation of the inflammosome. In this brief talk we will present the conceptual framework for a specific peripheral contribution to the spreading of AD pathogenic mechanisms, focusing on the role of monocytes. Particular reference will be made to the role of two proteins: TSPO-18 kDa in chemotaxis and TREM2 in phagocytosis, showing our preliminary ex vivo results in AD patients.

Do animal models recapitulate Alzheimer’s disease?

G. Forloni, C. Balducci

Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri (Milano)

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by synaptic dysfunction, memory loss, neuroinflammation and neuronal cell death. Together with the genetic and neuropathological observations the experimental results have contributed to clarify the pathogenesis of AD. In this contest the development of transgenic mouse models engineered with over- expression of the amyloid precursor protein carrying familial AD mutations alone or in combination with PS1 or PS2 mutated transgene has been useful. Transgenic mice closely reproduce the typical human AD hallmarks, throughout aging they start to display impairment in synaptic activity associated to cognitive deficits. These phenomena precede plaque deposition. Once plaques start to be detectable in brain parenchyma, they appear surrounded by activated microglia and astrocytes as a signature of an active inflammatory response. At structural level, mice develop progressive brain atrophy in mostly involved areas such as the cortex, hippocampus and striatum reminiscent of the AD cerebral condition as documented by our lungitudinal MRI analysis. Although animal models are widely used to investigate mechanisms of pathology and efficacy of new therapeutic approaches they still miss some important aspects of the disease. For instance, AD therapeutic agents tested in transgenic mice provide most of the time encouraging results which, however, are very disappointing when transferred in clinical trials. Neuronal cell death are not easily detectable in mouse models, most likely for a matter of insufficient longevity. Also NFTs are much harder to replicate in these mice, unless in the presence of specific tau mutations which are, however, not observable in AD patients, rather in human taupathies. However, all together mouse models of AD certainly offer a fundamental tool for understanding and solving dementia pathology, but their improvement would undoubtedly represent an even greater achievement in the field.

The concept of MCI and its variants

P. J. Nestor

German Center for Neurodegenerative Diseases (DZNE) (Magdeburg-D)

The pivotal diagnostic criteria for Alzheimer’s disease (AD), proposed over 30 years ago (McKhann et al, 1984), explicitly aimed at reducing false-positive diagnoses. This was achieved, in part, by building a severity threshold into the criteria—patients had to perform below a cut-off on cognitive assessment, and, they had to have involvement of multiple cognitive domains. While this approach improved specificity for a diagnosis of AD, as is often the case, the trade-off was sensitivity; it meant that a population of patients with Alzheimer pathology was excluded from the diagnosis in spite of being symptomatic. In particular, because people with symptomatic AD, have relatively isolated memory impairment in the early stages, they fail to meet the multiple domain criterion. ‘Mild cognitive impairment’ (MCI) became the favoured term to capture this group using the operational criteria of informant-corroborated symptoms of memory dysfunction combined with objective neuropsychological evidence of memory impairment. The problem emerges, however, that as one moves towards milder degrees of impairment, the risk of false-positives increases such that not all who fulfill MCI criteria will have AD as the cause. This problem can now be largely circumvented by inclusion of amyloid biomarkers leading to the concept of MCI- stage AD. Aside from this ‘amnestic MCI’ category, the application of neuropsychological cut-offs also introduced the possibility of being impaired on a non-memory domain (‘non-amnestic MCI’) or being impaired in multiple cognitive domains (‘multi-domain MCI’). Non-amnestic MCI tends to be a very unstable entity with follow-up—many having no definable degenerative pathology—while multi-domain MCI, unsurprisingly, tends to be highly associated with Alzheimer pathology.

Clinical variants of Alzheimer dementia

S. F. Cappa

IUSS (Pavia)

The concept of clinical variants (or “atypical”) AD is certainly not new. The typical (i.e. episodic memory) presentation of AD is associated with the most common pattern of neuropathological progression, which, however, is not without exceptions (Gertz et al., 1998). “Focal” progressive neuropsychological syndromes characterized by prominent language or visuo-spatial impairment with preserved memory function have been increasingly recognized, and in a proportion of cases associated to Alzheimer pathology (Galton et al., 2000) . More recently, a set of diagnostic criteria have been defined for atypical AD, based on the definition of specific clinical phenotypes (posterior variant, logopenic variant, frontal variant, Down’s syndrome variant) (Dubois et al., 2014). In line with the criteria for typical AD, the diagnosis requires in-vivo evidence of AD, as well as the exclusion of other conditions which may share clinical presentation with the variants. The diagnostic challenge is complex for all the variants, and requires the combination of in-depth cognitive and behavioural assessment with state of the art imaging techniques. The presentation phenotype faithfully reflects the neurodegeneration topography but bears only a probabilistic relationship with neuropathology. This may be relatively strong in the case of individual variants (posterior AD), but still largely undefined in the case of others (frontal variant). The role of pathophysiological biomarker is thus crucial for the diagnosis.

Other dementias

L. Bonanni, M. Onofrj

Department of Neuroscience Imaging and Clinical Sciences and CESI, University G d’Annunzio of Chieti-Pescara (Chieti)

Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia in elderly people after Alzheimer’s disease (AD), with approximately 10-15% of dementia cases at autopsy demonstrating the presence of Lewy body pathology [1]. In Parkinson’s disease (PD), dementia is a common outcome in up to 80% of patients with PD who will eventually develop dementia as their disease progresses [2, 3]. DLB and PD can be grouped under the umbrella term of Lewy body disease (LBD) due to the overlap in symptom profile, similar response to treatment and the common underlying alpha-synuclein aggregation neuropathology [4]. Together DLB and Parkinson’s disease with dementia (PDD) represent an important disease group in older age, with significant health and social impacts. LBD patients display marked deficits in executive and visuo-spatial/visuo-perceptual function, as well as marked variations in their level of arousal and attention which are known as cognitive fluctuations [5-8]. LBD clinical features also include spontaneous motor features of parkinsonism [6], and non-motor manifestations including symptoms such as visual hallucinations, autonomic dysfunction, syncope, repeated falls, REM sleep behaviour disorder, delusions and depression [6]. However, there are a number of important diagnostic challenges. For example, the differentiation of DLB from Alzheimer’s disease (AD) can be difficult, particularly in the early stages of disease when core DLB symptoms may be less evident [9]. Similarly, discrimination between PD, PD or DLB with mild cognitive impairment (PD-MCI, MCI-DLB) and PDD can be problematic as the development of cognitive impairment is often insidious and appears at a variable time after PD diagnosis [10]. There are also a number of treatment challenges. Profound cholinergic deficits occur in the LBDs, even more than in AD [11]. The use of cholinesterase inhibitors may have cognitive and neuropsychiatric benefits including improvements in global cognitive function, attentional function and activities of daily living [12]. However, there are frequently variations in treatment response [13]. The development of novel therapeutics is required, but this process has been hampered by the lack of LBD biomarkers which are sensitive to treatment response. In summary, therefore, there is a clear need to develop LBD biomarkers in order to facilitate early and differential diagnosis (during the prodromal phase of disease); improve our understanding of disease progression; provide a means to monitor therapeutic response; pave the way for early disease-modifying interventions. Existing biomarkers include a range of clinical, biochemical, genetic, proteomic, and, in particular, neuroimaging biomarkers [17, 18]. Generally the utility of these biomarkers has only been supported in a research context aside from dopamine transporter imaging, which due to its high specificity in differentiating LBD from AD [19] is now considered the gold standard for in vivo differential diagnosis between LBD and AD. However FP-CIT remains expensive, has a radioactive exposure and provides little or no information on the disease progression, prognosis, or correlation with cognitive/behavioural symptom severity. Biomarkers should ideally be inexpensive, non-invasive, simple to use and technically validated [20]. In this regard, neurophysiological measures, and in particular electroencephalography (EEG), are currently undergoing a renaissance as potential biomarkers of neurodegenerative disease.

The brain safe mode: evidence from normal and pathological ageing

G. Bottini^1,2,3, G. Salvato^1,2,3, M. Berlingeri ^2,3,4

¹Department of Brain and Behavioral Sciences, University of Pavia (Pavia)

²Cognitive Neuropsychology Centre, ASST Grande Ospedale Metropolitano Niguarda (Milano)

³Neuromi, Milan Center for Neuroscience (Milano)

⁴DISTUM, Department of Humanistic Studies, University of Urbino Carlo Bo (Urbino)

It is well known that there is not a direct relationship between the degree of brain damage and its clinical manifestation across subjects. This empirical evidence is at the basis of the concept of cognitive reserve (CR). CR usually refers to individual differences either in cognition, or in neural networks that lead some people to cope better than others with neurocognitive damages, promoting a sort of brain safe mode. It arises from the interplay between a purely anatomical neural reserve and a more behavioral neural compensation process. In particular, recent empirical findings suggest that compensatory processes may manifest them-selves as additional recruitment of new neural networks in healthy aging. These scaffolding networks would be task-dependent and triggered by the specific level of task-demand. Interestingly, this form of age-related neural plasticity seems to get lost even in the prodromal phases of degenerative diseases such as in amnestic Mild Cognitive Impairment. Likewise, a number of studies have demonstrated that the brain may deal with the risk of developing neurodegenerative diseases, such as in the case of Apolipoprotein ɛ4 (APOE ɛ4) genotype, a condition typically associated with late- onset Alzheimer Disease (AD). The APOE ɛ4 genotype and its influence on cognition may depend on age, gender, education, and lifestyle. Such variables would characterize the CR, which can be addressed as a possible moderator between brain changes and the clinical manifestation of AD. These findings could be considered as potential tailored interventions in case of brain injuries or pathological ageing.

Temporary binding: a promising cognitive marker for AD

S. Della Sala

Human Cognitive Neuroscience and Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology Department, University of Edinburgh (Edinburgh –UK)

Accurate diagnosis of Alzheimer’s Disease (AD) is essential for planning care, informing patients and carers, selecting patients for clinical trials, and assessing outcome of interventions. In clinical practice, diagnosis and monitoring of AD progression is aided by cognitive tests, which however are unreliable for follow-up testing and only identify cognitive impairment, not the underlying disease causing the impairment. Memory impairment is the hallmark of AD. However, memory impairment, as measured by current clinical assessment, is also affected by healthy ageing and chronic depression. There is an urgent unmet need for robust, reliable, cost-effective diagnostic tests to aid diagnosis and follow-up of patients with possible AD. We have developed a method that has been shown in multiple published studies to be specific to sporadic and familial AD relative to other dementias, to chronic depression and healthy ageing. The technique shows that individuals with AD have a specific problem in combining multiple sources of information, known as ‘temporary binding’ (TB). TB refers to the processes by which different aspects of stimuli such as colours and shapes are bound together on a temporary basis as an integrated object (i.e., a coloured shape). This particular binding task does not require learning, does not involve the hippocampus, is not affected by age, literacy or social background, does not show practice effects, it is inexpensive and it is easy and quick to administer. In sum, TB is a promising cognitive marker for AD.

