bluuebunny/crossref_metadata_2025 huggingface dataset:
Piloting a research registry for dementia: The Egyptian Dementia Network (EDN) registry
Authors: Heikal Shimaa Adel
Published: December 2023

Background

Dementia and aging problems are currently growing worldwide and are considered public health priorities. The availability of epidemiological and clinical data on the disease greatly impacts our understanding of the disease and, hence, improves disease management and prevention strategies. As part of the development of a national dementia registry for Egypt that would be of great importance as we currently lack the exact epidemiological data and rely only on estimates, the present study is aiming to pilot a cohort for the first national registry for dementia in Egypt, The Egyptian Dementia Network (EDN) registry.

Method

EDN will provide a huge set of data as a promising platform for analyzing the prevalence, incidence, and major causes of the disease in Egypt. Our study will coordinate the track of early‐onset AD (EOAD) and vascular dementia cases, which have recently shown a rising pattern, based on the first 100 cases from each cohort and a similar number of matched controls collected from different centers across Egypt.

Result

As a first stage, we developed an SOP for the registry workflow, a network of collaborating centers, and a unified sheet for data collection (both clinical and epidemiological). We will then develop a tool to register the collected data. The use of big data analytics will help analyze the collected data and identify the major causes of dementia in Egypt.

Conclusion

As a research registry, the main aim is to start understanding the causes, mechanisms, and courses of dementia in Egypt. The final long‐term goal is to validate the predictive ability of the registry data on the Egyptian HCAP (Harmonized Cognitive Assessment Protocol), where the ability of data to predict future dementia patients will be tested on a longitudinal cohort of aging population.
A novel Presenilin 2 mutation in two siblings with predominantly amnestic, early‐onset Alzheimer’s disease
Authors: Leochico Carl Froilan D. , Oliveira Ana Luiza Pinto , Masellis Mario , Mitchell Sara
Published: December 2023

Background

Familial, early‐onset Alzheimer’s Disease (AD) is a rare form of dementia resulting from autosomal dominant mutations in the amyloid precursor protein (APP), presenilin‐1 (PSEN1), or presenilin‐2 (PSEN2) genes with phenotypic diversity. PSEN2 mutations are rare and vary widely in age of onset.

Method

Case report and literature review.

Result

We report a novel PSEN2 variant (c.359T>G, p.Ile120Ser) that has been clearly segregated in two siblings in their fifties, presenting as predominantly amnestic AD. One of the siblings was also heterozygous in the PSEN1 gene (c.118_120del, p.Asp40del). There was no evidence of C9orf72 repeat expansion in either sibling. A third sibling has also started manifesting cognitive impairments. Their strong family history of cognitive dysfunction suggests that the PSEN2 mutation is pathogenic, and the causative variant has never been reported in Medline and the Alzgene genetic database of PSEN2.

Conclusion

As there are numerous PSEN2 mutations still incompletely characterized, there remains a need to systematically report patients either with familial or sporadic presentation and very early age of onset and classify their pathogenicity accordingly. Providing information about the genetic bases of AD can help allay the stress of patients and families about their diagnosis, individual risks, and possible care planning.
Lack of TREM2 and TYROBP effects on microglial homeostasis, activation and disease
Authors: Quipildor Gabriela E. Farias
Published: December 2023

Background

Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions in the brain, playing roles in neurotoxicity/neuroprotection – and in release of inflammatory and anti‐inflammatory cytokines – as well as roles in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that leads to intracellular signaling networks, and these proteins are important regulators of the transition from homeostatic microglia to its activation states. Recent findings have proposed a TYROBP‐dependent and TREM2‐independent molecular signature that is involved in the early transition step from homeostatic to disease‐associated microglia (DAM). Interestingly, the sequential step of DAM activation is TREM2‐dependent. However, the underlying mechanisms that determine how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown.

