bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole‐exome sequencing of a Portuguese cohort of early‐onset Alzheimer’s disease implicates X‐linked lysosomal gene GLA
Authors: Tábuas‐Pereira Miguel , Guerreiro Rita , Bras Jose , Santana Isabel , Tredici Kelly , Paquette Kimberly , Taipa Ricardo
Published: December 2023

Background

Cerebrovascular disease is a common comorbidity in patients with Alzheimer’s disease (AD) and other dementias. Accumulating evidence indicates that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. In fact, some studies have associated common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 with AD pathogenesis.

We aimed to identify rare genetic variants in genes associated with monogenic small vessel disease in in a cohort of Portuguese early‐onset AD patients.

Method

We performed whole‐exome sequencing in a cohort of 104 thoroughly studied patients with early‐onset AD, without known pathogenic variants in the genes associated with AD or frontotemporal dementia. In these patients, we searched for rare (MAF<0.001) non‐synonymous variants in genes associated with small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2, CSTA, GLA and TREX1.

Result

In total, we found 12 rare variants in 18 patients. We found 3 male AD patients with a pathogenic GLA variant. We found other rare variants in NOTCH3, COL4A2 and HTRA1. Of the 3 patients carrying a GLA variant, one had a neuropathological study confirming the diagnosis of AD . This individual also revealed Fabry disease pathology in the hippocampal formation (CA1 to CA4 and subiculum).

Conclusion

We found several rare variants on the genes of interest in our cohort. We provide evidence supporting the pathogenicity of the GLA variant. We show that 3 carriers of this variant, without other probable genetic cause responsible for the disease, developed early‐onset AD. One of those cases had post‐mortem confirmation of the diagnosis. We further show the localization of Fabry pathology in several areas that are vulnerable in AD. This poses the question of the variant’s possible role in AD pathogenesis.
Higher circulating cortisol is associated with amyloidogenesis in post‐menopausal women: The Framingham Heart Study
Authors: Salardini Arash , Zilli Eduardo Marques , Himali Jayandra Jung , Gonzales Mitzi M. , Himali Dibya , Ghosh Saptaparni , McGrath Emer R , Buckley Rachel F. , Satizabal Claudia L. , Johnson Keith A. , Decarli Charles , Fakhri Georges El , Vasan Ramachandran S , Seshadri Sudha
Published: December 2023

Background

Reports of a correlation between higher baseline cortisol and faster progression of Alzheimer’s disease (AD) in longitudinal cohorts and more advanced AD pathology in cross sectional studies raise the possibility that cortisol dysregulation contributes to AD pathogenesis. The current data, however, is less strong with regards to possible mechanisms underlying this relationship or the direction of influence between higher cortisol and AD severity. The goal of this study was to examine the associations between cortisol levels and incident cerebral amyloid and tau PET deposition.

Methods

We present a prospective cohort study of cognitively normal individuals derived from Framingham Heart Study (generation 3‐mean age 39.6±8.1 years, 48.5% women) who had measures of fasting morning plasma cortisol at baseline and PET measures of brain amyloid and tau 15±1.6 years later. Fasting cortisol levels were examined as tertitles (Cortisol level (min,max)‐ T1:3.92‐11.12; T2:11.13‐15.50; T3:15.76‐50.07). Linear regression was used to evaluate associations baseline plasma cortisol (in tertiles) with amyloid and tau deposition, adjusted for age, sex, and the duration between cortisol and PET imaging assessments. We assessed interactions by ApoE4 positivity, sex and menopausal status (women only).

Results

We found no association between serum cortisol and amyloid/tau burden, and no significant interaction with age or ApoE4 status. However, the association between cortisol and amyloid retention interacted significantly with sex in our primary regions of interest (posterior cingulate cortex [PCC] β:0.059±0.027, p = 0.031; precuneus [PC] 0.071±0.025, 0.005, and whole brain [represented by FLR] 0.039±0.014, 0.006). Comparing the highest relative to the middle cortisol (the referent) tertiles among women, amyloid deposition was higher in PCC (β±SE: 0.059±0.027, p = 0.031), PC (0.071±0.025, 0.005), and FLR ROIs (0.039±0.014, p = 0.006). The same relationships did not hold in men or in relations to tau. Furthermore, the effect was only present in postmenopausal women, with the higher amyloid deposition in PC (β:0.103±0.040, p = 0.012) and FLR ROIs (0.071±0.020, 0.001) as well as superior temporal sulcus (secondary outcome). We did not observe any statistically significant association comparing bottom to the middle cortisol tertile.

Conclusion

Although future research is needed, the results suggest that serum cortisol may contribute to Alzheimer’s pathogenesis by driving amyloidogenesis in postmenopausal women.
Sentinels of the Social geriatric program: implementation in rural areas of network for the identification of seniors at rick secondary to loss of autonomy or cognitve deficits
Authors: Lacombe Guy , Lemire Stéphane , Bouffard Marie‐Pier
Published: December 2023

Background

In a large rural area, isolated seniors rarely consult health services and often come to emergency rooms after severe deterioration. The implantation of “sentinels” in their environment could make it possible to identify them early.