Neuropsychological markers of progression in MCI

G. A. Carlesimo

S. Lucia Foundation and Systems Medicine Department, Tor Vergata University (Roma)

The early localization of neuropathological changes at level of mesio-temporal lobes (MTL) structures in typical Alzheimer’s disease (AD) makes patients in the pre-clinical stages of the disease similar, with regard to the neuropsychological pattern of impairment, to patients with MTL amnesia. Indeed, the amnesic syndrome in these patients is characterized by a failure in consolidating new memory trace so that these patients are unable to recall or recognize recently experienced information, irrespective of the nature of memorandum or of the support to encoding and/or retrieval provided by the experimental paradigm. Conversely, other physiological or pathological conditions of the elderly (included other forms of dementia) do not present such precocious involvement of MTL structures so that their possible memory deficit is generally the consequence of a reduced functionality of frontal lobes (for direct involvement by pathological changes or for a deafferentation from other cortical or subcortical projections). Similar to patients with focal frontal lobe damage, the memory impairment in these patients is not due to a failure in consolidating memory traces but, rather, to malfunctioning elaborative encoding of the incoming information and/or to failure in strategic retrieval of acquired data. Accordingly, these patients generally disclose very different memory performances depending on the nature of memorandum or the support to encoding and/or retrieval of the experimental task. Based on these premises, here we will review the studies which have been concerned with the distinction of MCI patients who convert or do not convert in AD based on their performance on episodic memory tests. Our aim is to provide experimental support to the above mentioned hypothesis that the qualitative profile of memory impairment in individuals with preclinical AD (deficit of memory trace formation and/or consolidation) differs from that of non-AD individuals (deficit mainly of elaborative encoding/strategic retrieval). For this purpose results of studies which have compared memory tests with short delay vs long delay intervals, memory tests for structured vs non structured material and, finally, memory tests with no help to encoding/retrieval vs memory tests which provided such help will be reviewed.

Predictive tests for dementia

B. Dubois, S. Epelbaum

Behavioral Neurology Unit (IM2A) and Dementia research center (ICM), Salpêtrière Hospital, University Pierre et Marie Curie (Paris-F)

Cognitive assessment is central to diagnosis and management of AD. Quantitative neuropsychological testing of the main cognitive domains (memory, executive functions and instrumental functions) ideally performed by someone trained in neuropsychology, should be considered in patients with questionable, prodromal, mild, or moderate dementia whereas it is less essential for severely demented patients. Episodic long-term memory impairment was recently proposed as central for the diagnosis of AD at least in the typical form of the disease (Dubois et al. Lancet Neurology, 2007 and 2014). To be recalled, the stimulus must go through three different and successive stages: 1) encoding, which is impaired in conditions that may interfere with attention processes: depression, anxiety, professional stress, sleep disorders, aging, treatment such as anticholinergic drugs or benzodiazepins... 2) storage, which relies on the hippocampus. In case of hippocampal lesions, such as in AD, the perceived information cannot be stored as memory traces in long term memory; 3) and retrieval, which is impaired in frontal lesions (fronto-temporal dementias, subcortico-frontal dementias) and in functional states (depression or even normal aging where the activation of retrieval strategies is decreased). In summary, the best way to identify an amnestic syndrome of the hippocampal type, as in AD, is to assess memory by tests that control for attention and that can facilitate retrieval. Using memory tests with cueing, either at bedside (5-Word Test) (Dubois et al. 2002) or by neuropsychologist (Free and Cued Selective Reminding Test) (Grober et al. 1988) is recommended because of their good specificity AD (Mormont et al. 2012, Wagner et al. 2012, Dierckx et al. 2009). Other memory tests, particularly those based on list learning and delayed recall, can also be effective in identification of the amnestic syndrome of AD. These tests include the paired-associate learning, the Rey auditory verbal learning tasks and the short-term memory binding test (Estevez-Gonzalez et al. 2003, Fowler et al. 2002, Lowndes et al. 2008, Della Sala et al. 2012).

The meeting of informatics with brain medicine: a new concept for biomarkers – disease signatures

R. Frackowiak

HBP & EPFL (Lausanne-CH)

Single human gene mutations may present with any of multiple phenotypes, and vice versa, a range of genetic abnormalities may cause a single disease phenotype. A major initial research aim of the Medical Informatics Platform of the Human Brain Project is to use big data techniques and algorithms to fill the multi-dimensional brain disease space, which ranges from psychiatry through behavioural disorders to neurological diseases, with groups of similar patients characterised by combinations of homogeneous features. We call such a group of specific features a “disease signature”. A disease signature brings together, in a systematic way, clinical features (phenomenology) and the results of genetic, biological, physiological and anatomical test results (biology). This reclassification should in the long-term supplant the symptom and syndrome based DSM and ICD disease catalogues by ones based on the same clinical features supplemented by patterns of abnormal investigations. This strategy has as its primary aim the definition of more precise diagnoses that reduce error variance in diagnostic categories for construction of clinical trial cohorts. A biological underpinning of phenomenological features may in combination with improved understanding of the functional and structural organisation of the human brain emanating from other parts of the Human Brain Project facilitate aspects of brain medicine such as identification of biological treatment targets, planning of potential benefits, risks and side effects of proposed treatments, as well as considerable reduction of clinical cohort sizes associated with more precise disease signature based definitions of diagnosis and prognosis. These ideas will be illustrated with reference to the human dementias.

Pre-clinical biomarkers – Imaging Biomarkers

A clinical role for fMRI in dementia: is the long wait over?

E. Paulesu

Psychology Department &NeuroMI, University of Milano-Bicocca, IRCCS Galeazzi (Milano)

Since their inception, the development of every imaging technique has been motivated also by the urgency of finding new answers to neurological disorders, dementias being one of the major challenges in modern times. fMRI is no exception. In spite of the tremendous technological progress in fMRI research, a practical role in dementia clinics is still missing for several reasons: on the one hand any advance in the identification of the disorders of their precursor conditions has been frustrated by the lack of any game changer in the therapy of dementia; on the other hand it remains unclear on whether task-based or resting state connectivity [1] fMRI studies are better suited to capture the transition from normal aging into conditions prodromal to dementia. Another unanswered question is how these techniques may fare in comparison with 18F-FDG PET or PET scanning of amyloid distribution. In addition, it is clear that a single index, as much as technological as it might be, it is most likely insufficient to represent a reliable biomarker of the disease and of the response to any treatment [2, 3]. In my communication I will briefly compare the achievements of task-based fMRI studies and resting state connectivity studies in dementia and in ageing. I will argue that, for the time being, none of the findings of these technologies on their own can represent the ideal biomarker that clinicians may seek to make clinical decisions when it comes to individuals. However, if incorporated into a sophisticated labelling procedures of the clinical and neurological status of a given patient [4], fMRI data may give a stronger contribution. For example, much as for other complex disorders (e.g. Gilles de la Tourette syndrome [5]), I envisage that pre-surgical fMRI profiling of patients candidate to deep brain stimulation (may this prove to be of some help in dementia) may help in deciding at the individual level who are the best candidates to the therapy. This may also apply to pharmacological treatments. This, however, has a long road ahead of clinical experimentation, for each and every candidate therapy, before turning into practice.

Cross validation of imaging biomarkers in clinical settings. The crucial role of FDG-PET imaging

D. Perani

Vita-Salute San Raffaele University, Nuclear Medicine Unit San Raffaele Hospital, Division of Neuroscience San Raffaele Scientific Institute (Milano)

Background: Although the use of research diagnostic criteria can improve dementia diagnosis at the individual level, it may be still challenging for clinicians. Effective strategies supporting for more certain early and differential diagnosis are needed for a better management of dementia, fitting in clinical trials and treatment options.

Aims: Evaluating in clinical-settings the supportive role of PET biomarkers for the early and differential diagnosis of dementia.

Methods: Large series of patients with neurodegenerative dementia, atypical parkinsonisms, and mild cognitive impaired (MCI) subjects with a long clinical follow-up assessed with conventional brain MRI, optimized voxel-based FDG-PET, and PET measures of amyloid load.

Results: SPM FDG-PET showed the highest diagnostic accuracy (AUC≈90%), providing both high sensitivity and specificity in the early and differential diagnosis of dementia and parkinsonisms, and it was the best predictor of conversion from MCI to AD or other dementias in MCI. PET Amyloid measures allowed to exclude AD pathology and showed some added value in MCI subgroups.

Conclusion: The SPM FDG-PET analysis at the individual level allows accurate early and differential diagnosis in neurodegenerative conditions, also in the prodromal disease phase, with a high disease exclusionary role.

Cerebrospinal fluid Aβ and tau

L. Parnetti

Section of Neurology, Centre for Memory Disturbances, University of Perugia, Perugia

Amyloid β1-42, total tau and phosphorylated tau represent the three core CSF biomarkers for Alzheimer’s disease. Each of them correlates to one of the key characteristics of Alzheimer’s disease pathology: low levels of CSF amyloid-β1-42 correlate with greater plaque load, high levels of total tau correlate with greater intensity of neuronal degeneration, and high levels of phosphorylated tau correlate with neurofibrillary tangle pathology. The presence of low levels of amyloid-β1-42 in combination with high levels of total tau and phosphorylated tau provide support for AD diagnosis with a sensitivity of 80–93% and specificity of 82–90% against cognitively normal controls, and high total tau and low amyloid β1-42 are most pronounced at more advanced stages. With respect to other dementia disorders, Alzheimer’s patients display the highest levels of total tau and phosphorylated tau, combined with low levels of amyloid-β1-42. Recent studies carried out in large independent cohorts of patients have shown that the use of the simple ratio of tau to Ab42 for differentiating AD patients from other patients and for predicting dementia due to AD in MCI patients represents a robust and generalizable parameter. Basically, in routine clinical context, the optimal CSF Alzheimer profile is whenever tau is more than half the value of Ab42. The use of the ratio is advantageous since its diagnostic performance is superior to what observed in single biomarkers, and also may overcome the differences observed among laboratories in terms of cut-off and absolute values.

Anti-abeta antibodies in CSF: markers for therapies?

F. Piazza

Coordinator of The inflammatory Cerebral Amyloid Angiopathy and Alzheimer’s disease βiomarkers (iCAβ) International Network & The iCAβ-ITALY Study Group of the Italian Society for the study of Dementia (SINdem)

School of Medicine and Surgery, Milan Center for Neuroscience (NeuroMi), University of Milano- Bicocca (Monza)

Advances in the biomarkers discovery for Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA) has sensibly accelerated the design of novel disease-modifying therapies (DMT), with different promising anti amyloid-beta (Aβ) therapeutic antibodies already in Phase II and III. Active and passive immunotherapies, however, have been both characterized by the occurrence of Amyloid-Related Imaging Abnormalities (ARIA), probably related to the drug and APOEɛ4 allele dose. In the last decade, ARIA have severely limited the development of immunotherapy, leading to the exclusion of several patients from the opportunity to be treated. The discovery of safety biomarkers to avoid, or at least enable, the early detection of ARIA will represent an important challenge to help stratify and personalize treatments, increasing the chances for developing more effective DMT. Biomarkers will have critical implications to predict individuals in a particular disease stage chosen as the therapeutic window for a specific treatment, especially as we move to more large and long duration prevention trials based on the selective enrolment of positive Amyloid-PET and/or CSF cases, potentially increasing the risk to incur in ARIA side effects of treatment. It is quite clear that without effective biomarkers we will have the consequence of further unacceptable delays in finding a cure for this devastating disease. Through the iCAβ International Network, we pioneered in showing that elevated CSF anti-Aβ autoantibodies are linked to a transient vascular leakage at the sites of major Aβ removal, causing a shift in CAA accumulation and increased vascular permeability, eventually leading to ARIA.