Method

We have isolated primary microglia from C57BL/6 wild‐type (WT) controls, Trem2 knock‐out (KO) and Tyrobp KO mice at post‐natal day 0‐3. Cells were stimulated with Alzheimer’s disease (AD)‐relevant provocations, such as amyloid beta (Aβ) oligomers, or ‘inflammatory’ stimuli, such as lipopolysaccharides (LPS). We explored protein and gene expression in the presence or absence of inhibitors within the TREM2/TYROBP downstream signaling pathway. We also performed immunofluorescence and functional assays.

Result

Our results show that absence of either TREM2 or TYROBP is associated with increased basal levels of the phosphorylation state of ERK in primary microglia, when compared to WT controls. In addition, TREM2 KO and TYROBP KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Ab oligomers or LPS leads to differential protein as well as gene expression outcomes in cells that lack either TREM2 or TYROBP.

Conclusion

The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggests their important roles not only in microglial homeostasis but also in the activation processes in response to different stimuli. Future goals include the investigation of the roles that these proteins play in the mechanisms underlying microglial activation in different contexts. We ultimately aim to identify potential therapeutic targets that could contribute to the delay or treatment of AD pathology.
Racial Differences in Inpatient Hospital Services Utilization and Expenditure between American Indian and Alaska Native and non‐Hispanic White Older Adults with Dementia
Authors: Abdulsalam Ruqoyat , O'Connell Joan , Jiang Luohua
Published: December 2023

Background

While American Indian and Alaska Native (AI/AN) and non‐Hispanic white (White) adults are at high risks for dementia, little is known about hospital utilization and expenditures among AI/ANs and Whites with dementia. The goal of this study is to examine characteristics associated with inpatient hospital services utilization and expenditures among AI/AN and White older adults with dementia, to understand what factors contribute to differences in utilization and expenditures between the two populations.

Method

We analyzed data on demographic characteristics, health coverage, chronic disease status, hospital utilization and expenditures from the CMS 2019 Medicare Master Beneficiary Summary File for all AI/AN (n = 16,324) and a 5% random sample of White (n = 139,335) adults aged ≥65 who had dementia in 2019. To examine associations between patient characteristics with utilization and expenditures, we employed Poisson and negative binomial models for utilization measures (1+ hospitalizations and number of inpatient hospital days) and a two‐part model (a gamma distribution with a log‐link function) for expenditures, while stratifying by race.

Result

AI/AN adults were younger than White adults; a larger percentage were dually enrolled in Medicaid, had diabetes and ESRD, and lived in a rural county (p<0.01). Medicaid coverage is associated with higher inpatient hospital days and expenditures among AI/ANs (Incidence Rate Ratio (IRR) = 1.079; Marginal Effect (ME) = $3,313, p<0.01) but is associated with lower days and expenditures among Whites (IRR = 0.874; ME = ‐$1,438, p<0.01). The association between living in a rural county with expenditures followed a pattern similar to that of Medicaid coverage. Unadjusted mean hospital days and expenditures were 4.84 and $27,559 (AI/ANs) and 3.86 and $23,009 (Whites), respectively. When data for AI/ANs and Whites were combined, the average marginal expenditure for AI/ANs, compared to Whites was $4,550 in unadjusted model, but reduced to $2,772 when we adjusted for age, gender, comorbidities, and social determinants of health.

Conclusion

Understanding and addressing characteristics associated with racial differences in hospital use and expenditures among dementia patients may be helpful for health care resource planning and efficient use. In‐depth research is required to understand the contrasting differences in the impact of Medicaid on expenditures between AI/AN and White adults with dementia.
Moderate to Vigorous Physical Activity Protects Deep Learning Derived Brain Volumes in 9637 Individuals
Authors: Raji Cyrus A. , Meysami Somayeh , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Nguyen Thanh Duc , Gouda Ahmed , Chodakiewitz Yosef Gavriel , London Sean , Merrill David A. , Attariwala Raj
Published: December 2023

Background

Regular physical activity has been linked to a reduced risk of dementia, while loss of brain volume as measured by MRI is a marker of neurodegeneration. However, it remains unclear whether engaging in moderate or vigorous physical activity has any positive impact on brain structure and potential neuroprotective effects.

