Journal of Alzheimer's Disease - Volume 63, issue 1

Authors: Galbiati, Andrea | Carli, Giulia | Hensley, Michael | Ferini-Strambi, Luigi

Article Type: Review Article

Abstract: Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson’s disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease’s (AD). Although AD is reported as a possible development …in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations. Show more

Keywords: Alzheimer’s disease, cognition, neurodegeneration, REM sleep behavior disorder

DOI: 10.3233/JAD-171164

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 1-11, 2018

Authors: Quinn, James P. | Corbett, Nicola J. | Kellett, Katherine A. B. | Hooper, Nigel M.

Article Type: Review Article

Abstract: With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of …different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies. Show more

Keywords: Biomarkers, dementia, proteases, proteolysis, tau, tauopathies

DOI: 10.3233/JAD-170959

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 13-33, 2018

Authors: de la Torre, Jack

Article Type: Research Article

Abstract: The vascular hypothesis of Alzheimer’s disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer’s disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion …as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD. Show more

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, brain hypoperfusion, cerebral blood flow, cognitive impairment, dementia prediction, neuroimaging, vascular hypothesis of Alzheimer’s disease

DOI: 10.3233/JAD-180004

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 35-52, 2018

Authors: Guzik-Makaruk, Ewa M. | Pływaczewski, Emil W. | Mroczko, Piotr | Olesiuk-Okomska, Magda | Kulczyńska-Przybik, Agnieszka

Article Type: Review Article

Abstract: According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer’s disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10–15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum …and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient’s consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients’ informed consent to medical procedures. Show more

Keywords: Alzheimer’s disease, consent to treatment, legal regulations, neurodegenerative diseases

DOI: 10.3233/JAD-171176

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 53-67, 2018

Authors: Høilund-Carlsen, Poul F. | Barrio, Jorge R. | Gjedde, Albert | Werner, Thomas J. | Alavi, Abass

Article Type: Editorial

Abstract: Referring to recent international articles stating that amyloid imaging or detection has a high additive value in making a diagnosis of Alzheimer’s disease (AD) when previous investigations are inconclusive, the authors of this editorial argue that this statement is based on circular reasoning and, hence, misleading. Since autopsy findings and other potential indicators fit poorly with amyloid PET, they conclude that this examination has no role in the diagnosis of AD.

Keywords: Alzheimer’s disease, amyloid PET, circular inference, dementia

DOI: 10.3233/JAD-180050

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 69-73, 2018

Authors: Tabira, Takeshi | Kawamura, Nobutoshi

Article Type: Short Communication

Abstract: Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer’s disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer’s Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6–12 weeks compared with baseline scores (p  = 0.007) and at 22–28 weeks (p  = 0.004). Thus, this supplement may be administered to dementia patients …as well as MCI individuals. Show more

Keywords: Alzheimer’s disease, curcumin, dementia with Lewy bodies, huperzine A, mild cognitive impairment

DOI: 10.3233/JAD-171154

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 75-78, 2018

Authors: Scheinin, Noora M. | Gardberg, Maria | Röyttä, Matias | Rinne, Juha O.

Article Type: Short Communication

Abstract: Our aim was to assess whether in vivo 11 C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer’s disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject’s plaques were predominantly diffuse. The predictive value of a negative 11 C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical …11 C-PIB binding upon PET is unlikely. Show more

Keywords: Aβ, amyloid, immunohistochemistry, neuritic plaque, neuropathology, PIB, positron emission tomography

DOI: 10.3233/JAD-170569

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 79-85, 2018

Authors: Julian, Adrien | Rioux-Bilan, Agnès | Ragot, Stéphanie | Krolak-Salmon, Pierre | Berrut, Gilles | Dantoine, Thierry | Hommet, Caroline | Hanon, Olivier | Page, Guylène | Paccalin, Marc

Article Type: Short Communication

Abstract: Peripheral inflammatory processes are involved in Alzheimer’s disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n  = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, …6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators. Show more

Keywords: Alzheimer’s disease, cognitive decline, cytokines, inflammation

DOI: 10.3233/JAD-171131

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 87-92, 2018

Authors: Cardillo, Giancarlo de Mattos | De-Paula, Vanessa de Jesus Rodrigues | Ikenaga, Eliza Hiromi | Costa, Luciana Rodrigues | Catanozi, Sergio | Schaeffer, Evelin Lisete | Gattaz, Wagner Farid | Kerr, Daniel Shikanai | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer’s disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen …transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p  = 0.0159) and in the parietal cortex (Li1, p  = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL. Show more