Blood biomarkers

E. Scarpini

Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico (Milano)

So far, no blood biomarkers for Alzheimer’s disease (AD) validated against pathology exist. Among candidates there are circulating proteins and a novel class of molecules, namely non coding RNA, which includes micro(mi)RNA, which are 18-22nt long small regulatory RNA. They are able to bind to the target messenger RNA and inhibit its translation. They play their regulatory role in cells, but can be found freely circulating in body fluids, including plasma and cerebrospinal fluid or in exosomes, particularly those of neural derivation. In this presentation, the current knowledge on the role of miRNA in AD and related dementias will be discussed, together with their potential future usefulness as peripheral biomarkers.

Longitudinal imaging and biochemical assessments

M. Marizzoni¹, S. Galluzzi¹, C. Ferrari¹, J. Jovicich², F. Nobili³, J.-P. Ranjeva⁴, D. Bartrés-Faz⁵, U. Fiedler⁶, P. Schönknech⁷, P. Payoux^8,9, A. Beltramello¹⁰, M. Caulo¹¹, A. Soricelli^12,13, L. Parnetti¹⁴, M. Tsolaki¹⁵, P. M. Rossini^16,17, P. Jelle Visser¹⁸, D. Albani¹⁹, G. Forloni¹⁹, R. Bordet²⁰, J. Richardson^21,22, O. Blin²³, G. B. Frisoni^1,24; on behalf of the PharmaCog Consortium

¹Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia)

²Center for Mind/Brain Sciences, University of Trento (Trento)

³Department of Neuroscience, Ophthalmology, Genetics and Mother–Child Health (DINOGMI), University of Genoa (Genova)

⁴CIC-UPCET, CHU La Timone, AP-HM, UMR CNRS-Universite de la Mediterranee (Marseille-F)

⁵Department of Psychiatry and Clinical Psychobiology, Universitat de Barcelona and IDIBAPS (Barcelona-E)

⁶LVR-Clinic for Psychiatry and Psychotherapy, Institutes and Clinics of the University Duisburg-Essen (Essen-D)

⁷University Hospital Leipzig (Leipzig-D)

⁸INSERM, Imagerie cérébrale et handicaps neurologiques, UMR 825 (Toulouse-F)

⁹Université de Toulouse, UPS, Imagerie cérébrale et handicaps neurologiques, (Toulouse-F)

¹⁰Department of Neuroradiology, General Hospital (Verona)

¹¹University “G. d’Annunzio” of Chieti (Chieti)

¹²IRCCS SDN (Napoli)

¹³University of Naples Parthenope (Napoli)

¹⁴Section of Neurology, Centre for Memory Disturbances, University of Perugia (Perugia)

¹⁵3rd Department of Neurology, Aristotle University of Thessaloniki (Thessaloniki- GR)

¹⁶Dept. Geriatrics, Neuroscience & Orthopaedics, Catholic University, Policlinic Gemelli (Roma)

¹⁷IRCSS S.Raffaele Pisana (Roma)

¹⁸Alzheimer Center and Department of Neurology, VU University Medical Center (Amsterdam-NL)

¹⁹Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri” (Milano)

²⁰Department of Pharmacology, EA1046, University of Lille Nord de France, 59045 Lille Cedex (Lille-F)

²¹Neurosciences Therapeutic Area U.K. (United Kingdom)

²²GSK R&D, China-UK, U.K. (United Kingdom)

²³Pharmacology, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille University-CNRS UMR 7289 (Marseille- F)

²⁴Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva (Geneva-CH)

Background: Markers sensitive to the progression of Alzheimer’s disease (AD) in its pre-dementia stages are important to develop disease modifying drugs.

Aim: To identifying biomarkers sensitive to disease progression in amnestic mild cognitive impairment (aMCI) patients classified into positives or negatives based on their baseline CSF Aβ42/ptau level.

Methods: 147 aMCI patients were enrolled in WP5 of PharmaCog (E-ADNI). ADAS-cog, structural, diffusion and functional MRI were performed each 6 months for at least 2 years. Patients converted to AD or other type of dementia were excluded from follow-up visits.

Statistical analysis: Linear Mixed Model with repeated ADAS-cog and MRI measures as dependent variables; time and CSF Aβ42/p-tau status as independent variable; age, gender, total intracranial volume (volume models) as covariates.

Results: The ADAS-cog score showed effects for CSF status and time-CSF status interaction (p<0.001) but not for time. Effect for CSF status, time and their interaction was reported for volumes (hippocampus including several subfields, lateral ventricles, thalamus), entorhinal cortex, and for diffusivity in the fornix (all p<0.025). The explained variability of ADAS-cog, volumes and fornix diffusivity was 0.54, higher than 0.82 and 0.35, respectively. Finally, rs-fMRI measures (e.g. default mode network connectivity) reported effect only for CSF status (p<0.045).

Conclusions: Structural MRI measures are the most sensitive to change over time even in a mildly progressing aMCI population. Volume measures were better than ADAS-cog in separating Aβ42/p-tau positive relative to negative aMCI patients in the 2-year period.

Pharmacog is funded by the EU-FP7 for the Innovative Medicine Initiative (grant n°115009).

Randomized, Placebo-Controlled, Phase 1b study of the anti–Beta-amyloid antibody Aducanumab (BIIB037) in patients with prodromal or Mild Alzheimer’s Disease: interim results

V. Viglietta¹, L. Williams¹, T. Chen¹, J. O’Gorman¹, P. Chiao¹, C. Hock², R. M. Nitsch², A. Sandrock¹

¹Biogen (Cambridge-USA)

²Neurimmune Holding AG and University of Zurich (Zurich-CH)

Aducanumab is a human monoclonal antibody against aggregated forms of beta-amyloid (Aβ) being investigated as a disease-modifying treatment for patients with Alzheimer’s disease (AD). The ongoing Phase 1b PRIME study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of aducanumab in patients with prodromal or mild AD. In this multicenter, randomized, double-blind, placebo-controlled, multiple-dose study, patients (age 50-90 years) had positive florbetapir (Amyvid) positron emission tomography (PET) scans and met clinical criteria for prodromal or mild AD. In a parallel staggered cohort design, patients were randomized to receive aducanumab (1, 3, 6, or 10 mg/kg or dose titration) or placebo (ratio of 3:1 active versus placebo) once every 4 weeks for 52 weeks within 9 treatment arms stratified by ApoE4 status. The primary endpoint assessed safety and tolerability; secondary endpoints included pharmacokinetic parameters, presence of anti-aducanumab antibodies, and change from baseline to Week 26 in amyloid plaque burden, as measured by PET imaging. Changes in clinical measures of cognitive decline (including change from baseline in Clinical Dementia Rating, sum of boxes [CDR-sb] and Mini-Mental State Examination [MMSE] scores) were assessed in exploratory endpoints. We report interim safety, Aβ reduction by amyloid PET, and exploratory clinical endpoints (changes from baseline in CDR-sb and MMSE). Patients (N=166) were randomized to placebo (n=40, pooled), 1 (n=31), 3 (n=33), 6 (n=30), or 10 (n=32) mg/kg aducanumab. The most common adverse events (AE) were amyloid-related imaging abnormalities (incidence as detected by MRI: 10%, 16%, 33%, and 47% for 1, 3, 6, and 10 mg/kg aducanumab, respectively, versus 5% for placebo) and headache (16%, 16%, 27%, and 28% versus 5%). Treatment- related dose- and time-dependent reductions in brain amyloid plaque burden (as shown by SUVR ratio reduction at Week 26 and further at Week 54) were observed within the doses tested. Dose-dependent attenuation of cognitive decline was observed with aducanumab in exploratory clinical endpoints. Dose-dependent ARIA was the main safety and tolerability finding. Aducanumab reduced amyloid plaque burden as measured by PET imaging in patients with prodromal or mild AD. A clinical signal was observed in exploratory analysis.

This study is funded by Biogen.

Amyposomes: a nanomedicine designed for treatment of Alzheimer disease

M. Masserini¹, S. Mancini¹, G. Sancini¹, C. Balducci², G. Forloni², F. Re¹

¹Nanomedicine Center and School of Medicine, University Milano Bicocca (Milano)

²Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche “Mario Negri,” (Milano)

A consistent body of evidence suggests that a pivotal role in the pathogenesis of Alzheimer disease (AD) is played by β-amyloid (Aβ). Currently, the therapy of AD is an unmet medical need. A possible contribution to solve this problem is offered by nanotechnology, with the possibility to design all-in-one nanodevices carrying different molecular components, whose cooperativity allows the accomplishment of a multitask action. Within this frame we previously designed, and patented, a nanotechnology taylored to dismantle Aβ aggregates and remove brain Abeta burden. The technology is based on Amyposomes, multi- functionalized nanoliposomes that proved in vitro the ability to bind Abeta with high affinity, to inhibit its aggregation, to destroy Abeta assemblies and to cross blood-brain barrier models without showing neuron toxicity. We evaluated the efficacy of Amyposomes on different Tg rodent models of AD, namely APP/PS1 or APP23 mice. The results suggest that Amyposomes, systematically administered, are able to enter the mice brain with effects either on brain Aβ burden or on memory impairment. The treatment is effective on “old” Tg mice upon acute treatment , promoting the decrease of brain Aβ and the amelioration of memory impairment, or on “young” mice upon long-term treatment, slowing down brain Aβ accumulation and memory impairment. Together, these data indicate Amyposomes as a new nanothecnological device potentially suitable for AD treatment. UNIMIB has taken the decision to spin-off the project and develop the technology. The Spin-off company Amypopharma is seeking for investors to carry Amyposomes to clinical phase, going through completion of the preclinical development and IMPD filing.

Mediterranean Diet

N. Scarmeas

National and Kapodistrian University of Athens, Columbia University (Atene – GR, New York –USA)

Background: There has been considerable research on the relation between nutrition and risk for Alzheimer’s disease but the results have been conflicting. Among the various methodological reasons for non-consistent results, the examination of individual foods or nutrients (vs. Dietary patterns) stands as an important one because we do not consume foods in isolation but as part of an overall diet.

Aims: To review the relevant literature and describe future perspectives

Methods: We briefly outline previous attempts of looking into dietary patterns in relation to cognition. We present some of our data on the association between a Mediterranean-type diet (MEDI) and Mild Cognitive Impairment (MCI), Alzheimer’s disease (AD). We also summarize some of our recent studies investigating potential biological mechanisms mediating the association between MEDI and cognitive performance.