Method

A total of 9637 healthy participants were scanned across four 1.5T MRI machines with a whole‐body MR imaging protocol. Brain sequences included isotropic MP‐RAGE. An ensemble of three Deep learning models corresponding to each axial, sagittal, and coronal views with FastSurfer architecture was trained on 134 participants aged 27‐66 segmented 96 brain regions. Partial correlations modeled moderate to vigorous physical activity, defined as sports, fitness and recreational activities that increased respiration and pulse rate for at least 10 continuous minutes, with brain volumes. Analyses controlled for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% accounted for multiple comparisons.

Result

Average age was 52.98 ± 13.06 years ranging from 11‐97 years with 52.5% biologically male. Overall, 7215 individuals (74.8%) reported moderate or vigorous physical activity on average 4.03 ± 3.48 days per week. Persons with vigorous activity were slightly older (mean age 54.3 versus 52.5 years) for non‐vigorous physical activity (p < .00001) and 54.8% men versus 45.2% women undertook moderate to vigorous physical activity compared to 45.4% men and 54.6% women. Fewer women engaged in moderate to vigorous physical activity compared to men (p = 9.92e‐16). Accounting for age, sex, and intracranial volume co‐variates and multiple comparisons, moderate to vigorous physical activity predicted larger volumes in multiple regions including: total gray matter volume (Partial R = 0.09, p = 2.59e‐18), total white matter volume (Partial R = 0.09, p = 4.21e‐19), hippocampus (Partial R = .098, p = 1.4e‐21), frontal cortex (Partial R = 0.08, p = 1.06e‐15), parietal lobes (Partial R = 0.055, p = 9.01e‐8), occipital lobe (Partial R = 0.071, p = 5.27e‐12). Whole brain volumes of gray matter and white matter were also larger with an increasing number of days engaged in moderate to vigorous physical activity (Partial R = 0.105, p = 6.31e‐25).

Conclusion

Engagement in moderate to vigorous physical activity was found to be associated with increased brain volumes, a metric of neural health.
Longitudinal genome wide association studies in Alzheimer’s disease
Authors: Zhuang Xiaowei , Xu Gang , Amei Amei , Oh Edwin
Published: December 2023

Background

A large number of subjects are generally required for the genome wide association studies (GWAS) in complex traits such as Alzheimer’s disease (AD)1,2. Here we incorporated longitudinal data in AD‐GWAS to improve the statistical power for the identification of AD‐associated genetic variants with a limited sample‐size. Time‐varying genetic contributions towards AD could also be modeled and captured in this longitudinal GWAS.

Method

1,877 subjects from the ADNI database3 with genotyping data available were included in this analysis. Subjects’ genotype data were imputed to the Haplotype Reference Consortium using the Michigan Imputation Server4, with 9,573,130 single nucleotide polymorphisms (SNPs) remaining after the quality control step. Subjects’ longitudinal diagnosis at each visit were obtained from ADNI, providing 10,832 phenotypes for 1,877 subjects. Subjects’ diagnoses were further binarized into the normal and diseased groups. We applied the retrospective varying coefficient mixed model association test (RVMMAT) to detect time‐varying genetic effect on this longitudinal binary phenotype5. Briefly, dynamic genetic effect was modeled using smoothing splines and estimated by maximizing a double penalized quasi‐likelihood function via a retrospective approach. Subjects’ sex, age at each diagnosis, and the first 5 principal components of whole genome were included as covariates. A categorical variable for genotyping platforms was included as an additional covariate.

Result

RVMMAT showed no evidence of inflation in the quantile‐quantile (Q‐Q) plot, with an inflation factor (lambda) of 0.99 (Fig. 1A). 45 SNPs reached genome‐wide significance after false discovery rate correction for multiple comparisons (Fig. 1(B)). Among these genetic variants, 35 SNPs were clustered at the APOE, APOC1, TOMM40, and NECTIN2 genes on chromosome 19, and 6 SNPs were associated with SLAIN2 gene on chromosome 4.