Method

The AGE Foundation, a charitable organization, in collaboration with the public health services of the Granit region (22,000 p/2731 Km2) in the province of Quebec developed care trajectories, identified caregaps and environments requiring sentinels. The project include the analysis of the implantation and the identified cases

Result

In 2022, the nurse “navigator” trains 80 sentinels in the use of tracking tools such as AD‐Plus. The sentinels are home care workers and non‐professionals (hairdresser, grocer, municipal agents, etc.) well established in 16 communities. In 9 months they have raised more and more alerts, from 2 to 25 per month for a total of 129. The alerts concerned seniors with an average age of 79, 56 were between 80 and 89 years old and 18 over 90 years old. The majority, 66%, are women. But more importantly, 73% had no follow‐up in the health system before. They required an average of 20 days of targeted interventions, the vast majority of which took place at home.

Conclusion

Many seniors suffer from loneliness. At the beginning of loss of independence or cognitive impairment, do not consult health services. The “Sentinels” and the Navigator present an effective tracking model.
Chronic traumatic encephalopathy pathology in a large population‐based study.
Authors: Rodriguez Roberta Diehl , Nowinski Christopher , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Ferretti‐Rebustini Renata Eloah de Lucena , Jacob‐Filho Wilson , Pasquallucci Carlos Augusto , Nitrini Ricardo , Grinberg Lea T.
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease predominantly found in former athletes and associated with repetitive brain injury (TBI). Despite the increased number of studies, several questions about prevalence and risk factors for CTE in the general population remain unknown.

Method

to investigate the presence of CTE pathology in a population‐based clinicopathological cohort, we analyzed brain sections immunostained with tau antibody (AT8) of 1151 individuals over 30 years of age with previous neuropathological assessment. The presence of CTE pathology was evaluated according to the current neuropathological consensus criteria. Demographic and clinical data were collected through interviews with a next‐of‐kin. All cases are from the Biobank for Aging Studies of the University of São Paulo University. Internationally accepted criteria were used to diagnose and stage the brain tissue pathologies.

Result

Only 7 cases (0.6%) met neuropathological criteria for CTE, contrasting with the high frequency of aging‐related tau astrocyte pathology (ARTAG) (50%) The mean age of death was 73.4 12.5 and only one individual were female. Presence of co‐pathologies was observed in all cases, being the most frequent comorbidity AD‐type pathology, followed by argyrophilic grain disease. Dementia was present in 43%, meanwhile 57% had some degree of neuropsychiatric symptoms (NPS). The most frequent NPS was depression, followed by anxiety. The history of sport practice was complete only for two cases. Both played soccer, however only one semi‐professionally.

Conclusion

The low frequency of CTE pathology corroborate findings from other studies that CTE is not a frequent finding in population‐based samples. The overlapping between CTE and ARTAG may contribute with the misclassification of ARTAG as CTE.
Alzheimer´s Disease initial cognitive profile in an Argentinian cohort of individuals with Down Syndrome
Authors: Pertierra Lucia , Clas Giulia Solange , Tapajoz Fernanda , Helou Belén , Guimet Nahuel Magrath , Bérgamo Yanina , Vazquez Silvia , Sevlever Gustavo , Allegri Ricardo Francisco , Surace Ezequiel
Published: December 2023

Background

Down Syndrome [DS] is the most frequent cause of genetic developmental and intellectual disability. The lifetime risk of Alzheimer’s Disease [AD] in people with DS is more than 90%, with an earlier age of onset than the general population. There is ongoing debate whether there are significant differences in dementia presentation in the specific context of DS, with some studies suggesting a predominantly frontal phenotype with behavioural symptoms and others suggesting a more frequent amnestic presentation.

The aim of this study was to characterize the initial cognitive profile of AD in a cohort of Argentinian adults with DS.

Method

Adults with DS and prodromal or established AD dementia who were part of the IASDA (Argentinian initiative for the study of DS and AD) cohort or spontaneusly attended our Memory Clinic were included. Initial cognitive profile was determined by a semi‐structured interview conducted by a cognitive neurologist with the subject, their family and caregivers.

Result

Sixteen adults with DS were included. Fifty‐six percent (n = 9) were males. Mean age was 51 yo (42‐59 yo). Sixty‐two percent (n = 10) had premorbid moderate intellectual disability [DI], 25% (n = 4) had severe DI and 13% (n = 2) had mild DI.

Fifty‐six percent (n = 9) had a clinical diagnosis of prodromal AD, and the remaining individuals had clinically established AD dementia. Fifty percent (n = 8) had positive amiloid biomarkers (determined by cerebral PiB‐PET or cerebrospinal fluid levels of Aβ42, phosphorylated‐tau and total‐tau), while the remaining subjects did not undergo amiloid biomarker assessment. Due to cognitive impairment, premorbid language impairment and/or premorbid severe DI, only 25% (n = 4) of individuals completed neuropsychological testing (CAMDEX‐DS, Cued Recall Task).

Initial cognitive profile was charactirized as amnestic (single‐domain amnestic or multiple‐domain amnestic) in 81% percent (n = 13) of the cohort. Only 13% (n = 2) of the subjects had initial non‐amnestic syndromes, and in one case (6%) the initial cognitive syndrome was uncertain.

Conclusion

Amnestic cognitive impariment was the most frequent presentation of AD in this small cohort of Latin American adults with DS.
Sharing History through Active Reminiscence and Photo‐imagery‐SHARP: Feasibility and acceptability of digital biomarker technology among older Black adults
Authors: Croff Raina , Beattie Zachary T , Gothard Sarah , Fuller Patrice , Fennell Charles T , Kaye Jeffrey A
Published: December 2023

Background

More nuanced data collection beyond pre/post measures can detect real‐time changes in activity levels, sleep, and other factors that may signal transition in cognitive health.