Results: The majority of the literature so far suggests that higher adherence to this diet is associated with lower risk for developing AD and MCI. Biological mechanisms of possible associations between MEDI and cognition may include vascular, anti-infammatory, antioxidative and metabolic pathways while associations with more direct AD related pathology such as amyloid and neurodegeneration is also conceivable.

Conclusions: Exploring diet via holistic approaches may provide additional useful insights into potential relations with cognitive outcomes and may result in information important from a public health perspective. Much work in relation to biological mechanisms needs to be performed. Most of the so far evidence derives from observational epidemiological studies and clinical trials are a necessary next step.

Cognitive Stimulation Therapy (CST) for dementia

A. Spector

Research Department of Clinical, Educational and Health Psychology, University College (London-UK)

CST is a brief, evidence-based intervention for people with mild to moderate dementia. Complex psychological techniques are embedded within simple, manualised group sessions which aim to stimulate and maximise cognitive skills. These include categorisation, word association and discussion of current affairs, all following guiding principles which encourage the making of new semantic connections to aid learning. More recently, an individualised, carer-led CST programme has been developed and evaluated. This talk will provide an overview of the CST research programme and key findings from three clinical trials. This includes standard CST, longer-term CST and individualised CST (iCST). In summary, changes following group CST may be comparable to those associated with anti- dementia drugs and it is cost-effective. Memory, executive functioning and language were significantly improved, and significant benefits in quality of life were maintained for six months. Individualised CST led to significant improvements in one’s relationship with their caregivers, although cognition did not improve – suggesting the importance of delivery within a group format. The CST research programme has led to changes in service provision in the UK. Government guidelines now recommend routine provision of Cognitive Stimulation, regardless of medication use and as the only non-pharmacological intervention for the cognitive symptoms of dementia. CST provision is now a key standard for memory service accreditation and used in over 66% of UK memory clinics. The World Alzheimer’s Report recommends routine provision of CST in early stage dementia, resulting in its use globally. The manual has been translated into numerous languages, including Italian.

Magnetic stimulation

L. Leocani, R. Chieffo

Dept. of Neurology and INSPE-Institute of Experimental Neurology, Hospital San Raffaele (Milano)

Alzheimer’s disease (AD), leading to progressive loss of memory, language and several other cognitive functions, representing the leading cause of dementia with has a strong socio-economic impact consequences. Considering that there are few available pharmacological therapies, other interventions, such as cognitive/behavioural therapy and repetitive transcranial magnetic stimulation (rTMS) are currently explored. In particular, rTMS is recognized as a promising intervention for treating motor and cognitive deficits in several neurological disorders, owing to its ability to modulate cortical activity beyond the stimulation period through mechanisms of brain plasticity. Although the available evidence on AD is overall conflicting, recent reports point to the advantage of combining rTMS with cognitive training, possibly owing to converging mechanisms of the two interventions on the same cognitive networks. Another potential improvement in this approach is the consideration that several and widespread brain networks are affected by the disease, potentially requiring the application of stimulation of several targets, with sequential focal stimulation or, as allowed by recent technological advances, with newly designed H-coils allowing a wider area of stimulation compared with traditional focal coils. Further studies are needed specifically addressing the possible advantage of other combination approaches, such as dietary or exercise. Another unmet need in the use of rTMS is the identification of factors predictive of a positive response, with particular focusing on cognitive and brain reserve, towards the identification of the best candidates with the goal of precision medicine and tailored interventions in AD.

Modulating the human hypothalamus with Deep Brain Stimulation

A. M. Lozano

University Professor and Canada Research Chair, University of Toronto (Toronto-CND)

Deep Brain Stimulation (DBS) is being used to modulate the activity of motor and limbic circuits in the treatment of movement disorders and psychiatric illness. More recently, we have applied DBS in the fornix to study its effects in the context of a clinical trial or Alzheimer’s disease. We have noted that the delivery of electrical stimulation here can produce striking clinical effects including in some cases, memory-related phenomenon. The rationale and preliminary observations seen with hypothalamic/fornix stimulation in our clinical trial for Alzheimer’s disease and in animal models will be reviewed.

Extracellular Vesicles Isolated From Bone Marrow Mesenchymal Stem Cells Induce An Anti-Inflammatory Phenotype In Microglia Exposed To Human Abeta 1-42

C. A. Elia¹, S. Marchetti², M. Losurdo², A. Saccomano², F. Filipello¹, M. Rasile¹, M. Tamborini¹, M. Matteoli³, S. Coco²

¹Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, IRCCS (Rozzano-MI)

²Dept. Medicine and Surgery, University of Milano Bicocca (Monza)

³Institute of Neuroscience, CNR, National Research Council (Milano)

In Alzheimer’s disease (AD), the presence of brain senile plaques, neurofibrillary tangles and activated microglial cells strongly contribute to generate an inflammatory environment. The aim of the project is to investigate a possible anti-inflammatory effect of bone marrow derived mesenchymal stem cell microvesicles (BM-MSC MVs) in microglia cultures exposed to human beta Amyloid peptide 1-42 (h-Abeta 1-42). BM-MSCs isolated from 4-12 week old C57BL/6 mice were expanded in vitro and tested for their ability to differentiate into specific mesenchymal lineages. BM-MSC MVs were isolated from the culture medium, by performing a series of centrifugations and then characterized by using FACS and Western Blot analysis for specific surface markers. Primary cultures of murine microglial cells, derived from post-natal day 2 mice, were treated with h-Abeta1-42 peptide in the presence of BM-MSC MVs or MV- deprived culture supernatant, to evaluate the expression of different inflammatory or anti-inflammatory markers by immunocytochemistry and cytokine production by ELISA. BM-MSC MVs down-regulate the inflammatory processes induced by exposure of microglia to h Abeta 1-42 peptide in vitro. In fact, microglial cells, following MV treatment, assume an amoeboid phenotype becoming less ramified and releasing anti-inflammatory cytokines without significantly affecting the release of the pro-inflammatory ones. Moreover, MVs lead to a decreased expression of MHC II, associated with a pro-inflammatory phenotype. As in AD the chronic pro-inflammatory environment is postulated to contribute to the cognitive deficits and neuronal loss that characterize the disease, the immunomodulatory properties of BM-MSC MVs may represent a powerful tool to modulate this aberrant process.

Neuroinflammation correlates with Hippocampus Atrophy in Alzheimer’s Disease

M. Saresella¹, F. Baglio², M. Cabinio², F. Piancone¹, F. Larosa¹, I. Marventano¹, E. Calbrese³, R. Nemni^3,4, M. Clerici^1,4

¹Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS (Milano)

²Laboratory of Imaging Department of Neurology, Don C. Gnocchi Foundation IRCCS (Milano)

³Department of Neurology, Don C. Gnocchi Foundation IRCCS (Milano)

⁴Department of Physiopathology and Transplants, University of Milano (Milano)

The pathogenesis of Alzheimer’s disease (AD) is characterized by two alterations that are the consequence of b-amyloid (Abeta) accumulation: neuroinflammation and hippocampus atrophy. We investigated possible correlations between these two AD-associated phenomena using structural Magnetic Resonance Imaging (MRI) to evaluate hippocampal volume (Hv) and immunologic analyses to analyze neuroinflammation. Results obtained in 30 AD individuals showed the presence of statistically significant: 1) positive correlations between either Left or Right Hv and circulating anti-inflammatory monocyte; 2) positive correlations between Left Hv and Abeta-stimulated CD14+ IL-10+ cells or TGFbeta+ or CD200R+; 3) negative correlation between Left Hv and circulating inflammatory monocyte or Abeta-specific-CD14+IL-6+ or IL-23+ cells; 4) negative correlations between either Left or Right Hv and Abeta-RORgamma+ CD4+T cells; 5) negative correlations between Left Hv and Abeta-IFNgamma CD4+ T cells. These correlations are immunologically sound as: 1) circulating anti-inflammatory monocyte, interleukin -10 and TGFbeta slow-down immune response and inflammation; 2) the interaction of CD200 protein with CD200R, inhibits immune stimulatory responses 3) circulating inflammatory monocyte, IL-6 and IL-23 elicit immune response; 4) CD4+ RORgamma+ T and CD4+IFNgamma cells identify the pro-inflammatory Th17 and Th1 subsets respectively of circulating lymphocytes. The observation that reduced Hv correlates with an impairment of anti-inflammatory Abeta-specific peripheral monocytes and, conversely, with a higher percentage of circulating proinflammatory monocyte and of Th1, Th17 Abeta-specific lymphocytes strongly suggest that neuroinflammation and hippocampus atrophy are indeed correlated in AD and indicate that monitoring of immune cells in peripheral blood could have a prognostic value in this disease.

Sirtuins modulation as a novel therapeutic strategy in in vitro and in vivo models of Alzheimer’s Disease

F. Fusco, G. Biella, A. Agrillo, D. Albani, G. Forloni

Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research (Milano)

Aims: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder with cognitive decline. Several data support the involvement of the deacetylase sirtuins (SIRTs) in neurodegeneration. Particularly, SIRT2 was reported to promote neurodegeneration, while SIRT1 seemed to be neuroprotective. Our aim is to evaluate SIRT2 inhibition as novel therapeutic approach in AD, also in synergy with SIRT1 activation.

Methods: In vitro treatments (SIRT2 inhibitors AGK2/AK7; SIRT1 activators resveratrol (RSV)/SRT1720) were performed on H4-SW/H4-native human neuroglioma cells. For in vivo tests we selected APP23 and 3xTg-AD mouse models, treated with the brain-permeable SIRT2 inhibitor AK7. Cognitive performance was assessed by novel object recognition test (NORT). For AD-relevant biochemical parameters, we performed Western Blotting (WB) or Immunohistochemistry.

Results: SIRT2 inhibition affected in vitro APP metabolism, reducing soluble APP (sAPP) fragments and Aβ-40/Aβ-42 peptides. We performed a cellular treatment with AK7 in combination with RSV to verify the potential toxicity, and cellular viability was unaffected by the treatment. In vivo, AK7 therapy counteracted the cognitive deficit revealed in Tg-vehicle mice by NORT. WB demonstrated an increased level of sAPPα, reduced sAPPβ, unchanged flAPP production and increased total tau expression, but no effect on neuroinflammatory markers (GFAP/IBA1).

Discussion: Our data suggest a positive role of SIRT2 inhibition in AD and support the possibility of a combined therapy on SIRT1/SIRT2 to look for a synergistic effect.

Conclusions: In conclusion, SIRTs modulation seems to be a useful tool, and finding an optimal brain-delivery protocol could be a step forward in AD research.