Conclusion

We demonstrate that RVMMAT could boost the statistical power in AD‐GWAS with a limited sample‐size. We expect this method to benefit the identification of genetic variants associated with pathological or clinical biomarker‐based longitudinal phenotypes in AD.
Screening of risk factors for Alzheimer’s disease in the general population in peripandemic
Authors: Brusco Luis Ignacio , Olivar Natividad , Dunovits Cynthia , Germani Sandra
Published: December 2023

Background

Since the start of the Covid‐19 Pandemic in 2020, we have seen interrupted outpatient care services for long periods of time, which has generated complications related to this new scenario: appearance of disorders neuropsychiatric disorders, complication in existing pictures, etc. The group of older adults has been more vulnerable in terms of the possible consequences of exposure to the virus without counting with immunization. Configuring a prone scenario to generate the increase in prevalence of risk factors for dementia of the Alzheimer type. The lack of information and the massiveness of the problem, added to the course of the peripandemic, requires a modification approach strategies, facilitating access to diagnostic and treatment services, constituting a new strategy adapted to a changing and dynamic demand.

Method

Semi‐structured interviews with epidemiological and clinical variables are carried out charge of medical personnel; and MMSE in charge of Neuropsychologists. data analysis and interweaving of variables.

Result

144 subjects attend, with an average age of 66.69 years, 92.37% present risk factors, the most frequent from the clinic: dyslipidemia, hypertension and diabetes; 75% presents mood, behavioral and/or cognitive disorders; 90.75% present evolution of more than a year; 20.83% of the contestants require a more complete ENC because they are below the cutoff for MMSE.

Conclusion

Social isolation, lack of medical controls and affective changes were triggers of cognitive impairment
Plasma Total‐Tau is Related to Risk of Heart Failure in the Community
Authors: Aparicio Hugo J , Himali Dibya , Pase Matthew P. , McGrath Emer R , Lioutas Vasileios‐Arsenios , Beiser Alexa S. , Vasan Ramachandran S , Seshadri Sudha , Himali Jayandra Jung
Published: December 2023

Background

Tau is mainly expressed in the neurons of the central nervous system, with elevated cerebrospinal fluid and plasma levels noted when pathologic extracellular aggregation of tau occurs in the setting of neurodegeneration. Plasma tau and phosphorylated tau species are currently being studied as biomarkers for diagnosis, prognosis, or to measure susceptibility risk for conditions such as Alzheimer’s disease. However, the potential for circulating tau protein or other toxic entities upstream or along the tau pathway to cause cardiac dysfunction via protein misfolding or abnormal aggregation has only received limited study.

Methods

We evaluated the association of plasma total‐tau and risk of congestive heart failure in a community‐based sample from the prospective Framingham Heart Study. Adult participants free from clinical heart failure at time of blood sample (Exam 8, 2005‐2008) were included. Participants with renal failure or on dialysis were excluded. Plasma total‐tau was measured using the Simoa platform. Total‐tau plasma values were natural log‐transformed to approximate a normal distribution. Using Cox regression models, total‐tau was related to incident congestive heart failure (up to 2019), adjusting for age and sex (Model 1) and additionally adjusting for cardiovascular risk factors: systolic blood pressure, prevalent diabetes, antihypertensive medication use, smoking status, total cholesterol‐to‐high density lipoprotein ratio, and prevalent atrial fibrillation (Model 2).

Results

We studied 2792 participants (mean age 67±9 years, 55% women) over a mean follow‐up period of 10.7±3.2 years (Table 1). There were 215 incident cases of heart failure. Each standard deviation unit increase in the log of plasma total‐tau was associated with a 42% increased risk of incident heart failure (95% confidence interval:1.26‐1.61; p<0.0001) in Model 2 (Table 2). Among individuals with plasma total‐tau values in the top quintile compared to the bottom four quintiles, risk for incident heart failure was increased by 69% (1.26‐2.28; p = 0.0005).