Method

Nine Black adults (n = 4 healthy, mean age 71.1; n = 5 mildly cognitively impaired (MCI), mean age 79.2) tested the feasibility of adding digital biomarker technology to the SHARP walking study in Portland, Oregon. Up to 8 weeks, participants wore an actigraphy watch that captured continuous activity data, used an under‐the‐mattress sensor that captured daily sleep data, and completed online health forms that captured weekly changes. The second 4‐8 weeks and in triads, participants walked and conversationally reminisced together on three 1‐mile routes/week using the SHARP smartphone application. Means were calculated from group aggregated data (MCI/healthy). Content analysis of group discussions assessed technology acceptability.

Result

Watch step data was collected on average 60.4±51.2 days per participant, representing on average 75.0±29.2% of the days step data was collected. Watch sleep data was collected on average 47.6±40.5 days per participant, representing on average 62.5±33.7% of the days sleep data was collected. Under‐the‐mattress sensor sleep data was collected on average 79.3±42.9 days per participant, representing on average 79.0±24.8% of the days sensor data was collected. MCI participants had lower mean daily step count at 1140 compared to 2570 steps for healthy participants, and lower mean sleep time at 5.07 hours compared to 6.71 hours for healthy participants. MCI had lower mean survey response rates, even with weekly reminders, at 60% compared to 91% for healthy participants, and notably longer mean response times at 472 seconds compared to 195 seconds for healthy participants. Participants generally accepted technology, with caveats: more explanation of technology, better watch step count displays, and watch band options as silicone was uncomfortable in heat and water, prompting discontinuous wear.

Conclusion

Using digital biomarker technology for more continuous data capture with older adults including those with MCI is feasible. However, teams should anticipate increased support for MCI participants and potentially longer technology deployment and set‐up. More continuous data reveal real‐time changes that may signal transitions in cognitive health, allowing for a timelier response from healthcare partners.
HSV‐1 reactivation in AD mouse model reveals longitudinal reduction in synaptic gene expression in the brain
Authors: Funk Cory C , Robinson Max , Schaffer Caitlyn , Battaglia Christian , Aubert Martine , Wiley Jesse C , Cary Gregory A. , Johnston Christine , Darvas Martin
Published: December 2023

Background

Mounting evidence supports the contribution of neurotrophic herpesvirus family infections to Alzheimer’s Disease (AD) etiology on the molecular, physiologic, and epidemiologic levels. As chronic viral infections have substantial variability in reactivations, and AD pathology is known to begin over a decade prior to symptoms, understanding the longitudinal impact of herpesviruses on AD pathogenesis is a challenging and complex problem.

Method

We developed a mouse model of herpes‐simplex virus type 1 (HSV‐1) infection in C57B6/J mice containing humanized APP and APOE4. Using 10 mice per group (5 male, 5 female), and after initial infection at 2 months of age via corneal scarification with 106 PFU HSV‐1 strain 17, we reactivated the virus with the bromo‐domain compound JQ1 at 4, 6 and 10 months, with 1x, 3x and 6x reactivations respectively. We included both mock transfected and JQ1‐only treated mice as controls.

Result

We found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. One month post reactivation, we harvested multiple brain regions (brainstem, hippocampus, entorhinal cortex, and dural sinus) for RNAseq expression profiling one month after the last reactivation (i.e. latent HSV‐1 infection) to allow for the immune system to clear the active reactivation and observe long‐term changes in gene expression. We found many synaptic genes down regulated in the entorhinal cortex at 10 months, with 6 reactivations, compared to mock infected. We additionally saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways. In the brain stem, where HSV‐1 viral levels were found at higher levels, gene expression patterns showed increase immune‐cell related activity.

Conclusion

Our HSV‐1 reactivation mouse model enables characterization of the impacts of HSV‐1 infections on neuronal gene expression. These changes are consistent with observed changes in gene expression in humans, and help contextualize the putative mechanisms by which HSV‐1 contribute to Alzheimer’s disease etiology.
COVID19 and cognitive impairment ‐ A follow‐up study with cognitive and neuroimaging evaluation of the Clinical Hospital of São Paulo
Authors: Spera Raphael Ribeiro , Luca e Tuma Raphael , Rodrigues Júlia Chartouni , Peixoto Satiko Andrezza Takano , Neto Adalberto Studart , Coutinho Arthur , Miotto Eliane C , Brucki Sonia Maria Dozzi
Published: December 2023

Background

Post‐COVID19 syndrome is characterized by signs and symptoms that occur within 3 months of the onset of COVID19 and last for at least 2 months. Cognitive impairment has frequently been associated with COVID19 with descriptions of attentional, executive, memory, and language disorders. Moreover, some morphological and metabolic changes have been described in MRI and FDG PET‐CT, respectively. There is no formal treatment for this condition.

Method

We selected patients less than 65 years of age with COVID19 at least 3 or more months of symptoms and no more than 6 months, no relevant structural brain lesions, no record of neurodegenerative disease. A cross‐over design study was performed with neuropsychological rehabilitation. They were evaluated 3 times by a neurologist (0, 3, and 6 months) with specific cognitive battery tests and questionnaires and then by a neuropsychologist for evaluation and training. Finally, most patients underwent neuroimaging with cranial MRI and FDG PET CT or MRI.