Keywords: Alzheimer’s disease, hippocampus, lithium, olfactory epithelium, parietal cortex, telomere, transgenic mice

DOI: 10.3233/JAD-170838

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 93-101, 2018

Authors: Ransmayr, Gerhard | Hermann, Philipp | Sallinger, Katharina | Benke, Thomas | Seiler, Stephan | Dal-Bianco, Peter | Marksteiner, Josef | Defrancesco, Michaela | Sanin, Günter | Struhal, Walter | Guger, Michael | Vosko, Milan | Hagenauer, Karin | Lehner, Riccarda | Futschik, Andreas | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. Objective: Analysis of known and hypothesized factors of CB in home care of dementia patients. Methods: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer’s disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency …Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). Results: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21–40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. Conclusion: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation. Show more

Keywords: Caregiver burden, dementia, dementia severity, dependency, home care, Zarit Caregiver Burden Interview, neuropsychiatric symptoms

DOI: 10.3233/JAD-170657

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 103-114, 2018

Authors: Dunkelmann, Tina | Schemmert, Sarah | Honold, Dominik | Teichmann, Kerstin | Butzküven, Elke | Demuth, Hans-Ulrich | Shah, Nadim Joni | Langen, Karl-Josef | Kutzsche, Janine | Willbold, Dieter | Willuweit, Antje

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in …detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42 ). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models. Show more

Keywords: Alzheimer’s disease, behavior, motor neurons, motor phenotype, mouse model, neurodegeneration, pathology, pyroglutamate modified amyloid-β3-42

DOI: 10.3233/JAD-170775

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 115-130, 2018

Authors: Agostini, Simone | Mancuso, Roberta | Hernis, Ambra | Costa, Andrea Saul | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: Human Herpes Simplex Virus type 1 (HSV-1) infection is suggested to play a role in the development of Alzheimer’s disease (AD). Immunoglobulin G (IgG) neutralize HSV-1 activity, but the virus can evade IgG-mediated immune responses by expressing receptor that efficiently binds the Fc portion of all IgG subclasses with the exception of IgG3 . We analyzed HSV-1-specific IgG subclasses and IgG-mediated serum neutralization activity against HSV-1 in individuals with a diagnosis of either AD or mild cognitive impairment (MCI), comparing the results with those obtained in age-matched healthy controls (HC). 186 individuals were enrolled in the study: 67 AD, 58 …MCI, and 61 HC. HSV-1 IgG titers and subclasses, neutralizing antibody (NAb) titers, and complement C3 concentration—critical component of antibody-mediated effector activity—were measured in sera by ELISA; IgG neutralizing activity was performed on HSV-1 infected Vero cells. Results showed that, whereas HSV-1-specific IgG1 , IgG2 , and IgG4 titers as well as complement C3 serum concentration were comparable in all groups of individuals, IgG3 were more frequently detected in MCI (89%) compared to AD (75%; p  < 0.05) and HC (68%; p  = 0.003), whereas the titer is similar among the three groups (AD: 0.66±0.21 OD; MCI: 0.68±0.24 OD; HC: 0.72±0.28 OD). Notably, HSV-1 specific neutralizing ability of AD sera was reduced even in the presence of high quantity of IgG3 . As IgG3 plays a key role in counteracting the ability of HSV-1 to evade immune responses, these data reinforce the hypothesis of a pathogenetic role of HSV-1 in AD. Show more

Keywords: Alzheimer’s disease, HSV-1, HSV-1-IgG subclasses, mild cognitive impairment, neutralization activity

DOI: 10.3233/JAD-170966

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 131-138, 2018

Authors: Wang, Ye-Ran | Wang, Jun | Liu, Yu-Hui | Hu, Gong-Ling | Gao, Chang-Yue | Wang, Yan-Jiang | Zhou, Xin-Fu | Zeng, Fan

Article Type: Research Article

Abstract: The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer’s disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct …synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , cysteine-rich repeat domains, p75 neurotrophin receptor

DOI: 10.3233/JAD-171012

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 139-147, 2018

Authors: Krell-Roesch, Janina | Feder, Nathanael T. | Roberts, Rosebud O. | Mielke, Michelle M. | Christianson, Teresa J. | Knopman, David S. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Research Article