Conclusion

Elevated levels of plasma total‐tau at baseline in this community‐based sample were associated with incidence of congestive heart failure. Circulating tau protein, or possibly byproducts of related neurodegenerative pathways, may represent a shared substrate of protein misfolding, in the brain and the heart, resulting in Alzheimer’s disease and heart failure.
Alzheimer’s disease induces pathological changes in the lungs of humans and the AppNL‐G‐F mouse model
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Ambhore Nilesh , Venkatachalem Sathish , Combs Colin K
Published: December 2023

Background

Alzheimer’s disease (AD) is an age‐related neurodegenerative disorder characterized by brain accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, neuron death, robust gliosis, and neuroinflammation, affecting around 35 million individuals worldwide. It is well known that brain immune changes are a component of the disease, but immune dysfunction in secondary organs has also been reported. To assess peripheral immune changes in AD, we asked whether lung dysfunction and inflammatory change are present during the disease.

Method

Male and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were sacrificed, and broncho‐alveolar lavage fluid (BALF) and lungs were collected. BALF was used to quantify immune cell phenotype by flow cytometry, and the BALF supernatant was used to determine Aβ and cytokine concentrations and total protein content. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue and Masson’s trichrome. In addition, lung sections from wild‐type and AppNL‐G‐F mice and human AD patient and healthy controls were immunostained for APP, Aβ and claudin 4.

Result

AD mice showed significantly increased pulmonary airway thickening and mucus and collagen production as indicated by hematoxylin and eosin, Alcian blue and Masson’s trichrome staining, respectively, compared to the wild‐type controls. Female but not male AppNL‐G‐F
mice also demonstrated reduced B cell and neutrophil numbers and elevated IL‐1β in their BALF compared to controls. Although there were no differences in BALF supernatant total protein content between wild‐type and AppNL‐G‐F
mice, lungs from both sexes of AppNL‐G‐F
mice had decreased claudin‐4 immunoreactivity suggesting altered epithelial permeability. BALF supernatant from male and female AppNL‐G‐F
mice also contained soluble Aβ1‐40 and Aβ1‐42 correlating with lung APP immunoreactivity. Human AD male and female lungs had reduced claudin‐4 immunoreactivity and increased APP and Aβ staining compared to controls verifying lung changes are also present in human disease.

Conclusion

These data demonstrate disease‐associated changes in the lungs of both human AD patients and the AppNL‐G‐F
mouse model. Further characterization of lung dysfunction and its contribution to brain changes may define a novel lung‐to‐brain contribution to disease.
SEX EFFECTS ON THE QUALITY OF SLEEP IN DOWN SYNDROME
Authors: Giménez Sandra , Clos Susana , Bejanin Alexandre , Carmona‐Iragui Maria , Arranz Javier , Benejam Bessy , Videla Laura , Fernandez Susana , Rodríguez‐Baz Íñigo , Barroeta Isabel , Lleo Alberto , Fortea Juan
Published: December 2023

Background

Sex differences in biological factors, such as sleep, might contribute to sex differences in dementia risk. Down’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), with disrupted sleep and a high prevalence of obstructive sleep apnea (OSA). However, sex differences in nocturnal sleep in adults with DS have not been yet investigated. Thus, we aimed to evaluate the sex effect on polysomnographic sleep measures in adults with DS.

Method

Cross‐sectional study of 187 adults with DS from the Down‐Alzheimer Barcelona Neuroimaging Initiative (DABNI) that underwent a nocturnal polysomnography study. Sleep macrostructure parameters of i)sleep continuity [Total sleep time(TST), Sleep efficiency(SE), Wake after sleep onset(WASO), Sleep latency and latency to REM sleep], ii) NREM (phase N1, N2, N3) and REM stages, in minutes and percentages, and iii) respiratory parameters to determine the presence of OSA were evaluated. Chi‐squared and Mann‐Whitney tests were used to test differences between categorical data, and continuous variables, respectively. To evaluate the sex effects on sleep parameters, we performed ANCOVAs using sleep measurements as dependent variables, the sex, presence of dementia, and OSA as fixed effects, and age as a covariate. Interactions between subjects effects were aso calculated