Result

44 patients performed the first baseline evaluation, 34 matched inclusion criteria and were referred to neuropsychological rehabilitation. 20 underwent functional and structural neuroimaging. This sample had a mean age of 44 (SD8.9) years, 61% of females, 16.1 (SD5.1) years of education, 17.6% of hypertension, 2.9% diabetes, 11.8% dyslipidemia and 23.5% obesity. Cognitive evaluation depicted that 90.6% had memory complaints; MMSE of 27.7 (SD1.8); delayed recall of 8.68 (SD1.6) out 10 in the brief cognitive screening battery; semantic verbal fluency of 18.24 (SD5.1); lexical fluency of 31.7 (SD11.7); forward digit span 6.62 (SD0.7); backward digit span 4.82 (SD 1.3); clock drawing test of 9.12 (SD1.6) and Boston naming test‐15 of 14.06 (SD1.5). 46.9% reported more than 5 points on the depression scale and 41.2% somnolence on the Epworth scale. 60% had abnormal findings (hypometabolism) in brain FDG PET, 16% with frontotemporal involvement, 33% basal ganglia, 8% frontoparietal, 41% cerebellum, 8% parietal only, 8% frontalmedial, and 25% temporal. Some (33%) had mixed patterns.

Conclusion

post‐COVID19 syndrome and cognitive impairment are relatively common and we need prospective studies in low and middle‐income countries to understand the cognitive profile, structural and metabolic patterns in neuroimage, and the role of neuropsychological rehabilitation.
Call for Collecting and Reporting Disaggregated Data for Centering Racial Inclusion and Equity in the U.S. and Globally: Examining Multimorbidity and Risk for Cognitive Impairment in the Asian American Populations
Authors: Zanwar Preeti Pushpalata , Taylor Robyn , Heyn Patricia C
Published: December 2023

Background

Asian American subgroups are underrepresented in Alzheimers Disease and Related Dementias (ADRD) research in the U.S. and globally.

Method

Our approach was threefold: First, we identified data collection and reporting gaps for ADRD among Asian Americans in the U.S from multiple nationally representative surveys, e.g. Health and Retirement Survey, Medical Expenditure Panel Survey, and the Census. Second, we examined multi‐morbidity (e.g. diabetes, hypertension, cardiovascular disease and stroke) burden among a specific group of Asian Americans, South Asian Indians. Third, we provide knowledge gaps and recommendations for inclusion of Asian Americans to center racial equity in ADRD science.

Result

Despite being a highly heterogeneous group and diverse in terms of culture, diet, language, Asian Americans are lumped together in national surveys. The three national surveys we examined in the U.S. have not collected disaggregated data on Asian Americans, a group that is growing in the U.S. Moreover, there is a lack of disease registers for different groups of Asian Americans which makes it difficult to assess and quantify the prevalence and burden of ADRD in this group. Due to a lack of systematic data collection efforts, the extent of dementia burden and classification of dementia cannot be accurately examined in the sub‐groups of Asian Americans. The data gaps in the collection and reporting of data on sub‐groups of Asian Americans prevent from designing culturally and linguistically sensitive interventions which are highly needed for sub‐groups of Asian Americans. South Asian Indians, a sub‐group of Asian Americans, considered to be of higher socioeconomic background in the U.S. were seldom omitted from the minority classification despite having a higher burden of multiple chronic conditions such as diabetes, hypertension, cardiovascular disease, and stroke, i.e. multi‐morbidity combinations which can greatly contribute to increased ADRD risk in this sub‐group.

Conclusion

There is a critical need for the collection and reporting of disaggregated ADRD data on Asian Americans for centering racial equity in ADRD science in the U.S. Such efforts will aid in the understanding of mechanistic pathways for vascular cognitive impairment via inclusion of unique Asian populations that have been underrepresented in ADRD research both in the U.S. and globally.
Identifying human‐relevant genetic interactors of APOE using genetically diverse mouse strains
Authors: Onos Kristen D , Elk Kevin J , Uyar Asli , Keezer Kelly J , Marola Olivia J , Kasper Rachel , Pandey Ravi S , Carter Gregory W , Sasner Michael , Howell Gareth R
Published: December 2023

Background

APOEe4 is the greatest risk factor for late‐onset Alzheimer’s disease (AD), accounting for ∼30% of genetic risk and significantly decreasing age of onset. APOE is implicated to play central roles across multiple pathways such as neuroinflammation, lipid metabolism and vascular health. Current mechanistic work has introduced humanized APOE alleles in mouse models of AD on a single laboratory mouse strain, C57BL/6J (B6). Recent work from our lab has taken advantage of genetically diverse wild‐derived strains which were captured from different geographical regions and then inbred, thus, their genomes are closer to recapitulating combinations that would exist in the natural world. Here, we seek to identify and validate human‐relevant genetic interactors of APOE within these contexts and in the presence of amyloid.