Abstract: We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and …APOE ɛ 4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41–0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association. Show more

Keywords: APOE ɛ4, cohort study, incident dementia, mild cognitive impairment, physical activity

DOI: 10.3233/JAD-171141

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 149-155, 2018

Authors: Yan, Tingxiang | Wang, Luwen | Gao, Ju | Siedlak, Sandra L. | Huntley, Mikayla L. | Termsarasab, Pichet | Perry, George | Chen, Shu G. | Wang, Xinglong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson’s disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation …at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration. Show more

Keywords: Alzheimer’s disease, dystrophic neurites, granulovacuolar degeneration, neurofibrillary tangles, neuropil threads, phosphorylated Rab10, senile plaques

DOI: 10.3233/JAD-180023

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 157-165, 2018

Authors: De Marco, Matteo | Venneri, Annalena

Article Type: Research Article

Abstract: Background: There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer’s disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. Objective: We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. Methods: Structural and resting state functional MRI scans, and neuropsychological …scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. Results: VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. Conclusion: Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dopaminergic neurons, early diagnosis, functional neuroimaging, gray matter, hippocampus, memory, mild cognitive impairment, neuroimaging, tegmentum mesencephali, ventral tegmental nucleus

DOI: 10.3233/JAD-171018

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 167-180, 2018

Authors: D’Amelio, Marcello | Serra, Laura | Bozzali, Marco

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and …Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD. Show more

Keywords: Alzheimer’s disease, dopamine, hippocampus, memory, midbrain, ventral tegmental area

DOI: 10.3233/JAD-180094

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 181-183, 2018

Authors: Fernández, Gerardo | Orozco, David | Agamennoni, Osvaldo | Schumacher, Marcela | Sañudo, Silvana | Biondi, Juan | Parra, Mario A.

Article Type: Research Article

Abstract: Patients with Alzheimer’s disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older …adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers. Show more

Keywords: Visual short-term memory binding, Alzheimer’s disease, eye movements, gazing, visual processing

DOI: 10.3233/JAD-170728

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 185-194, 2018

Authors: Redaelli, Veronica | Salsano, Ettore | Colleoni, Lara | Corbetta, Paola | Tringali, Giovanni | Del Sole, Angelo | Giaccone, Giorgio | Rossi, Giacomina

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is clinically characterized by behavioral changes, language impairment, and executive dysfunction. FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT , GRN , C9ORF72 , TARDBP , CHMP2B , VCP , and FUS . However, FTD can also be associated with different clinical or pathological phenotypes caused by mutations in other genes, whose heredity can be dominant or recessive. In this work we report on a familial case of FTD characterized …by behavioral changes and aphasia, very early onset and very long duration, choreic movements, and white matter lesions at magnetic resonance imaging. We performed a wide-range genetic analysis, using a next generation sequencing approach, to evaluate a number of genes involved in neurodegeneration. We found a previously unreported compound heterozygous mutation in TREM2 , that is commonly associated with the recessively inherited Nasu-Hakola disease. We discuss the differential diagnosis to be taken into account in cases of FTD presenting with atypical features. Show more

Keywords: Chorea, differential diagnosis, frontotemporal dementia, genetic analysis, Nasu-Hakola disease, next generation sequencing, TREM2 , white matter

DOI: 10.3233/JAD-180018

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 195-201, 2018

Authors: Bonanni, Laura | Franciotti, Raffaella | Martinotti, Giovanni | Vellante, Federica | Flacco, Maria Elena | Di Giannantonio, Massimo | Thomas, Astrid | Onofrj, Marco

Article Type: Research Article

Abstract: Background: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. Objective: To assess whether PTSD is associated with a specific dementia. Methods: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6–10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia. Retrospective study: 849 dementia patients followed during 1999–2014 (509 Alzheimer’s disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of …PTSD in their history. Results: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ 2  = 10, p  = 0.001, and χ 2  = 6, p  = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, χ 2  = 8, p  = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%). Discussion: PTSD was associated with the development of semantic FTD. Show more

Keywords: Clinician-Administered PTSD Scale for DSM-IV-TR, dementia, post traumatic stress disorder, semantic frontotemporal dementia

DOI: 10.3233/JAD-171134

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 203-215, 2018

Authors: Xie, Long | Shinohara, Russell T. | Ittyerah, Ranjit | Kuijf, Hugo J. | Pluta, John B. | Blom, Kim | Kooistra, Minke | Reijmer, Yael D. | Koek, Huiberdina L. | Zwanenburg, Jaco J.M. | Wang, Hongzhi | Luijten, Peter R. | Geerlings, Mirjam I. | Das, Sandhitsu R. | Biessels, Geert Jan | Wolk, David A. | Yushkevich, Paul A. | Wisse, Laura E.M.

