Journal of Alzheimer's Disease - Volume 88, issue 3

Authors: Babiloni, Claudio

Article Type: Editorial

DOI: 10.3233/JAD-220582

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 801-807, 2022

Authors: Tok, Sean | Ahnaou, Abdallah | Drinkenburg, Wilhelmus

Article Type: Review Article

Abstract: Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological indicator of Alzheimer’s disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential indicator of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this readout. Several hypotheses have been put forward to explain the prevalence of …NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, epilepsy, hippocampus, hyperexcitability, laboratory animal models, tau proteins, translational research

DOI: 10.3233/JAD-210397

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 809-836, 2022

Authors: Stoiljkovic, Milan | Gutierrez, Karel Otero | Kelley, Craig | Horvath, Tamas L. | Hajós, Mihály

Article Type: Research Article

Abstract: Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Objective: Our …aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Methods: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Results: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Conclusion: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations. Show more

Keywords: Alzheimer’s disease, hippocampus, microglia, theta oscillation, seizure, TREM2

DOI: 10.3233/JAD-210041

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 837-847, 2022

Authors: Jin, Nanxiang | Babiloni, Claudio | Drinkenburg, Wilhelmus H. | Hajós, Mihály | Nygaard, Haakon B. | Tanila, Heikki

Article Type: Review Article

Abstract: Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer’s disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models. Transgenic rodent models of AD pathology exhibit various forms of epileptiform EEG activity related to the abnormal levels of amyloid species in the brain. Among them, large-amplitude …cortical and hippocampal EEG spikes in mouse and rat AD models may be reminiscent of the subclinical epileptiform EEG spikes recorded in some AD patients. This article reports the recommendations of a multidisciplinary panel of experts on optimal EEG markers and experimental designs to measure and report epileptiform activities and their response to symptomatic and disease-modifying drugs in transgenic AD model rodents. These recommendations may harmonize future preclinical EEG studies in the drug discovery research and may increase the comparability of experimental outcomes and their translational clinical value. Show more

Keywords: Drug, EEG, epilepsy, epileptiform, mouse, rat, transgenic

DOI: 10.3233/JAD-210209

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 849-865, 2022

Authors: Joseph, Shaylyn | Patterson, Rachel | Wang, Wei | Blumberger, Daniel M. | Rajji, Tarek K. | Kumar, Sanjeev

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS) due to underlying neurodegenerative pathology. Some studies using electroencephalography (EEG) have shown increased epileptiform and epileptic activity in AD. Objective: This review and meta-analyses aims to synthesize the existing evidence for quantitative abnormalities of cortical excitability in AD and their relationship with clinical symptoms. Methods: We systematically searched and reviewed publications that quantitatively assessed cortical excitability, using transcranial magnetic stimulation (TMS) resting motor threshold (rMT), active motor threshold (aMT), motor evoked potential (MEP) or directly from the cortex using TMS-EEG via TMS-evoked potential (TEP). …We meta-analyzed studies that assessed rMT and aMT using random effects model. Results: We identified 895 publications out of which 37 were included in the qualitative review and 30 studies using rMT or aMT were included in the meta-analyses. The AD group had reduced rMT (Hedges’ g  = –0.99, 95% CI [–1.29, –0.68], p  < 0.00001) and aMT (Hedges’ g  = –0.87, 95% CI [–1.50, –0.24], p  < 0.00001) as compared with control groups, indicative of higher cortical excitability. Qualitative review found some evidence of increased MEP amplitude, whereas findings related to TEP were inconsistent. There was some evidence supporting an inverse association between cortical excitability and global cognition. No publications reported on the relationship between cortical excitability and NPS. Conclusion: There is strong evidence of increased motor cortex excitability in AD and some evidence of an inverse association between excitability and cognition. Future studies should assess cortical excitability from non-motor areas using TMS-EEG and examine its relationship with cognition and NPS. Show more

Keywords: Alzheimer’s disease, cognition, cortical excitability, electrophysiology, neuropsychiatric symptoms, transcranial magnetic stimulation

DOI: 10.3233/JAD-210311

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 867-891, 2022

Authors: Costa, Cinzia | Vecchio, Fabrizio | Romoli, Michele | Miraglia, Francesca | Nardi Cesarini, Elena | Alù, Francesca | Calabresi, Paolo | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Background: Although people with late onset epilepsy of unknown etiology (LOEU) are at higher risk of cognitive decline compared to the general population, we still lack affordable tools to predict and stratify their risk of dementia. Objective: This pilot-study investigates the potential application of electroencephalography (EEG) network small-world (SW) properties in predicting cognitive decline among patients with LOEU. Methods: People diagnosed with LOEU and normal cognitive examination at the time of epilepsy diagnosis were included. Cerebrospinal fluid biomarkers, brain imaging, and neuropsychological assessment were performed at the time of epilepsy diagnosis. Baseline EEG was analyzed for …SW properties. Patients were followed-up over time with neuropsychological testing to define the trajectory of cognitive decline. Results: Over 5.1 years of follow-up, among 24 patients diagnosed with LOEU, 62.5% were female, mean age was 65.3 years, thirteen developed mild cognitive impairment (MCI), and four developed dementia. Patients with LOEU developing MCI had lower values of SW coefficients in the delta (p  = 0.03) band and higher SW values in the alpha frequency bands (p  = 0.02) compared to patients having normal cognition at last follow-up. The two separate ANOVAs, for low and alpha bands, confirmed an interaction between SW and cognitive decline at follow-up. A similar gradient was confirmed for patients developing dementia compared to those with normal cognitive function as well as to those developing MCI. Conclusion: Baseline EEG analysis through SW is worth investigating as an affordable, widely available tool to stratify LOEU patients for their risk of cognitive decline. Show more