Method

Novel wild‐derived mice were developed by backcrossing the respective strain (PWK/PhJ, WSB/EiJ) to B6.APOEe4 (N5). These were crossed with congenic APP/PS1 carriers, and offspring intercrossed to generate cohorts of 4‐ and 8‐month males and females homozygous for APOEe4, with and without APP/PS1. A cohort of B6.APOEe4 carrying APP/PS1 were also generated for comparison. Neuropathology was assessed along with blood chemistry, and transcriptional profiling was performed on brain hemispheres.

Result

Brain transcriptional profiling revealed that APOEe4 had the greatest impact on differential gene expression (dE) in the PWK genetic context at both timepoints, with the strongest effect in females. Comparison with AMP‐AD human‐derived consensus clusters also indicated the broadest overlap when variants were present in the PWK context. Furthermore, APOEe4 genotype was sufficient to cause neuronal damage at 8 months, despite other studies indicating neuronal resilience to amyloid and aging in PWK. In both WSB and B6 carrying APP/PS1, APOEe4 increased the incidence and severity of cerebral amyloid angiopathy (CAA). Further neuropathological assessments are ongoing, and will be correlated with dE.

Conclusion

This work highlights the importance of assessing risk alleles for AD in a variety of genetic contexts. We have also created genetically diverse panels of mice that carry humanized amyloid beta and humanized tau in that hope that these strains will provide an improved preclinical platform for therapeutic discovery and testing.
Bilingualism is associated with a later age of symptom onset in bilinguals with Alzheimer’s disease positive biomarkers
Authors: Grasso Stephanie M , Marques‐Kiderle Sonia Karin , Calabria Marco , Sala Isabel , Rodríguez‐Baz Íñigo , Zhu Nuole , Arranz Javier , Rubio‐Guerra Sara , Illán‐Gala Ignacio , Carmona‐Iragui Maria , Alcolea Daniel , Fortea Juan , Lleo Alberto , Santos‐Santos Miguel A
Published: December 2023

Background

Cognitive reserve factors may provide protection against the manifestation of symptoms associated with neurodegenerative diseases (Stern, 2012). Although results are mixed, it has been observed that bilingualism may contribute to cognitive reserve by delaying the age of onset of symptoms of Alzheimer’s disease (AD) (e.g., Alladi et al., 2013, 2017; Bialystok et al., 2007, 2010; de Leon et al., 2020).

Methods

In the current study, we examined the effects of bilingualism on age of symptom onset in a large cohort of Catalan‐Spanish bilingual speakers (n = 446) with positive Alzheimer’s disease cerebrospinal fluid biomarkers. We conducted a retrospective study in which participants were characterized as bilingual or monolingual based on self‐report at the time of neuropsychological testing. Analyses of covariance (ANCOVA) were conducted to investigate the association between bilingualism and age of symptom onset while controlling for a proxy of disease severity (Mini‐Mental State Exam (Folstein et al., 1975) and education.

Results

The results of our ANCOVA revealed that Catalan‐Spanish bilinguals with AD positive CSF biomarkers present with a significant, approximate two‐year delay in symptom onset relative to monolingual speakers (see Figure 1; bilingual M = 71.41, monolingual M = 69.75).

Conclusion

Although previous reports in the literature indicate that bilingualism may delay the onset of symptoms on the order of 4‐5 years, we observed an approximate 2‐year difference in the onset of symptoms. This finding is consistent with previous literature conducted in Catalan‐Spanish bilinguals (Calabria et al., 2020) and likely reflects that even ‘monolingual’ speakers in this particular sociocultural context are exposed to more than one language and may exhibit a form of passive bilingualism.
A Randomized, Double‐blind, Sham‐controlled, Adaptive‐Design Pivotal Trial of Sensory Stimulation in Subjects with Alzheimer’s Disease
Authors: Boasso Alyssa , Houser Celine , Hajos Mihaly , Newberger Jennifer , Seshagiri Chandran , Leach Julia , Konisky Alexandra , Galley Alyssa , Hempel Evan , Dickson Samuel P. , Hendrix Suzanne B. , Malchano Zach , Megerian Jonathan Thomas
Published: December 2023

Background

In three prospective clinical trials (Overture: NCT03556280, Etude: NCT03661034, Flicker: NCT03543878) non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation diminished Alzheimer’s disease (AD) symptoms, including a reduction in decline in cognitive and functional symptoms. These trials initiated the design of the Cognito Therapeutics sponsored Hope pivotal trial which examines the safety and efficacy of Cognito Therapeutics’ Sensory Stimulation System.

Method

The US‐based multicenter Hope trial will randomize (1:1) approximately 500 subjects aged 50 and older diagnosed with mild to moderate AD (MMSE 15‐26) and will stratify them to active and sham in a blinded manner across MMSE score ranges: 15‐20 and 21‐26. Subjects in both study arms will self‐administer therapy via the Sensory Stimulation System for 60 minutes daily for 12 months. An interim analysis will employ the promising zone methodology, allowing the sample size to be adjusted if the effect is trending toward success, but additional subjects are needed to maintain greater than 80% power.

Result

The primary outcome measure will be the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS‐ADL) test. Changes in function and cognition will be evaluated using a combined statistical test for ADCS‐ADL and the Mini Mental State Exam (MMSE). The key secondary outcome is change in cognition using the MMSE. Other clinical efficacy assessments include instrumental activities of daily living (IADL), Zarit Burden Index (ZBI), the Clinical Dementia Rating Scale (CDR) and The Neuropsychiatric Inventory anxiety subscale (NPI – Anxiety). Key biomarker assessments include whole brain, white matter, and hippocampal volume and occipital cortical thickness. Sleep fragmentation will be assessed in a subgroup of subjects using actigraphy. Exploratory measures will include additional brain structural change, plasma biomarkers, EEG assessed coherence, and at‐home tablet‐based tasks. Safety will be evaluated via routine clinical laboratory assessments, review of adverse events, concurrent medication use, physical and neurological exams, vital signs, MRI, and a suicidality scale.