Multiplex ligation-dependent probe amplification (MLPA) assay in PSEN1 and APP genes in early-onset Alzheimer disease patients

I. Ricca¹, G.S. Grieco¹, M. Valente¹, P. Bini², P. Vitali³, C. Cereda¹

¹Center of Genomics and post-Genomics, Mondino National Institute of Neurology Foundation (Pavia)

²Neurological Department, Mondino National Institute of Neurology Foundation (Pavia)

³Neuroradiology and Brain MRI Mondino Research Center, Mondino National Institute of Neurology Foundation (Pavia)

Mutations in PSEN1 gene account for 30-70% of cases of early-onset familial Alzheimer disease (EOFAD). More than 200 mutations are reported in PSEN1, spanning throughout the coding sequence. Exonic rearrangements are thought to be very rare with the exception of the deletion involving exon 9 in the Finnish population. These rearrangements can be missed using conventional sequencing techniques. To date, there are few reports about the use of quantitative analysis, such as MLPA or qPCR, in the screening of EOFAD. We performed MLPA analysis of PSEN1 and APP genes on a group of 7 EOAD cases and we found one deletion of exon 7. The deleted patient presented global cognitive decline, disorientation and depression starting from the age of 60. Family history was unremarkable. 3T MRI showed mild ventricular enlargement , bilateral moderate mesial temporal atrophy and diffuse cortical atrophy, more prominent in the left parietal lobe. Cerebral blood flow map by Arterial Spin Labeling showed predominant hypoperfusion within the parietal lobe. This is the first report of exon 7 deletion in a patient affected by EOAD. Exon 7 contains a catalytic residue implicated in the active site of gamma-secretase, so deletions of this part of the PSEN1 gene could affect the protein function [1]. The neuroradiological pattern is typical for early onset AD, with predominant parietal over temporomesial atrophy [2]. Our work highlights the importance of studying exonic rearrangements in AD genes and suggests that these mutations could be more frequent than expected (1/7 in our sample).

Comparison of molecular biomarkers for the prediction of conversion to dementia in a large multicentric MCI cohort

S. Caminiti¹, T. Ballarini¹, L. Presotto¹, A. Sala¹, C. Cerami², F. Fallanca³, EG. Vanoli³, D. Perani³, F. Nobili⁴, L. Parnetti⁵, G. Frisoni⁶, E. Scarpini⁷

¹Division of Neuroscience, San Raffaele Scientific Institute (Milano)

²Clinical Neuroscience Department, San Raffaele Scientific Institute (Milano)

³Nuclear Medicine Unit, San Raffaele Scientific Institute (Milano)

⁴Department of Neuroscience, Ophthalmology, Genetics and Mother-Child Health (DINOGMI), University of Genoa (Genova)

⁵Section of Neurology, Centre for Memory Disturbances, University of Perugia (Perugia)

⁶IRCCS Foundation San Giovanni Di Dio - Fatebenefratelli (Brescia)

⁷Department of Neurology, University of Milan (Milano)

Aim: This multicentre study aimed at comparing the accuracy of FDG-PET and CSF biomarkers in predicting conversion to dementia.

Materials: N=99 MCI-subjects (mean-age 70.42±7.3) were evaluated.

Methods: We applied an optimized SPM method [1-2], obtaining single-subjects FDG-PET SPM-t maps. Each patient SPM-t map was classified by imaging experts, blind to clinical information, as negative, AD-like, DLB-like or FTD-like patterns. Pathological CSF-values were defined on the basis of the standard cut-off [3]. Multivariate Cox regression analysis was performed in order to assess biomarkers prediction accuracy.

Results: The 84% SPM-t maps were classified as pathological (33% AD-like, 33% FTD-like, 17% DLB-like), and, at follow-up (20.2±10 months), the 55% MCI among those converted to dementia of different types. 16% MCI showed normal metabolism and none of them converted to dementia after follow-up (15% were MCI-stable and 1% MCI-reverter). As for CSF, 77% MCI showed alterations in at least two CSF-biomarkers, and among those the 53% converted to AD. Of note, 15% MCI with normal CSF-values converted to AD at follow-up. Cox regression analysis indicated as most accurate predictor for dementia conversion FDG-PET SPM t-maps (expβ=28.7, CI=1.14–722.74, p<0.05; Sens=100% and Spec=65%), whereas the CSF biomarkers did not survive the statistical threshold.

Discussion: FDG-PET SPM t-maps classification had the highest predictive value in identifying patterns of brain hypometabolism characteristic of different neurodegenerative diseases and normal metabolism in MCI-stable or reverter.

Conclusion: The high predictive power of FDG-PET SPM method supports its role in clinical settings for risk evaluation of dementia progression in the early prodromal phase.

Memory impairment in AD and PDD: hippocampal subfields involvement and category cued recall

F. Novellino¹, R. Vasta¹, G. Nicoletti¹, C. Chiriaco¹, M. Vaccaro², M. Morelli², M. Salsone¹, G. Arabia², A. Sarica², A. Quattrone²

¹Institute of Bioimaging and Molecular Physiology, National Research Council (Catanzaro)

²Institute of Neurology, University “Magna Graecia” (Catanzaro)

Objective: We investigated how changes in whole hippocampus and hippocampal subfields relate to memory recall in different forms of dementia, as Alzheimer’s Disease(AD) and Parkinson’s Disease with Dementia(PDD).

Methods: We compared 22 AD, 18 PDD, 21 PD, and 17 healthy subjects through a combination of a multimodal MRI hippocampal subfields evaluation and a memory assessment with the Free and Cued Selective Reminding Test (FCSRT), a hippocampal-targeted neuropsychological paradigm. Volume, mean diffusivity (MD) and fractional anisotropy (FA) of automatically segmented hippocampus (whole and subfields) were obtained. Correlations between MRI-derived metrics and clinical and neuropsychological evaluations were performed.

Results: ANOVA yielded a strong overall difference among the groups in the entire hippocampus in volume and MD, showing a grading in the increase of both hippocampal atrophy (left:F=8.237/p<0.0001; right:F=9.650/p<0.0001) and MD values (left:F=17.713/p<0.0001; right:F=15.696/p<0.0001) according to the order AD>PDD>PD>controls. In the subfields analyses, the comparison between AD and PDD groups revealed a significant volume reduction in the right subiculum (p=0.02), an increased MD in the bilateral CA1 (right p=0.004; left p=0.016), left presubiculum (p=0.015), right CA4-DG (p=0.018) and subiculum (p=0.013). Correlation analyses showed significant correlation between FCRST scores and hippocampal subfields measurement in AD group.

Discussion and conclusion: Our results show that hippocampal subregions have different vulnerability to AD-linked damage. Subiculum, CA4DG and presubiculum were the regions more strictly involved in AD and related to cued recall. These results may help explain how memory processing is associated with the function of specific hippocampal subfields and improve the knowledge of specific AD-related mnesic profile.

“Mitochondrial Alterations in Peripheral Blood Mononuclear Cells (PBMCs) from Alzheimer’s Disease and Mild Cognitive Impairment Patients: new potential blood biomarkers for AD”

M. Marziano, G. Abate, D. Uberti

DMMT, University of Brescia (Brescia)

Objective: Evaluation of different mitochondrial markers in Peripheral Blood Mononuclear Cells (PBMCs) of Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) subjects as possible AD biomarkers. Materials: AD, MCI and healthy subjects were enrolled and their PBMCs were isolated.

Methods: The expression of mitochondrial markers were evaluated with quantitative rtPCR and immunoblotting. Mitochondrial DNA was measured by qPCR. Cytochrome C oxidase and citrate synthase activity was also measured by enzymatic assays.

Results: Cytochrome C and cytochrome B were decreased in AD, while MCI showed only a reduction of cytochrome C. AD and MCI exhibited highly nitrated MnSOD. TFAM, a regulator of mitochondrial genome replication and transcription, was decreased in both patient groups while PGC-1α that regulates the expression of nuclear encoded mitochondrial factors, was reduced only in AD. Also the mtDNA amount was reduced in both patient groups.

Discussion: We found some differences and some similarities between AD and MCI when compared with healthy subjects. For example, cytochrome C and cytochrome B were decreased in AD, while MCI showed only a statistical reduction of cytochrome C. On the other hand, both AD and MCI blood cells exhibited highly nitrated MnSOD, index of a prooxidant environment inside the mitochondria. TFAM, was decreased in both AD and MCI. Moreover also the mitochondrial DNA amount was reduced in PBMCs from both patient groups.

Conclusion: These data confirmed peculiar peripheral mitochondrial impairment in AD and AD progression.

A cognitive preventive intervention by means of Memory Training (MT) in a sample of older adults aged 65+

M. Veneziano¹, C. Prete¹, B. Senesi¹, M. Puntoni², M. Gianelli³, A. Pilotto¹

¹Centre for Cognitive Disorders and the Dementias (CCDD), Geriatric Unit, Geriatric Care Department, Orthogeriatrics and Rehabilitation, Galliera Hospitals (Genova)

²Clinical Experimentation Planning and Management, Biostatistics. Scientific Coordinator’s Office, Galliera Hospitals (Genova)

³University Academic Researcher, INTERDEM (Genova)

Aims: Primary goal of the study is to prove the efficacy of MT in a 930 subject, cognitively intact, aged 65-80. Secondary goals: how participants evaluate themselves and their cognitive performances and depressive symptoms.

Materials and Methods: The project is in collaboration with Regione Liguria. All participants in the study were evaluated via a clinical conversation and administration of neuropsychological screening tests. Inclusion criteria: age between 65 and 80 years; absence of psychiatric pathologies; absence of sensorial deficits; absence of dementia. Evaluation tests for cognitive status include: MMSE1 and CDT2. The cognitive stimulation programme includes: 1,30 minutes meetings, once a week, over three months. Each meeting include a maximum of 20 participants. At baseline, at conclusion of intervention is measured: cognitive status, by learning test of three word lists3 and verbal fluency by letter (Tognoni,1986); self-perception of cognitive functionality by MACQ (Crook,1992); depression by GDSsv (Almeida,1999).

Results: The score of the outcomes at conclusion of intervention presented a statistically significant improvement with respect to base values.

Conclusions: The study proves that the MT produce significant improvement of cognitive status, self-perception of cognitive wellness by participants and reduction the depressive symptoms. The results to suggest that the use of MT is feasible even into an advanced age, and that the improvement of cognitive activity, mood status and social well-being are protective factors with respect to cognitive deterioration. MT is to be considered primary social health preventive interventions, in their capacity of slowing down the negative effects of cerebral aging.

Evaluation of the acceptability of a caring service robot (MARIO)

G. D’Onofrio¹, O. James², D. Sancarlo¹, F. Ricciardi³, K. Murphy², F. Giuliani³, D. Casey², A. Greco¹

¹Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, Fondazione “Casa Sollievo della Sofferenza” (San Giovanni Rotondo-FG)

²National University of Ireland (Galway-IRL)

³ICT, Innovation and Research Unit, Fondazione “Casa Sollievo della Sofferenza” (San Giovanni Rotondo-FG)

Objectives: In the frame of the European Community funded MARIO project, the caregivers of 139 dementia patients were recruited in National University of Ireland (NUIG), in Geriatrics Unit of IRCCS “Casa Sollievo della Sofferenza”-Italy (IRCCS) and in Alzheimer Association Bari-Italy (AAB) for a multicenter survey to determine the needs and preferences of caregivers to improve the assistance of patients with dementia and to guide the technological development of the MARIO companion robot.

Materials and Method: A six minute video on technological devices and functions of MARIO was showed, and all caregivers fulfilled a 43-item questionnaire that explored four areas: A) Acceptability, B) Functionality, C) Support devices, and D) Impact.