Keywords: Cognitive decline, electroencephalography network small-world analysis, late onset epilepsy of unknown etiology, mild cognitive impairment

DOI: 10.3233/JAD-210350

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 893-901, 2022

Authors: Babiloni, Claudio | Noce, Giuseppe | Di Bonaventura, Carlo | Lizio, Roberta | Eldellaa, Ali | Tucci, Federico | Salamone, Enrico M. | Ferri, Raffaele | Soricelli, Andrea | Nobili, Flavio | Famà, Francesco | Arnaldi, Dario | Palma, Eleonora | Cifelli, Pierangelo | Marizzoni, Moira | Stocchi, Fabrizio | Bruno, Giuseppe | Di Gennaro, Giancarlo | Frisoni, Giovanni B. | Del Percio, Claudio

Article Type: Research Article

Abstract: Background: Patients with amnesic mild cognitive impairment due to Alzheimer’s disease (ADMCI) typically show a “slowing” of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that “slowing.” Objective: Here we tested the hypothesis that the “slowing” of rsEEG rhythms is related to EEA in ADMCI patients. Methods: Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG …cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals. Results: EEA was observed in 15% (N = 8) of the ADMCI patients. The ADMCI-EEA group showed: 1) more abnormal Aβ42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (<4 Hz) rsEEG source activities as compared to the ADMCI-noEEA and Nold groups. Those source activities showed moderate accuracy (AUROCC = 0.70–0.75) in the discrimination between ADMCI-noEEA versus ADMCI-EEA individuals. Conclusion: It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance. Show more

Keywords: Epileptiform EEG activity, exact low-resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-220442

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 903-931, 2022

Authors: Fairley, Andrea | Stewart, Christopher J. | Cassidy, Aedín | Woodside, Jayne V. | McEvoy, Claire T.

Article Type: Review Article

Abstract: Given the complex bidirectional communication system that exists between the gut microbiome and the brain, there is growing interest in the gut microbiome as a novel and potentially modifiable risk factor for Alzheimer’s disease (AD). Gut dysbiosis has been implicated in the pathogenesis and progression of AD by initiating and prolonging neuroinflammatory processes. The metabolites of gut microbiota appear to be critical in the mechanism of the gut-brain axis. Gut microbiota metabolites, such as trimethylamine-n-oxide, lipopolysaccharide, and short chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. Emerging data suggest that the fungal microbiota …(mycobiome) may also influence AD pathology. Importantly, 60% of variation in the gut microbiome is attributable to diet, therefore modulating the gut microbiome through dietary means could be an effective approach to reduce AD risk. Given that people do not eat isolated nutrients and instead consume a diverse range of foods and combinations of nutrients that are likely to be interactive, studying the effects of whole diets provides the opportunity to account for the interactions between different nutrients. Thus, dietary patterns may be more predictive of a real-life effect on gut microbiome and AD risk than foods or nutrients in isolation. Accumulating evidence from experimental and animal studies also show potential effects of gut microbiome on AD pathogenesis. However, data from human dietary interventions are lacking. Well-designed intervention studies are needed in diverse populations to determine the influence of diet on gut microbiome and inform the development of effective dietary strategies for prevention of AD. Show more

Keywords: Gut microbiome, gut metabolites, dietary patterns, Alzheimer’s disease

DOI: 10.3233/JAD-220205

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 933-941, 2022

Authors: Flicker, Leon | Anstey, Kaarin J. | Almeida, Osvaldo P. | Waller, Michael | Fitzgerald, Patrick | de Crespigny, Fleur | Vu, Thao | Dobson, Annette J.

Article Type: Short Communication

Abstract: Abstract: Population-based surveys were used to estimate community prevalence of dementia, but have low response fractions due, among other things, to difficulties in obtaining informed consent from people with diminished capacity. Cohort studies of younger people are subject to recruitment bias and non-random drop-outs. Dementia registries can delineate sub-types of dementia but have limited population coverage and are costly to maintain. Administrative datasets have low costs but may be subject to selection bias and uncertain sensitivity. We propose that astute combination of methodologies, including assessment of coverage and validity of administrative datasets, is the most cost-effective process to estimate and …monitor community prevalence. Show more

Keywords: Data linkage, dementia, methodology, population-based, prevalence, surveys

DOI: 10.3233/JAD-220093

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 943-948, 2022

Authors: Mabrouk, Rana | Gotkiewicz, Maria | Rauramaa, Tuomas | Tanila, Heikki

Article Type: Short Communication

Abstract: DAPI is conventionally used as a nuclear stain for cells in culture or tissue. Here we demonstrate that it binds specifically to the β-sheet core of amyloid-β plaques but not diffuse amyloid-β at the plaque periphery. The specific DAPI induced blue fluorescence is much stronger than amyloid plaque autofluorescence. DAPI staining of fibrillar amyloid deposit may yield a misleading impression of damaged or dying cells. On the other hand, it provides a handy and low-cost means of staining compact amyloid plaques together with cell nuclei in double or triple immunofluorescent studies.

Keywords: Alzheimer’s disease, amyloid-β plaques, autofluorescence, DAPI

DOI: 10.3233/JAD-220072

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 949-955, 2022