Conclusion

The Hope pivotal trial is designed to demonstrate the efficacy and safety of daily in‐home gamma sensory stimulation in AD patients to support a regulatory filing with the FDA.
Assessment of brain oxygen extraction in aging and Alzheimer’s disease with MRI images
Authors: Hosseini Seyyed Ali , Servaes Stijn , Therriault Joseph , Tissot Cécile , Rahmouni Nesrine , Macedo Arthur C. , Lussier Firoza Z , Stevenson Jenna , Wang Yi‐Ting , Arias Jaime Fernandez , Aumont Etienne , Socualaya Kely Quispialaya , Nazneen Tahnia , Stevenson Alyssa , Gauthier Serge , Pascoal Tharick A. , Rosa‐Neto Pedro
Published: December 2023

Background

There is a growing body of evidence suggesting changes in blood flow and metabolism as a trigger of the cascade of events leading to Alzheimer’s disease (AD). Oxygen extraction fraction (OEF) MRI images provide valuable information about the brain’s metabolism and blood flow in stroke, brain injury, and recently neurodegenerative diseases. However, OEF is a research tool, and its clinical utility is still being evaluated. Here, we aimed to assess brain oxygenation in aging and AD using OEF images. We test the hypothesis that OEF reduction is associated with the clinical stages of AD.

Method

A cohort of 310 subjects with cognitively unimpaired (CU) (n = 182), mild cognitive impairment (MCI) (n = 80), and AD (n = 48), were recruited. All participants received 3D gradient‐recalled echo sequence MRI. All OEF images were constructed by QSM+qBOLD model with CCTV (Temporal clustering, tissue composition, and total variation) (Figure1). Eighty‐two various brain regions of interest (ROI) and 6 Braak ROI were investigated in the current study.

Result

Our results demonstrated that the OEF mean value in almost all of the brain ROI encompassed the lowest amount of OEF in AD compared with MCI and CU. In most parts of the brain, the OEF mean value was AD<MCI<CU including bilateral caudate. However, in other parts of the brain, the OEF mean value increased from CU to MCI and then dipped to lower than CU in AD including the bilateral hippocampus, which clearly shows that brain metabolism and blood flow are decreasing in AD (Table1).

Conclusion

OEF is an affordable and relevant non‐invasive MR approach to assess brain metabolism during disease progression or therapeutic interventions. OEF decreased in symptomatic cases. Further studies should explore the mechanisms underlying increased OEF in MCI. Our results support the potential of OEF to improve our understanding of metabolic changes associated with AD pathophysiology.
Cognitive Domains and Functional Assessment Questionnaire (CDFAQ): accuracy and correlation with IQCODE
Authors: Maia Isabelle de Aguiar , Tavares Caio Peixoto , Ferreira Jéssica Diniz , Gomes Giulia Costa , Mutz Bruna Hellen Barbosa , Guerson Giovanna Lins , Diniz Júlia Moreira , Engelmann Gabriela Tomé Oliveira , de Paula Jonas Jardim , Diniz Maissa Ferreira , Romano‐Silva Marco Aurélio , Bicalho Maria Aparecida Camargos , De Mattos Viana Bernardo
Published: December 2023

Background

The Cognitive Domains and Functional Assessment Questionnaire (CDFAQ) assesses cognitive domains and functional decline based on the DSM‐5 criteria for Neurocognitive Disorders. It has two versions, one for the patient (CDFAQ‐PV) and another for the informant (CDFAQ‐IV) assessing: Complex Attention (CA), Executive Functions (EF), Learning and Memory (LM), Language (L), Perceptual‐Motor Domain (PM) and Social Cognition. Recently, the CDFAQ was translated and adapted to English.

Method

To describe the performance of the CDFAQ‐PV and CDFAQ‐IV assessing Brazilian older adults compared with the Informant Questionnaire on Cognitive Decline in the Elderly Long Version – IQCODE‐LV. This study was approved by the ethical committee of the UFMG and the CDFAQ was applied to 132 subjects in the University Hospital. The CDFAQ‐PV was applied to 66 older adults and the CDFAQ‐IV, as well as the IQCODE‐LV, to their 66 respective informants. Non‐parametric correlation with IQCODE‐LV and accuracy assessment by Receiver Operating Characteristic (ROC) with cutoff for dementia were performed.

Result

The median age of the patients was 70.5 years (IQR = 13.5) and 5 years of schooling (IQR = 7), while the informants had a median age of 55 years (IQR = 24.5) and 12 years of schooling (IQR = 8). The CDFAQ‐IV showed a strong positive correlation (Rho:0.708, p<0.001) to IQCODE‐LV. Interestingly, the LM Domain had an even higher positive correlation (Rho:0.758, p<0.001), while the CDFAQ‐PV had moderate (Rho:0.405, p = 0.001) and its LM Domain had a weak (Rho:0.348, p = 0.004) positive correlations. The CDFAQ‐IV had a good area under the curve (0.871) as well as its LM (0.861), L (0.832), EF (0.854) Domains, while SC, PM were considered only fair. The cutoff values were assessed by Youden’s J statistics: CDFAQ‐IV Total score ≥66.5 (SE:88.9%; SP:89.6%) and the LM Domain score ≥11,5 (SE:88.9; SP:77.1%) had the best performances.