Results: Caregivers declared that facilitating acceptance (over 17.5%) and improving functionality of MARIO (over 29%) should be important/likely/useful. Over 20.3% of caregivers reported that following support devices in MARIO could be useful for their patients: 1) to monitor bed-rest and movements, 2) to monitor medication use, 3) to monitor the ambient environmental conditions, 4) to regulate heating, humidity, lighting and TV 5) to undertake comprehensive geriatric assessment, 6) to link to care planning, 7) to monitor physiological deterioration, and 8) to monitor cognitive deterioration. Over 21.8% of caregivers declared that MARIO should be useful to improve quality of life, quality of care, safety, emergency communications, home-based physical and/or cognitive rehabilitation programs, and to detect isolation and health status changes of their patients.

Conclusions: MARIO is a novel approach employing companions robot and its effect will be: 1) to facilitate and support persons with dementia and their caregivers, and 2) to reduce social exclusion and isolation.

CLINICAL MANAGEMENT

EPIDEMIOLOGY

GENETICS

NEUROBIOLOGY

NEUROIMAGING

NEUROPSYCOLOGY AND BEHAVIOUR

CLINICAL MANAGEMENT

Author Index

Abate, G., S19, S37

Abete, C., S39

Abutalebi, J., S43

Agosti, V., S42

Agostini, S., S29

Agrillo, A., S17

Agosta, F., S9

Airoldi, C., S30, S59

Albani, D., S11, S17, S59

Albargothy, N., S3

Alberghina, L., S57, S60

Alberti, P., S54

Aliprandi, A., S33

Amanzio, M., S48

Ambrogio, T., S45

Amigoni, L., S59

Andreoni, S., S35, S39

Appollonio, I., S23, S33, S51

Aprea, F., S57

Arabia, G., S19

Arcangeli, E., S66

Arosio, A., S33, S55, S60

Asti, A., S30

Ayakta, N., S44

Baggi, F., S30

Baglio, F., S16, S29, S34, S47

Balducci, C., S4, S13, S36

Balestrino, M., S22

Ballarini, T., S18, S43, S44

Balling, R., S57

Banfi, G., S62, S63, S67

Bartrés-Faz, D., S11

Baselice, F., S42

Basilico, S., S45

Beeg, M., S33

Beghi, E., S23

Beghi, M., S51

Belloli, S., S40, S41

Beltramello, A., S11

Bentivegna, A., S54

Berlingeri, M., S6, S22, S25, S61

Bernasconi, M., S25

Bertoja, R., S65

Bertoli, M., S49

Bianchi, E., S23

Biella, G., S17

Bini, P., S17, S27, S29

Biscetti, L., S40

Blin, O., S11

Boda, E., S33

Bodini, B., S63

Bomba, M., S61

Bonanni, L., S5

Bonanomi, M., S59

Bonaretti, L., S22

Bordet, R., S11

Borella, E., S23

Borghese, A., S61

Bottini, G., S6, S22, S25, S45, S61, S66

Botto, E., S65

Botto, L., S34, S36

Braida, B., S33

Brighina, L., S60

Bruno, M., S62

Buffo, A., S33

Bugiani, O., S1

Buglione, E., S57

Bulbarelli, A., S34, S36

Bussei, R., S30

Cabinio, M., S16, S29, S34

Caffarra, P., S23, S24

Calabrese, E., S29, S34

Calabresi, P., S40

Calbrese, E., S16

Caminiti, S., S18

Campini, I., S26

Cappa, S., S46

Cappa, S. F., S5

Carare, R. O., S3

Cardamone, R., S31

Carlesimo, G. A., S7

Carpinelli, A., S40

Caruso, F., S27

Casey, D., S21

Cashman, J., S27

Cassetti, A., S58

Catricala’, E., S46

Caulo, M., S11

Cavaletti, G., S54, S55, S58

Cecchetti, G., S25, S31

Cerami, C., S18, S41

Cereda, C., S17, S27, S29

Cereda, D., S39

Ceresa, C., S55

Cerizza, M., S56

Cerri, C. G., S45

Cerri, C., S52, S65

Chen, T., S12

Chiao, P., S12

Chiarini, P., S40

Chieffo, R., S14

Chipi, E., S40

Chiriaco, C., S19

Ciaramelli, C., S30

Cilibrasi, C., S54

Ciocca, G., S51

Cipolla, L., S37, S56

Ciresa, S., S45

Ciricugno, A., S45

Clerici, M., S16, S29, S34

Coco, S., S16, S34

Colangelo, A. M., S57

Colangelo, A., S60

Colasuonno, F., S32

Colombo, L., S30

Comi, G., S25, S31

Consonni, A., S30

Consonni, M., S46

Conti, E., S32, S33, S39, S4, S61

Corbetta, F., S61

Corchs, S. E., S51

Corchs, S., S64

Corna, G., S53

Cornaggia, C., S51, S65

Costaggiu, D., S39

Cova, I., S26

Curinga, T., S25

Da Re, F., S32

Dalla Bella, E., S46

Danelli, L., S61

d’Arma, A., S47

De Luigi, A., S30

De Santis, A., S62

De Santis, C., S22, S63

Della Sala, S., S7

Di Francesco, J. C., S23

Di Grigoli, G., S40, S41

Di Luca, M., S2

DiFrancesco, J., S35

Dodich, A., S41

Doglia, S. M., S59

Donato, F., S22

D’Onofrio, G., S21

D’Onofrio, M., S46

Dore, G., S46

Dubois, B., S8

Elia, C. A., S16

Epelbaum, S., S8

Eusebi, P., S40

Faggian, S., S23

Falautano, M., S25

Fallanca, F., S18

Farina, E., S47

Farina, F., S34, S36

Farotti, L., S40

Farsad, M., S43

Federico, A., S26

Fernandez, I., S25

Ferrarese, C., S4, S23, S32, S33, S39, S53, S55, S57, S60, S61

Ferrari, C., S11

Ferrari, S., S65

Ferri, A., S53

Fiedler, U., S11

Filipello, F., S16

Floridi, P., S40

Forloni, G., S4, S11, S13, S17, S36, S59

Formenti, M., S57, S60

Fracassi, A., S32

Frackowiak, R., S8

Francione, S., S66

Franzin, A., S31

Frisoni, G. B., S11

Frisoni, G., S18

Fumagalli, G., S54

Fusco, F., S17

Gabrielli, M., S33

Gagliardi, S., S27

Galluzzi, S., S11

Gamberini, G., S47

Gandin, V., S55

Gandola, M., S62

Gandolfi, M., S26

Gardini, S., S23, S24

Gardoni, F., S33

Garibotto, V., S43

Gasparini, F., S51, S64

Gavazzo, P., S56

Gelosa, G., S45

Gerardi, F., S55

Gessa, V., S46

Gianelli, M., S20

Gioda, M., S52

Giovannoni, R., S54

Giuliani, F., S21

Giussani, C., S54

Giussani, G., S23, S65

Gobbi, M., S33

Gorno-Tempini, M., S44

Grana, D., S32, S33, S55

Grande, G., S26

Greco, A., S21

Greco, L. C., S41

Gregori, M., S32, S39

Grieco, G. S., S17, S29

Grimaldi, R., S27

Grossi, A., S64

Gualandris, E., S65

Guerini, F. R., S29

Guizzardi, R., S56

Hao, K., S28

Heneka, M. T., S3

Hernis, A., S29

Ho, L., S28

Hock, C., S12

Hoeschele, J., S55

Iaccarino, L., S41, S44

Iannaccone, S., S41

Invernizzi, P., S62

Isella, V., S64

Iurato, L., S27

Jacini, F., S42

Jagust, W., S44

James, O., S21

Jelle Visser, P., S11

Joshi, P., S33

Jovicich, J., S11

Knezovic, A., S38

Kolodkin, A., S57

La Rosa, F., S34

Lanfranconi, F., S53

Larosa, F., S16

Lauria, G., S46

Lazzati, G., S47

Lecchi, M., S56

Leo, E., S65

Leocani, L., S14

Lo Russo, G., S66

Lonati, E., S34, S36

Longoni, M., S35

Lorenzi, G., S65

Lorenzi, V., S63

Losurdo, M., S16

Lozano, A. M., S15

Lubian, F., S43

Lucchelli, F., S47

Lucchese, M., S61

Lunetta, C., S53, S55

Luzzatti, C., S47, S64

MacGregor-Sharp, M., S3

Maggiani, A., S52, S53

Maggioni, D., S58

Maggioni, L., S33

Magnani, G., S25, S31, S41, S43, S44

Mai, R., S66

Maier, A., S26

Malacrida, A., S58

Malpetti, M., S43

Mancini, S., S13, S36

Mancuso, R., S29

Mandas, A., S39

Mantegazza, R., S30

Mapelli, C., S64

Mapelli, D., S26

Marcello, E., S2, S33

Marchesi, N., S30

Marchetti, S., S16

Margiotta, N., S55

Mariani, C., S26

Marinig, D., S57, S60

Marizzoni, M., S11

Markova, A., S26

Marsili, G., S49

Martini, E., S47

Martorana, F., S57

Marventano, I., S16, S34

Marziano, M., S19, S37

Marzorati, M., S49

Masiello, V., S41

Masserini, M., S13, S32, S36, S37, S39

Matteoli, M., S16, S33

Mauri, I., S64

Mazzeo, S., S25, S31

Mazzitelli, S., S33

Mazzola, P., S28

Mazzoni, V., S30

Meroni, R., S51, S52, S65

Michelini, G., S23, S24

Milani, C., S34, S36

Miller, B., S44

Miloso, M., S58

Modica, J., S59

Molinari, A., S65

Monfrini, M., S58

Monterisi, C., S40, S41

Morciano, E., S23, S24

Morelli, M., S19

Moreno, S., S32

Moresco, R. M., S3

Moresco, R., S40, S41

Morris, A., S3

Murphy, K., S21

Murtaj, V., S40, S41

Musicco, M., S1

Nacinovich, R., S61

Naso, M. G., S27

Natalello, A., S59

Negroni, C., S54

Nemni, R., S16, S29, S34, S47

Neri, F., S61

Nestor, P. J., S5

Nicoletti, G., S19

Nicolini, G., S55, S58

Nicotra, F., S30, S37

Nitsch, R. M., S12

Nobile, M., S60

Nobili, F., S11, S18

Novellino, F., S19

Occhipinti, C., S27

O’Gorman, J., S12

Onofrj, M., S5

Osmanovic Barilar, J., S38

Palermo, S., S48

Palestini, P., S34, S36

Palmioli, A., S30

Panina-Bordignon, P., S40

Pannese, M., S40

Papa, L., S52

Papa, M., S57

Parnetti, L., S10, S11, S18, S40

Pascale, A., S30

Pasinetti, G., S28

Passerini, G., S25, S31

Passoni, S., S25

Pastori, V., S56

Paulesu, E., S9, S22, S61, S62, S63, S66, S67

Payoux, P., S11

Pellei, M., S55

Pelliccari, L., S52

Pelosi, C., S63

Pelucchi, S., S33

Perani, D., S10, S18, S41, S43, S44

Perin, C., S45, S51, S65

Peroni, F., S51

Petecchia, L., S56

Piancone, F., S16, S34

Piazza, F., S11, S35

Picelli, A., S26

Pilotto, A., S20

Pinto, P., S25, S31

Piscitelli, D., S52

Policicchio, S., S27

Polita, M., S51

Polonia, V., S23

Pomati, S., S26

Ponzoni, L., S33

Porcelli, S., S49

Pradelli, S., S23

Presotto, L., S18, S43

Prete, C., S20

Preti, M., S63

Proverbio, A. M., S49, S63

Puntoni, M., S20

Quattrone, A., S19

Raccagni, I., S40

Raimondi, I., S59

Rainero, I., S48

Randisi, M. G., S27

Ranjeva, J. -P., S11

Rasile, M., S16

Ravasi, M., S58

Re, F., S13, S32, S36, S37

Redaelli, S., S54

Regazzoni, R., S65

Regonesi, M. E., S59

Restelli, A., S34

Reutter, W., S38

Ricca, I., S17, S29

Ricciardi, F., S21

Richardson, J., S11

Rigamonti, A., S53

Rigolio, R., S58

Ripamonti, E., S47

Riva, C., S57, S60

Riva, G., S54

Riva, N., S53

Rizza, M. F., S60

Rizzi, E., S49

Rodilossi, S., S59

Rodriguez-Menendez, V., S39, S55

Rolandi, E., S62

Rolle, G., S52

Romano, G., S54

Roppolo, M., S52

Rossi, G., S65

Rossini, P. M., S11

Rubino, E., S48

Rucco, R., S42

Ruma, D., S52

Rungratanawanich, W., S37

Russo, L., S37, S56

Russo, M., S40

Saccomano, A., S16

Saccucci, S., S30

Sacheli, L. M., S63, S66

Saetta, G., S62

Saibene, F. L., S47

Sala, A., S18

Sala, B., S57

Sala, G., S34, S55, S57, S60

Sala, M., S33

Salerno, D., S34

Salkovic-Petrisic, M., S38

Salmaggi, A., S65

Salsone, M., S19

Salvadori, N., S40

Salvalaio, E., S23

Salvato, G., S6, S66

Sancarlo, D., S21

Sancini, G., S13, S36

Sandrock, A., S12

Santangelo, R., S25, S31

Santini, C., S55

Saresella, M., S16, S34

Sarica, A., S19

Sassella, A., S37

Sassos, D., S22

Savarese, L., S57

Sberna, M., S22, S61

Scaccabarozzi, C., S65

Scalise, A., S49

Scarano, E., S66

Scarmeas, N., S13

Scarpa, P., S66

Scarpini, E., S11, S18

Schönknech, P., S11

Scioli, S., S47