Result

Our cohort includes 187 adults with DS (57,2% females and 42.8% males). OSA was present in 76,2% of the subjects, and 22% of the subjects had symptomatic AD (prodomal/demented) without significant differences in both prevalences between sexes(p = 0.23, p = 0.08 respectively) (table 1). Females presented significant longer TST, WASO, NREM (m), N2(m), N3(m), with higher SE and N3(%), and decreased N1(%) compare to males. These sex differences were maintained after age correction. Results remain essentially similar when including dementia and OSA in the statistical models. No significant interactions between sex and OSA and sex and dementia were observed(Table2).

Conclusion

As in general euploid population, females with DS presented a better objective sleep quality with more deep sleep than men. Further work is needed to investigate how sex differences in sleep parameters can influence clinical and biomarker profiles of AD in adults with Down syndrome.
Interactions of synaptic and inflammatory biomarkers in Alzheimer’s Disease
Authors: Rahmouni Nesrine , Tissot Cécile , Servaes Stijn , Therriault Joseph , Macedo Arthur C. , Stevenson Jenna , Lussier Firoza Z , Machado Luiza Santos , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Alyssa , Socualaya Kely Quispialaya , Kunach Peter , Nazneen Tahnia , Hosseini Seyyed Ali , Gauthier Serge , Karikari Thomas K , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R , Rosa‐Neto Pedro
Published: December 2023

Background

The sequential model predicts synaptic depletion as a downstream of amyloid, tau and neuroinflammation. However, synaptic toxicity might be consequence of toxic forms of amyloid in the absence of tau. In this study we explore the role of synaptic depletion and neuroinflammation as determinants of tau pathology. GAP‐43 and neurogranin are pre‐ and post‐synaptic biomarkers known to be detected at elevated levels in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD).

Method

We included 126 individuals from TRIAD cohort. Brain inflammation, tau tangle and amyloid‐β (Aβ) deposition were assessed via [11C]PBR28‐PET, [18F]MK6240‐PET and [18F]AZD4694‐PET, respectively. All patients had plasma GFAP quantified, and a subset of 78 individuals had CSF GFAP, CSF Neurogranin and CSF GAP‐43 quantifications available. Voxel and region of interest regression models evaluated the relationship between PET tracers and the fluid biomarkers. Models with [18F]AZD4694‐PET as the outcome were adjusted for [18F]MK6240‐PET voxel‐wise and vice‐versa. A linear regression interaction model evaluated the interaction between CSF GFAP and both synaptic biomarkers with Aβ‐ and tau‐PET as the outcome.

Result

Positive associations were found between CSF neurogranin and Aβ‐, tau‐ and brain inflammation‐PET in AD related regions; the strongest associations were found with tau‐pet and CSF neurogranin in the medial temporal lobe. GAP‐43 was also positively associated with tau‐ and TSPO‐PET, but no associations were found with Aβ‐PET. Both plasma and CSF GFAP were associated with Aβ‐, tau‐ and TSPO‐PET in AD related regions, with the strongest t‐values in the model including plasma GFAP and amyloid‐PET. A negative interaction was found between CSF GFAP and both synaptic biomarkers with amyloid‐ and tau‐PET as the outcomes. These associations were stronger with tau‐PET and were found in the temporal, occipital and parietal areas.