Conclusion

The strong correlation of the CDFAQ‐IV and its LM Domain to the IQCODE‐LV, as well as the good area under the curve, points a good accuracy for assessing neurocognitive disorders when applied to their informants. Nevertheless, this is still preliminary data, and more assessments in different scenarios, as well as, comparing with objective cognitive assessment is still needed.
Perseverations and switching during a verbal fluency task
Authors: Dubey Neha , Basu Jayanti , Ghosh Amitabha
Published: December 2023

Background

Perseverations during a verbal fluency task can be immediate or delayed. There is a general agreement that delayed perseveration may occur due to impaired working memory (WM). However, experiments to establish this have been complex and time consuming. It is also not known if perseverations are caused by similar mechanisms of impairment in WM in healthy controls and in the cognitively impaired. On a semantic fluency task, switching between subcategories produces an automatic self‐generated interference. Impairment in WM capacity may lead to perseveration when switchback to a previous subcategory occurs. The number of switches preceding this switchback may also be considered to extend the WM load and result in perseveration. We hypothesize that individuals with WM impairment (aMCI and AD) are likely to perseverate only after few initial switches. In contrast, a healthy control (HC), with a relatively intact WM, may have fewer perseverations for similar number of switches and may be able to sustain more switches quantitatively.

Objective

To study how clusters and switches during verbal fluency tasks can help understand WM contributions to perseveration in patients with cognitive impairment as opposed to cognitively normal controls.

Method

We studied three groups, aMCI (n = 30), AD (n = 30) and HC (n = 60) based on their performance on a semantic fluency task along with tests of executive function. Our primary analysis, focussed on number of switches in between subcategories of index word and first perseverative error. Additionally, average word distance between the two was analysed. Finally, relationship between perseveration, switching and switch back was also studied.

Results

Forty‐eight percent of perseverative errors occurred after the third switch for individuals with cognitive decline. In contrast, thirty‐five percent of cognitively healthy perseverated after three switches and forty‐three percent after five. Further, perseverations in HC group, were found to be more attributable to longer subcategory lists exceeding the normal word list span, even within the same cluster. Finally, at a given distance between index word and perseveration, cognitively impaired performed hierarchically worse than HC.

Conclusion

These findings suggest that switching across subcategories creates self‐generated interference which further amplifies working memory impairment among the cognitively impaired.
A role of tau‐induced astrocyte dysfunction and senescence in AD
Authors: Makhlouf Haneen , Dorigatti Angela O , Hussong Stacy A , Perez Viviana , Kayed Rakez , Galvan Veronica
Published: December 2023

Background

Under certain conditions and during aging, cellular stress and damage can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescent‐associated secretory phenotype” (SASP). In Alzheimer’s disease (AD), neuronal tau becomes hyperphosphorylated and misfolded, forming pathogenic soluble aggregates (tau oligomers) and destabilizing the microtubule cytoskeleton. Pathogenic soluble tau is released from neurons during neuronal activation and is transmitted in a prion‐like fashion to postsynaptic cells. In addition to neurons, tau is expressed in a variety of brain cell types including astrocytes. In the present study, we tested the central hypothesis that soluble pathogenic tau can be transmitted to astrocytes and that tau transmission to astrocytes induces cytoskeleton destabilization and cellular dysfunction, contributing to the progression of AD.

Methods

To test the molecular consequences of tau transmission, we treated primary human astrocytes with purified tau oligomers. We used advanced biochemical tools, immunocytochemistry, and live‐cell microscopy to measure cell and nuclear size, cell cycle arrest, and SASP activation. We also co cultured human astrocytes undergoing tau‐induced senescence with primary mouse or non‐human primate neurons to determine the functional impact of senescent astrocytes on neurons, then utilized immunocytochemistry and 3D image analyses to measure parameters of dendrite and spine morphology.

Results

We found that pathogenic soluble tau is readily transmitted to primary human astrocytes, and that pathogenic tau transmission triggers phosphorylation of endogenous astrocyte tau, leading to the destabilization of the microtubule cytoskeleton. Further, we found that transmission of pathogenic tau to astrocytes potently upregulated multiple markers of cellular senescence, demonstrating for the first time tau‐induced astrocyte senescence. Density of dendritic spines and dendritic area were pronouncedly decreased in neurons co‐cultured with astrocytes undergoing tau‐induced senescence.

Conclusion

We showed transmission of pathogenic tau to human astrocytes and that this event triggers astrocyte senescence in mouse models of AD tauopathy. Our data suggest that senescent astrocytes may be critical mediators of neuronal dysfunction in AD tauopathy.
Genetic overlap between cortical brain morphometry and frontotemporal dementia risk
Authors: Diaz‐Torres Santiago , Ogonowski Natalia , García‐Marín Luis M , Bonham Luke W. , Duran‐Aniotz Claudia , Yokoyama Jennifer S. , Renteria Miguel E.
Published: December 2023

Background

Frontotemporal dementia (FTD) has a complex genetic aetiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown.