Scocchia, L., S67

Scuteri, A., S58

Semperboni, S., S55

Senerchia, A., S49

Senesi, B., S20

Serchisu, L., S39

Sesana, S., S39

Sgambato, A., S56

Silani, V., S53

Sinforiani, E., S27

Sironi, V. A., S2

Somalvico, F., S52

Soricelli, A., S11

Sorrentino, G., S42

Sorrentino, P., S42

Sorriso, A., S42

Spaziante, F., S52

Spector, A., S14

Stefanoni, G., S33

Stravalaci, M., S33

Stucchi, N., S67

Taglialatela, G., S32

Tallarita, E., S52

Tamborini, M., S16

Tamburin, S., S26

Tarducci, R., S40

Tassi, L., S66

Terruzzi, A., S65

Terzi, A., S65

Terzuoli, S., S22

Tettamanti, M., S22

Tirelli, P., S24

Toraldo, A., S25

Tornatore, G., S52

Torrisi, J., S27

Tortora, P., S59

Totino, L., S35

Trabattoni, S., S37

Tredici, G., S58

Tremolizzo, L., S4, S23, S32, S33, S39, S52, S53, S55, S61

Trentin, M., S26

Tresoldi, V., S34

Tsolaki, M., S11

Uberti, D., S19, S37

Ursino, N., S63

Vaccaro, M., S19

Valente, M., S17, S29

Valsecchi, M., S67

Vanoli, E. G., S18

Varriale, P., S42

Vassalli, M., S56

Vasta, R., S19

Vecchio, M. M., S27

Veneziano, M., S20

Verderio, C., S33

Verma, A., S3

Verniccio, L. S., S27

Vianello, G., S26

Viganò, B., S51

Viglietta, V., S12

Visentin, C., S59

Vitali, P., S17, S29

Weller, R. O., S3

Williams, L., S12

Zanette, G., S26

Zani, A., S49, S63

Zapparoli, L., S62, S63, S67

Zerbi, A., S63, S67

Zoia, C. P., S33, S39

Zoia, C., S32, S57

Zucca, M., S48

Zucca, S., S27

Challenges of modern neuroscience

Understanding brain function, mechanisms of healthy nervous system development and aging, mechanisms of neurological and psychiatric disorders represents one of the major challenges for hu-mans.

With world-wide aging populations, the burden of neurological diseases is increasing and represents a major cost for society.

Despite the recent technological and scientific advances (high throughput technologies, NMR, PET, discovery of genetic determinants of diseases and of their molecular pathways), disorders such as autism, schizophrenia, Alzheimer, Parkinson, Multiple Sclerosis, Amyotrophic Lateral Sclerosis can be accurately diagnosed at the earliest phases, but still lack effective long-term disease-modifying treatments.

We recently recognized that molecular mechanism leading to these disorders may start even decades before clinical presentation, and that effective treatments should start before brain damage become clinically relevant. For this reason, a major challenge for modern neuroscience is to detect the border between brain function and dysfunction with a multidisciplinary approach: clinical neurology and psychiatry, psychology, neuroimaging, computational science, genetics and biology.

Furthermore, congenital or acquired brain damage most frequently leads to severe impairment of sensorimotor and superior cognitive functions (e.g. language, memory, attention, awareness) that need accurate diagnosis and effective rehabilitation. Hence the compelling needs to further understand the cognitive functions of the normal brain and to develop novel strategies for rehabilitation of brain-damaged individuals, following multidisciplinary approaches and up-to-date instrumental monitoring.

Finally, the challenge of modern society and its economic and social determinants, more and more strongly rely upon the contribution of the modern cognitive neuroscience, to understand the core mechanisms regulating interactions among individuals and social behaviour.

NeuroMi Goals

To promote high-level and multidisciplinary research and education in the field of neuroscience, to uncover mechanisms of nervous system function and dysfunction across the life cycle.

Strategy

The effort to accomplish this challenging goal must be based on a multidisciplinary team encom-passing basic and clinical neuroscientists, and taking advantage of collaborations with institutions at regional, national and international level.

Expertise spans from genetics, molecular biology, cell-, tissue- and in vivo-neuroimaging, psychology, neurology, neuropsychology, neurosurgery, psychiatry, child neuropsychiatry, computational technologies, informatics, statistics, system biology, economy, physics with the use of a large variety of technological platforms.

Research Areas

Clinical Neurosciences

Molecular and Cellular Neurosciences

Biotechnology and Nanomedicine

Computational and Systems Neurosciences

Neuroimaging and Methodological Research

Cognitive and Behavioral Neurosciences

Research area Clinical Neuroscience

The research activity of the Clinical Neuroscience Area takes advantage of the presence of different clinical disciplines, such Neurology, Neurosurgery, Neurotology, Maxillo-facial Surgery, Psychiatry, Child Neuropsychiatry, Geriatric Medicine and Neurorehabilitation.

Clinical and translational studies are performed on patients, animal and cellular models of diseases to elucidate the mechanisms involved in the pathophysiology of neurologic and mental diseases at the molecular, cellular and system levels, and to translate these findings into clinical diagnosis, treatment and prevention strategies. Genetic and epidemiological studies take advantage of large cohorts of patients, in collaborations with international networks.

Main research areas involve mechanisms of neurodegenerative processes, focused on glutamate excitotoxicity, oxidative stress, the amyloid cascade and vascular damage in the brain. These phenomena are studied in patient samples, with the aim to identify molecular markers of disease and to test possible pharmacological interventions. In parallel, neuropsychological and imaging projects are carried out for a better characterization of neurodegenerative disorders (typical and atypical dementias and mild cognitive impairment, Parkinson’s disease and amyotrophic lateral sclerosis), and for the development of accurate diagnostic tools (with a special interest for Positron Emission Tomography tracers and MR imaging).

Phase II and III trials are ongoing in patients with Alzheimer’s disease and mild cognitive impairment, multiple sclerosis and stroke. A multi-national observational registry on acute stroke recanalization therapies is ongoing since 2005, and a translational research programme of experimental neurology and neurosurgery using rat models of focal cerebral ischemia and intracerebral haemorrhage is being carried out since 2011. International, multicentric clinical trials on chemotherapy-induced peripheral neurotoxicity are coordinated by researchers of this area, but interest is also focused on metabolic, inflammatory and inherited neuropathies.

Other research areas are molecular and genetic and immunological treatment of gliomas, miniinvasive surgical techniques for the treatment of craniofacial and craniovertebral junction malformations and neuroendoscopy for pediatric hydrocephalus and neural tube defects, autism spectrum diseases or chromosomal and genetic abnormalities. Moreover, research interests encompass fine-grained psychopathological description of developmental profile of premature babies, along with the dynamics of couples whose children are affected by psychiatric disorders, and with the clinical endophenotypes and possible biological correlates of anorexia nervosa and borderline personality.

A motion-capture tool is available for studies on treatment of movement dysfunctions (eg. low back pain) and paretic hand. The neuropsychological research spans from the use of Transcranial Direct Current stimulation for the improvement of focal deficits like apraxia and hemianopia, to the use of specific operative strategies like the Constrain Induced Aphasia Therapy.

Specific aspects of psychiatric disorders, such as addiction, social cognition in schizophrenia, correlations between personality and mood disorders, or impact of severe mental disorders on family members are investigated.

Geriatric cognitive syndromes such as delirium are widely investigated, in collaboration with national and international research groups.

Research Area Molecular and Cellular Neurosciences

The research activity of this area involves several aspects of basic neuroscience, with a focus on the translational aspects of the studies in both the central and the peripheral nervous system. Advanced in vitro, ex vivo and in vivo models have been specifically developed to investigate the processes leading to the normal development, maturation and ageing of the nervous system, as well as the detection of pathogenetic mechanisms at the basis of neurological and psychiatric diseases. Multidisciplinarity is an area key word, since basic researchers work in strict collaboration with neurologists, neurosurgeons, psychiatrists and clinical researchers from related fields.

In the field of neurodegeneration, research on oligomeric Abeta and glutamate toxicity, as well as Pin1 isomerase activity are coupled with experimental therapeutic attempts in fibroblasts from Alz-heimer’s disease patients and neuroblastoma cells. Voltage-gated currents and postsynaptic potentials, functional alterations of the blood-brain barrier (BBB) are also investigated. The role of Parkinson’s disease-related toxins, genetic alterations and neuroprotective agents on lysosomal catabolic pathways for alpha-synuclein are also investigated, as well as cholinergic and hypocretinergic regulation of synaptic circuits in the prefrontal cortex. Cerebrotendinous xanthomatosis and Spastic paraplegia type 5 are used as models of neurodegeneration due to defective cholesterol metabolism. Metalloprotease ADAM10 is investigated as a new potential target in the Huntington’s disease brain. Prion Protein (PrPc) folding in neuronal membranes and lipid rafts constituents are also established research topics, linked with investigations on air pollution relevance in protein misfolding and neurodegenerative diseases. Recently, the studies in the advanced field of induced pluripotent stem (iPS)-derived neurons from fibroblasts have also been started.