Article Type: Research Article

Abstract: Background: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images (“atlases”) to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer’s disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy. Objective: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD …at 3T and 7T. Methods: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T. Results: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set. Conclusion: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions. Show more

Keywords: Alzheimer’s disease, ASHS, high-field magnetic resonance imaging, mild cognitive impairment, multi-atlas label fusion

DOI: 10.3233/JAD-170932

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 217-225, 2018

Authors: Marešová, Petra | Dolejš, Josef | Kuca, Kamil

Article Type: Research Article

Abstract: Background: There is now a general attempt in developed countries to implement strategic plans to fight against Alzheimer’s disease and other dementia disorders. Among others, attention is paid to the issues of registers and calculations of economic burden. Currently available calculations of costs are difficult to compare. The problem is a different breakdown of cost categories and non-unified monitoring of cost types. Objective: The aim of this paper is to note the problem of poor availability and inconsistencies in cost monitoring. Furthermore, the intersection of cost items that are comparable and consistently monitored in expert studies are specified. …Methods: The Web of Science, Elsevier Science Direct, PubMed, and Scopus databases are used in a systematic review. Two independent reviewers screened the identified records and selected relevant articles published in the period from 2010 to 2016. A meta-analysis of costs is performed in four categories related to patients suffering from Alzheimer’s disease. Results: The resulting estimation of total costs per patient per month through meta-analysis is € 3,896, with 95% CI [2078, 5713]. The highest costs arise from informal care following non-medical and medical care. Conclusion: The results confirm assumption that inconsistencies in cost monitoring of the treatment and care of people with dementia exists in Europe. Homogeneity could be assumed only in the medical costs of severe patients. Heterogeneity is assumed in non-medical costs, informal costs. Cost items should be defined and collected more precisely for future more precise monitoring of the economic burden. Show more

Keywords: Alzheimer’s disease, data collection uniformity, developed countries, meta-analysis

DOI: 10.3233/JAD-171028

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 227-238, 2018

Authors: Krämer, Julia | Lueg, Gero | Schiffler, Patrick | Vrachimis, Alexis | Weckesser, Matthias | Wenning, Christian | Pawlowski, Matthias | Johnen, Andreas | Teuber, Anja | Wersching, Heike | Meuth, Sven G. | Duning, Thomas

Article Type: Research Article

Abstract: Background: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging. Objective: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI. Methods: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a …“typical” pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a “non-typical”/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses. Results: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET. Conclusion: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary. Show more

Keywords: Behavioral symptoms, diffusion tensor imaging, frontotemporal dementia, frontotemporal lobar degeneration, magnetic resonance imaging, positron-emission tomography, sensitivity, specificity

DOI: 10.3233/JAD-170224

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 239-253, 2018

Authors: Jin, He | Wang, Rong | Liu, Zhaohui | Jia, Qiang | Wu, Yanchuan | Zhao, Zhiwei | Wang, Yulan | Zhang, Xu

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer’s disease (AD). Objective: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme-linked immunosorbent assay (ELISA). Methods: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4°C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative …(untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d-g) were stored at –20°C and (h-k) were stored at –70°C, respectively, detected at different time points. All of the results were compared with the baseline urine. Results: The urine AD7c-NTP levels at different time points behaved stably (p  > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at –20°C and –70°C led to an obviously false positive. Conclusions: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended. Show more

Keywords: Alzheimer-associated neuronal thread protein, biomarker, enzyme-linked immunosorbent assay, urine

DOI: 10.3233/JAD-171109

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 255-262, 2018

Authors: Kero, Mia | Raunio, Anna | Polvikoski, Tuomo | Tienari, Pentti J. | Paetau, Anders | Myllykangas, Liisa

Article Type: Research Article

Abstract: Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85+ study includes all inhabitants of the city of Vantaa, who were >85 years in 1991 (n  = 601). Neuropathological assessment was possible …in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE- staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p  < 0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p  < 0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination. Show more

Keywords: Dementia, hippocampal sclerosis, hippocampal sclerosis without any comorbid neurodegenerative pathology, laterality, population-based, TDP-43, very old

DOI: 10.3233/JAD-171068

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 263-272, 2018

Authors: Masoud, Anwar M. | Bihaqi, Syed W. | Alansi, Bothaina | Dash, Miriam | Subaiea, Gehad M. | Renehan, William E. | Zawia, Nasser H.