Method

We leveraged summary‐based data from genome‐wide association studies (GWASs) and performed LD‐score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolate specific genomic loci with a shared aetiology between FTD and brain structure. We also performed functional annotation, summary‐based‐data Mendelian randomisation for eQTL using human peripheral blood and brain tissue data and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes.

Result

Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified five brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified eight protein‐coding genes. Building upon these findings, we show in a mouse model of FTD that cortical NSF expression decreases with age.

Conclusion

Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the aetiology of FTD.
Towards the Biomechanics of Alzheimer’s Disease: Computational Models
Authors: Saeidi Saeideh , Terzano Michele , Holzapfel Gerhard A.
Published: December 2023

Background

Physical changes in the brain microenvironment are highly associated with changes in mechanosensitivity of neuronal cells and mechanical properties of brain tissue. The progression of amyloid plaques and neurofibrillary tangles in the brain network significantly affects brain microstructure in Alzheimer’s disease (AD). To better understand the underlying mechanisms of AD, it is crucial to explore the effect of neuropathologies that cause brain tissue softening.

Method

We propose a microstructural model of brain white matter characterized by axons embedded in an extracellular matrix (ECM). The microscale is described by a representative volume element and includes features such as mechanical properties of axons and ECM, distribution of axon diameters, and axon tortuosity from experimental observations. The aim of this work is to investigate how the presence of β‐amyloid as hard senile plaques in the ECM and neurofibrillary tangles leads to softer mechanical properties of the brain during AD. The model is validated by simulating healthy brain tissue and comparing the homogenized response with existing experimental data.

Result

Preliminary analyses to validate the model have shown tissue behavior similar to that seen in the mechanical experiments. In the case of AD, as expected, changes in the mechanical properties of the ECM due to the presence of hard senile plaques, demyelination due to the detachment of hyperphosphorylated tau proteins and neuronal death significantly affect the material properties at the macroscale.

Conclusion

The combination of computational mechanical models with experimental observations opens a window to assess the structure‐function relationship of brain tissues in neuropathological disorders, which may be particularly useful to precisely design biomarkers for early detection or more informed therapeutic strategies.

References

• Schäfer, J. Weickenmeier, and E. Kuhl, “The interplay of biochemical and biomechanical degeneration in Alzheimer’s disease”, Comput. Methods Appl. Mech. Eng., vol. 352, pp. 369‐388, 2019.

• M. Hall, E. Moeendarbary, and G.K. Sheridan, “Mechanobiology of the brain in ageing and Alzheimer’s disease”, Eur. J. Neurosci., pp. 1‐28, 2020.

• Budday, G. Sommer, C. Birkl, C. Langkammer, J. Haybaeck, J. Kohnert, M. Bauer, F. Paulsen, P. Steinmann, E. Kuhl, G.A. Holzapfel, “Mechanical characterization of human brain tissue”, Acta Biomater., pp. 319‐340, 2017.
Integrative omics studies to discover genetic determinants of brain cell type proportions
Authors: Reddy Joseph S. , Allen Mariet , Patel Tulsi , Quicksall Zachary , Wang Xue , Carnwath Troy , Min Yuhao , Golde Todd E , Ertekin‐Taner Nilufer
Published: December 2023

Background

Neurodegenerative disorders affect different brain regions at different time points and to varying degrees, although the underlying reasons for this variability in regional susceptibility is unknown. Brain regions have different proportions of cell types. This cell proportion variability may be further influenced by presence and degree of brain disorders, including neurodegenerative diseases. We postulate that genetic and other factors that influence brain cell type proportions may also provide insights into brain regional susceptibility to neurodegenerative diseases.

Methods

Utilizing bulk transcriptomics data from 7 brain regions obtained from 3 cohorts and corresponding whole genome sequencing (WGS) data, genetic variants were evaluated for association with cell type proportions across brain regions. Utilizing cell type specific marker genes for deconvolution provided by McKenzie et.al, we estimated surrogate variables for proportion (SVP) of various cell types using BRETIGEA. We then evaluated relationship between SVP and AD as well as Age, Sex, APOE ε4 and neuropathology measures. Genetic variants from WGS were then tested for association with SVP to identify distinct and conserved patterns across 6 cell types and 7 brain regions.

Results

Analysis of SVP by diagnosis, sex, age, APOE ε4 and neuropathology measures identified significant differences in cell proportions in various cell types and brain regions. GWAS of SVP identified 134 loci that reached genome‐wide significance (5e‐8). After conservative adjustment for multiple testing (6 cell types and 7 brain regions; 42 tests), variants proximal to SYNPR and VENTXP7 remained significant (p‐value<1.19E‐09). Variants proximal to SYNPR were associated with increased proportion of oligodendrocytes in cerebellum whereas variants near VENTXP7 were associated with reduced proportion of astrocytes in DLPFC. Variants in SYNPR have previously been associated with neurofibrillary tangles and diffuse plaque measurements while variants in VENTXP7 have been associated with measurement of neurofibrillary tangles, cognitive decline, unipolar depression, and bipolar disorder.

Conclusions

It is likely that there are genetic variants associated with cell proportion in brain, may vary by cell type and brain region, while others may act more broadly. Identification of genetic variants associated with cell proportions in different brain regions may provide insights into affected cells and regional vulnerabilities.