Experimental stroke models in vivo have been developed in order to reproduce transient focal cerebral ischemia and intracerebral hemorrhage, with the final aims to determine the pathogenesis of neuronal damage and to test advanced experimental therapies, including collateral therapeutics and selective cerebral spinal fluid hypothermia.

Search for new candidate genes involved in epileptic phenotypes and autism through next generation and microarray techniques and identification, in vitro and in vivo characterization of new mutations in known genes involved in epilepsies are performed by genetists in collaboration with neurologists, neurophysiologists and child neuropsychiatrist. The effects of newly developed peptidic and non peptidic drugs are studied in the in vivo model of pilocarpine-induced epilepsy.

Neuro-oncology is a field of close contact between basic researchers, neurosurgeons, genetists and pathologists, addressing the issue of the pathogenesis and treatment of brain cancer. Innovative treatments based on the use of frontline therapy using synchrotron radiation and photoactivation of suitable drugs (e.g. high z-number compounds) are under investigation in collaboration with the European synchrotron radiation source in Grenoble.

Together with radiotherapy, systemic chemotherapy is one of the cornerstones of cancer treatment, but neurotoxicity is currently the major dose limiting side effect after hematological toxicity. Cellular and animal models of chemotherapy-induced peripheral neurotoxicity have been originally developed and characterized by researchers of this area, and they represent the international “gold-standard” in this fields.

Neuropathic pain, a challenging clinical problem in affected patients, is investigated in vitro and in vivo at the behavioral, pharmacological, pathological and neurophysiological levels and innovative therapeutic approaches are attempted, also in collaboration with leading International pharmacological companies.

The possibility to allow effective neuro-regeneration and immune-modulation using mesenchymal stem cells (MSCs) is tested in well-characterized cellular and animal models. The paracrine actions of MSCs on different cell populations of the central nervous system are investigated in in vitro cellular models. Moreover, the critical aspect of genetic stability of MSCs is investigated through their genomic-epigenomic profiling and non-nervous adult cell transplants are explored to treat neurological complications of systemic diseases (e.g. diabetes).

Multiple sclerosis, and more broadly the field of neuro-inflammatory diseases of the central and -peripheral nervous system, is investigated in close collaboration with neurologists and experts in basic immunology at the cellular and animal levels. Integrated chemical-biology approach to the study of Toll-Like Receptor 4 (TLR4) activation and signaling, implication of TLR4 in innate immunity, inflammation and neuro-inflammation, development of small molecule TLR4 modulators as new therapeutics for neuro-inflammatory and neurodegenerative diseases are main topics in this field.

The cellular and molecular mechanisms underlying synaptic formation and function and their roles in the developmental of neuro-behavioural disorders, such as autism and schizophrenia are carried out in collaboration by pharmacologists and adult/child psychiatrist, while another research line is focused on the genetic study of rare malformative syndromes associated to mental retardation.

Several transduction and intracellular signaling systems are explored in neurons and glial cells, including small G-proteins, Ras and Ral activators, Map kinases, deubiquitinating enzyme USP8, mitochondrial structures and their modulation as well as the use of trophic factors (e.g. NGF, NGF-like molecules) for therapeutic aims is investigated also profiting from system biology methods. Functional and pharmacological studies of ion channels are applied to genetic diseases.

Research Area Biotechnology and Nanomedicine

The Biotechnology and Nanomedicine Area encompasses competencies in biochemistry, biology, physics, chemistry, material science, physiology, pharmacology, neurology. Translational studies are performed on human specimen, animal and cellular models of disease to elucidate the molecular bases of brain dysfunction involved in the pathophysiology of neurologic diseases and to translate these findings to clinical diagnosis and treatment. Biotechnology is any technological application using biological systems, living organisms or derivatives, to make or modify products or processes. Biotechnology in UNIMIB has its main applications in clinical proteomics, in biosensing and therapy. Nanomedicine, an offspring of biotechnology, is exploiting the use of devices with size in the order of billionths of meters (nanoparticles, nanobiosensors) for therapy and diagnosis of human diseases. Nanomedicine in UNIMIB has its main applications in diagnostics, therapy and tissue regeneration.

Electrophysiology is crucial in the understanding of the electrical functioning of neurons in the central nervous system (CNS). Both, the single cell- and the slice-level approaches on samples coming from normal tissue and from diseased brains are central for the analysis of the pathophysiological mechanisms responsible for diseases and for the development of new specific drugs. The availability of 64- and 256-electrode multi-site recording apparatus (MEA) allows to test nanomedicine tools and pharmacological agents on living neuronal networks. This offers a way to study in vitro the effects on neuronal cell health, neurotransmission and neurodegenerative processes.

Proteomics is devoted to assess protein pattern in human samples, with the aim to identify molecular markers of disease and to follow the outcome of pharmacological interventions of neurological diseases. Proteomics unit is accustomed with the main proteomics strategies. Nanomedicine researchers have achieved particularly significant advancements in the applications of nanomedicine for theranostic of the diseases that affect the Central Nervous System (CNS). This approach makes the Athenaeum an outstanding reference Centre in Europe for this particular branch. Relevant results have been achieved thanks to several past and currently running grants devoted to design of nanoparticles (NPs) for treatment and diagnosis of CNS diseases.

Research Area Computational and Systems Neurosciences

The variety and complexity of data gathered from biomolecular and neuroimaging studies require an appropriate support, both algorithmic and numerical, from the disciplines of computer science, mathematical modeling, and statistical modeling, in order to provide researchers from the biomedical fields with a more extended toolset capable to aid in the identification of particular pathological phenomena; e.g., using novel “pattern recognition” techniques. Modern neurosciences are not limited to the study and description of single altered parameters, but they frame them in the context of different processes and stages, and, in the clinical case, in the context of “disease and disorder models”, which are concerned with the progression of several observable phenomena. Such progressions need to be measured and often reconstructed from cross-sectional data; moreover they need to be described by means of controlled vocabularies and ontologies in order to communicate concise, shared, and informative summaries to different researchers and clin-ical practitioners. Many of the algorithmic and numerical underpinnings of such multifarious methods require sophisticated and large-scale computational infrastructure, not to mention the special issues that arise from direct modeling and, above all, simulation of neuronal assemblies and activities. Moreover, there are several novel research directions which combine HW and SW technologies in order to provide neuromorphic computing systems, whose aim can be both applicative and explorative, especially when targeted toward simulation of brain functions.

Within the H2020 program, the area “Information and Communication Technology”, alongside the theme “Exascale and Parallel Computing”, is foundational to most “Excellent Science” research programs, including those clustered under the Health heading. Among these, the theme “Systems Biology” appears under different guises. Within this framework, the Computational and Systems Neurosciences research area fosters several integration activities of the data generated from the different kinds of studies just mentioned, also as a consequence of the cross-cutting effort on ICT, Parallel Computing, Big Data administration and management, and more traditional algorithmic and computational research.

Research Area Neuroimaging and Methodological Research

The neuroimaging and methodological research program is an interdisciplinary program that applies imaging, computer sciences and signal analysis techniques to the study of brain functions. The program allows the access to advance technologies and instrumentation located in different institution of the Center. The methodological group is composed by neurologists, psychologists, nuclear physicians, pharmacologist, physicists, computer scientists, statisticians radio-chemists, with expertise in neuroimaging and signal analysis. The program is focused on bringing together clinicians and scientists with the common goal of studying the neurobiology of the brain in normal conditions and diseases at structural, functional and molecular levels using state of the art neuroimaging and signal processing techniques. Imaging and signal processing methodologies may be applied to different fields of neurosciences both at preclinical and clinical levels using both in vitro and in vivo approaches. Main technologies and methodological expertise available for the program are: functional and structural MRI imaging, in vivo and in vitro molecular imaging, signal processing and instrumentation development/optimization, computer sciences and statistics.

The Institute of Molecular Physiology and Bioimaging of the National Research Council (IBFM-CNR) contributes with research activities aimed at developing methods to support the study, prevention, diagnosis, prognosis and treatment of neurological diseases. These includes: Statistical Parametric Mapping -SPM of PET, SPECT, MRI images, Support Vector Machine – SVM); 2) methods for Quantification of characteristic parameters of neurological diseases (Segmentation techniques of MRI images, for the estimation of volumes, eg. hippocampus in AD; Techniques for correction of physical effects on PET images – partial volume correction); 3) Methods for measuring brain connectivity under health and pathological conditions (Statistical Parametric Mapping -SPM of PET and MRI images for the study of connectivity in several cognitive domains – eg. memory); Methods of integration of biomedical parameters obtained for each subject using a variety of methods: diagnostic and in vivo functional PET, SPECT, CT, MRI imaging, ex vivo molecular imaging (histopathology, proteogenomics), response to therapy; multivariate analysis techniques – eg cluster analysis).

Research Area Cognitive and Behavioral Neurosciences

Born around a core-group coming from the Milan experimental psychology and neuropsychology schools, founded by Cesare Musatti and Ennio De Renzi respectively, the group has attracted top scientists from the whole of Italy and now counts about 50 members including also developmental psychologists, experimental social psychologists, linguists, all based at the local Psychology Department. The group also includes clinical neuropsychologists of the Clinical Neuroscience Departments and economists interested in cognitive neuroscience. The scientific production of the CNG fares more than 60.000 citations and more than 560 points of H index. With this record-track, the CNG has a leading role in Italian cognitive neuroscience.

Aim of this area is the study of the healthy and diseased mind in developing and adult individuals. Intervention areas comprise cognitive psychology in healthy individuals, social psychology and quantitative psychology, neuropsychology in brain-damaged and psychiatric patients for heuristic and rehabilitative purposes, clinical psychology in psychological and psychiatric diseases, neuroeconomics. More specifically, typical areas of enquiry are attention and controlled processes, reasoning, spatial cognition, motor control, language and reading, memory, visual perception and semantics, face processing, social cognition and theory of mind, motivation and emotion. These topics are studied in both normal and abnormal populations along the life cycle. Methods comprise behavioral studies in dedicated labs, as well as advanced instrumental methods for the study of the nervous system activity including neuroimaging (fMRI, PET, EEG mapping and ERP), neurostimulation (tDCS, TMS, EEG/TMS), motion capture (SMART), EMG, GSR, Eye tracking. Fruitful interactions are ongoing with all sectors of the NeuroMi Center, with particular attention to quantitative computational modelling of cognitive processes and improved statistical inference on neurophysiological and imaging data. Innovative interactions are planned with the neurobiology oriented (genetics, pharmacology, neurology and psychiatry. etc.) members of NeuroMI as well as with the Clinical Neurosciences area.