Conclusion

This study supports the role of synaptic dysfunction and neuroinflammation on tau load. As both synaptic biomarkers and GFAP increase as a function of tangles load, tau accumulation is linked to the relationship between synaptic abnormalities and inflammation in early stages of the disease. Our results suggest that synaptic depletion is a phenomenon that might start prior to tau tangles.
123I‐Ioflupane SPECT Striatal Binding Ratio Predicts Progression of Parkinsonism in a Dementia with Lewy Bodies Cohort
Authors: Maly Emily F , Leverenz James B , DiFilippo Frank A
Published: December 2023

Background

The criteria for diagnosis of dementia with Lewy bodies (DLB) remain predominantly clinical. However, use of striatal dopamine transporter visualization is suggested as an “indicative” biomarker for DLB under the most recent published DLB criteria (McKeith, Neurology, 2017). The objective of this study is to determine if 123I‐ioflupane SPECT (DaTscan) striatal binding ratio (SBR) correlates with parkinsonian symptoms measured on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale Part III (MDS‐UPDRS‐III) in patients with either probable DLB or high‐likelihood DLB individuals with mild cognitive impairment (MCI). A secondary aim of this study is to determine if DaTscan SBR measured at baseline can predict progression of parkinsonian symptoms over 2 years in this study population.

Methods

This is a retrospective cohort study using the U.S. Dementia with Lewy Bodies Consortium (DLBC) dataset (U01 NS100610). The sample group included in this study are individuals with either probable DLB (McKeith, Neurology, 2017) or MCI‐LB (McKeith, 2020). Each participant had a baseline DaTscan analyzed with DaTQUANT software and physical examination scored with MDS‐UPDRS‐III. Participants without these data were excluded. Mixed effect models were fit with UPDRS score as the dependent variable and SBR z‐score as the primary independent variable. Data were adjusted for age, gender, diagnosis, and dopaminergic medication at time of examination.

Results

An analysis between 53 participants’ baseline MDS‐UPDRS‐III and SBR z‐scores revealed a moderate negative correlation, indicating SBR is a significant predictor of baseline MDS‐UPDRS‐III score. An analysis between 23 participants’ baseline SBR z‐scores and 24‐month MDS‐UPDRS‐III revealed a moderate negative correlation, indicating that baseline SBR is a significant predictor of 24‐month MDS‐UPDRS‐III scores.

Conclusion

These data reveal a significant relationship between DaTscan SBR and motor examination in DLB. Additionally, there is a significant relationship between baseline SBR and progression of parkinsonian features. We conclude that in DLB, DaTscan at time of diagnosis could be used to confirm underlying dopamine deficiency in the context of clinical parkinsonism and predict progression of parkinsonian symptoms in DLB. This could aid in guiding therapies and prognostication of symptom progression.
Longitudinal cognitive change in older adults with elevated tau PET signal in the absence of amyloid
Authors: Weigand Alexandra J. , Thomas Kelsey R. , Edwards Lauren C. , Bondi Mark W.
Published: December 2023

Background

Most theoretical frameworks for Alzheimer’s disease (AD) pathogenesis propose amyloid as the primary pathologic process, whereas tau in the absence of amyloid (A‐/T+) is considered a “non‐AD pathologic change” (Jack et al., 2018). Previous research has demonstrated AD‐like characteristics of the A‐/T+ biomarker profile, including poorer memory and language performance and entorhinal thinning (Weigand et al., 2022; Yoon et al., 2022). Assessment of domain‐specific longitudinal cognitive decline in this group, however, has not yet been addressed. Our study sought to evaluate 1‐year memory, language, and attention/executive function trajectories of A‐/T+ older adults.

Method

We included 756 older adults at baseline across the AD clinical continuum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 359 had 1‐year follow‐up cognitive data. Four A/T groups were classified based on cortical amyloid‐beta and medial temporal tau positron emission tomography positivity. Linear mixed effects models examined 1‐year trajectories of each baseline A/T group in domains of memory, language, and attention/executive function. Both statistical significance and effect size estimates were evaluated.

Result

The following proportions of A/T groups were observed at baseline: 47.0% A‐/T‐, 13.2% A‐/T+, 13.4% A+/T‐, and 26.4% A+/T+. Only the A+/T+ group exhibited a statistically significant decline in language and attention/executive function domains relative to the A‐/T‐ group. Examination of effect sizes, however, revealed that the A‐/T+ group had a quantitatively similar degree of decline as the A+/T+ group in memory (A‐/T+ and A+/T+ bs = ‐0.13), and an intermediate degree of decline between the A‐/T‐ and A+/T+ groups for language (A‐/T+ b = ‐0.17) and attention/executive function (A‐/T+ b = ‐0.19). Similar patterns were observed when examining cognitively unimpaired participants only.