Article Type: Research Article

Abstract: Amyloid deposits originating from the amyloid-β protein precursor (AβPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer’s disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AβPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and protein levels of AβPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid …and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl– CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AβPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AβPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation. Show more

Keywords: Alzheimer’s disease, AβPP, DNMT3a, lead, MAPT, miRNA, SP1

DOI: 10.3233/JAD-170824

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 273-282, 2018

Authors: Dong, Yang-Ting | Cao, Kun | Tan, Long-Chun | Wang, Xiao-Ling | Qi, Xiao-Lan | Xiao, Yan | Guan, Zhi-Zhong

Article Type: Research Article

Abstract: In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein …and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2 O2 , O2 ·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective. Show more

Keywords: AβOs, APP/PS1 mice, oxidative stress, primary neurons, resveratrol, SIRT1, suramin

DOI: 10.3233/JAD-171020

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 283-301, 2018

Authors: Zhao, Ming-Liang | Chen, Shi-Jin | Li, Xiao-Hong | Wang, Li-Na | Chen, Feng | Zhong, Shi-Jiang | Yang, Cheng | Sun, Sheng-Kai | Li, Jian-Jun | Dong, Hua-Jiang | Dong, Yue-Qing | Wang, Yi | Chen, Chong

Article Type: Research Article

Abstract: Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons …but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP-expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro . By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using β-catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP-expressing cells facilitated survival and maturation probably through the Wnt/β-catenin signaling cascade. Show more

Keywords: Adult neurogenesis, cognition, depolarization, optical, traumatic brain injury

DOI: 10.3233/JAD-180002

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 303-318, 2018

Authors: Tebrügge, Sarah | Winkler, Angela | Gerards, Diana | Weimar, Christian | Moebus, Susanne | Jöckel, Karl-Heinz | Erbel, Raimund | Jokisch, Martha | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: Background: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare. Objective: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample. Methods: At the third examination of the Heinz Nixdorf Recall study (n  = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin’ Sticks Screening Test measuring olfactory function on a scale of 0–12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7–10 or ≥11 points, respectively). …All participants performed eight validated cognitive subtests. Age- (55–64 years, 65–74 years, 75–86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance. Results: Women showed better olfactory function than men (p  < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests. Conclusion: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65–74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia. Show more

Keywords: Adults, Alzheimer’s disease, cognition, olfaction, population-based

DOI: 10.3233/JAD-170863

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 319-329, 2018

Authors: Mc Ardle, Ríona | Morris, Rosie | Hickey, Aodhán | Del Din, Silvia | Koychev, Ivan | Gunn, Roger N. | Lawson, Jennifer | Zamboni, Giovanna | Ridha, Basil | Sahakian, Barbara J. | Rowe, James B. | Thomas, Alan | Zetterberg, Henrik | MacKay, Clare | Lovestone, Simon | Rochester, Lynn

Article Type: Research Article

Abstract: Gait is emerging as a potential diagnostic tool for cognitive decline. The ‘Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study’ (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer’s disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health …Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD. Show more

Keywords: Alzheimer’s disease, cognition, free-living, gait, phenotyping, wearables

DOI: 10.3233/JAD-171116

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 331-341, 2018

Authors: Gerritsen, Adrie A.J. | Bakker, Christian | Verhey, Frans R.J. | Bor, Hans | Pijnenburg, Yolande A.L. | de Vugt, Marjolein E. | Koopmans, Raymond T.C.M.

Article Type: Research Article

Abstract: Background: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown. Objective: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course. Methods: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types. …Results: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p  = 0.012) and was not significantly different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p  = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p  = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p  < 0.001) and hyperactivity (p  = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p  < 0.001). Conclusion: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function. Show more

Keywords: Cognitive decline, progression of dementia, young onset dementia

DOI: 10.3233/JAD-170859

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 343-351, 2018

Authors: Klöppel, Stefan | Kotschi, Maria | Peter, Jessica | Egger, Karl | Hausner, Lucrezia | Frölich, Lutz | Förster, Alex | Heimbach, Bernhard | Normann, Claus | Vach, Werner | Urbach, Horst | Abdulkadir, Ahmed | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Older patients with depression or Alzheimer’s disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n  = 28) or moderate and severe depression (n  = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of …AD versus depression. We found that our algorithm learned discriminative patterns in the subject’s grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments. Show more

Keywords: Alzheimer’s disease, depression, magnetic resonance imaging, supervised machine learning, support vector machine

DOI: 10.3233/JAD-170964

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 353-363, 2018

Authors: Silbert, Lisa C. | Lahna, David | Promjunyakul, Nutta-on | Boespflug, Erin | Ohya, Yusuke | Higashiuesato, Yasushi | Nishihira, Junko | Katsumata, Yuriko | Tokashiki, Takashi | Dodge, Hiroko H.

Article Type: Research Article

Abstract: Background: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear. Objective: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly. Methods: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and …essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers. Results: Decreased MCT was associated with SBP 140 + (p  = 0.029) and increased serum IL-6 (p  = 0.036), HgbA1C (p  = 0.002), and Cu (p  = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p  = 0.004) was associated with greater WMH volume. Conclusions: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer’s disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals. Show more

Keywords: Aging, Alzheimer’s disease, atrophy, brain, cerebrovascular disorders, cognitive aging, copper, inflammation, magnetic resonance imaging, micronutrients, vascular disease

DOI: 10.3233/JAD-171153

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 365-372, 2018

Authors: Niemantsverdriet, Ellis | Feyen, Bart F.E. | Le Bastard, Nathalie | Martin, Jean-Jacques | Goeman, Johan | De Deyn, Peter Paul | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt. Objective: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis. Methods: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer’s disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42 , T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three …neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses. Results: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively. Conclusion: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses. Show more

Keywords: Ambiguous diagnosis, Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, differential dementia diagnosis, neuropathology

DOI: 10.3233/JAD-170927

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 373-381, 2018

Authors: Kristensen, Rachel Underlien | Nørgaard, Ane | Jensen-Dahm, Christina | Gasse, Christiane | Wimberley, Theresa | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described. Objective: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population. Methods: Cross-sectional study of the Danish population aged ≥65 in 2014 (n  = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n  = 35,476) and without dementia (n  = 994,231) were compared, stratified …by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM. Results: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p  < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p  < 0.001; PRISCUS: 24.4% versus 13.2%, p  < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45–1.55]; red-yellow-green: 1.27 [1.23–1.31]; PRISCUS: 1.25 [1.20–1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents. Conclusion: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, polypharmacy, potentially inappropriate medication list

DOI: 10.3233/JAD-170905

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 383-394, 2018

Authors: Kim, Clara Tammy | Myung, Woojae | Lewis, Matthew | Lee, Hyewon | Kim, Satbyul Estella | Lee, Kyungsang | Lee, Chunsoo | Choi, Junbae | Kim, Ho | Carroll, Bernard J. | Kim, Doh Kwan

Article Type: Research Article

Abstract: Background: There is a growing concern that general anesthesia could increase the risk of dementia. However, the relationship between anesthesia and subsequent dementia is still undetermined. Objective: To determine whether the risk of dementia increases after exposure to general anesthesia. Methods: A population-based prospective cohort study analyzing the Korean National Health Insurance Service-National Sample Cohort database was conducted of all persons aged over 50 years (n  = 219,423) from 1 January 2003 and 31 December 2013. Results: 44,956 in the general anesthesia group and 174,469 in the control group were followed for 12 years. The …risk of dementia associated with previous exposure to general anesthesia was increased after adjusting for all covariates such as gender, age, health care visit frequency, and co-morbidities (Hazard ratio = 1.285, 95% confidence interval = 1.262–1.384, time-varying Cox hazard model). In addition, the number of anesthetic agents administered, the number of exposures to general anesthesia, the cumulative exposure time, and the organ category involved in surgery were associated with risk of dementia. Conclusion: In light of the increasing societal burden of dementia, careful surveillance for dementia and prevention guidelines for patients after general anesthesia are needed. Show more

Keywords: Anesthesia, dementia, postoperative complications, risk factor

DOI: 10.3233/JAD-170951

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 395-405, 2018

Article Type: Correction

DOI: 10.3233/JAD-189001

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 407-407, 2018