Conclusion

Older adults with the A‐/T+ biomarker profile demonstrate a degree of cognitive decline across multiple domains consistent with a possible AD trajectory. The systematic exclusion of these individuals from AD clinical trials may hinder early intervention efforts to attenuate the cognitive decline observed in this biomarker group, and an expansion of our conceptualization of the AD continuum to include A‐/T+ individuals may offer improved insight into the pathologic and cognitive changes that occur in the context of preclinical AD.
Plasma p‐tau 181 outperforms FDG‐PET and plasma‐NfL in the diagnosis of biological AD
Authors: Socualaya Kely Quispialaya , Therriault Joseph , Aliaga Antonio , Servaes Stijn , Tissot Cécile , Rahmouni Nesrine , Macedo Arthur C. , Arias Jaime Fernandez , Hosseini Seyyed Ali , Vitali Paolo , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2023

Background

To compare the performance of plasma p‐tau181, plasma‐NfL and FDG‐PET in the diagnosis of biological AD.

Method

We included 787 participants (cognitively unimpaired (CU, n = 251), mild cognitive impairment (MCI, n = 412), and Alzheimer’s dementia (AD, n = 124) from the ADNI database. Participants underwent measures of plasma p‐tau181, plasma‐NfL, CSF P‐tau181, [18F]FDG‐PET, amyloid‐PET and cognitive screening tests. ROC analyses were used to determine diagnostic accuracy of plasma P‐tau181, NfL and [18F]FDG‐PET using clinical diagnosis and core AD biomarkers (amyloid‐PET and CSF P‐tau181) as reference standards. We assessed whether plasma P‐tau181 and [18F]FDG‐PET diagnostic accuracies were significantly different with a bootstrap‐based test (pROC package in R). Second, correlations of [18F]FDG‐PET, plasma‐NfL, plasma P‐tau181 with P‐tau181 CSF, Aβ‐PET, and cognitive performance were evaluated. Correlation coefficients were compared via Cocor package, a statistical framework for comparing associations between intercorrelated measurements.

Result

Across the total sample we observed that plasma P‐tau181, plasma‐NfL, and [18F]FDG‐PET were able to identify individuals with CSF evidence of AD as well as participants who are amyloid‐PET+. In the MCI group, plasma P‐tau181 outperformed [18F]FDG‐PET and plasma‐NfL in identifying AD pathophysiology measured via CSF P‐tau181 (p = 0.0007), and amyloid‐PET (p = 0.001). We also observed that both plasma P‐tau181, plasma‐NfL and [18F]FDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET). However, [18F]FDG‐PET was more closely associated with cognitive outcomes than plasma P‐tau181 and plasma NfL (MoCA: p < 0.0001; MMSE: p< 0.0001; CDR‐SB: p < 0.0001)

Conclusion

This study investigated the diagnostic properties of plasma P‐tau181 and two neurodegenerative biomarkers (plasma‐NfL and [18F]FDG‐PET) as well as their to identify biological AD. While plasma P‐tau181, plasma‐NfL concentrations and [18F]FDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET), plasma P‐tau181 outperformed [18F]FDG‐PET and plasma‐NfL in identifying individuals with AD pathophysiology. However, we also observed that [18F]FDG‐PET was more strongly associated with neuropsychological assessments than plasma P‐tau181 and plasma‐NfL. Taken together, our study suggests that plasma P‐tau181 may aid in the evaluation of individuals by identifying those with underlying AD pathophysiology.
Preliminary Data on the Rural‐Urban Commuting Area Codes for the ALLFTD Cohort
Authors: Forsberg Leah K. , Brushaber Danielle , Heuer Hilary W. , Rosen Howard J. , Boxer Adam L , Boeve Brad F.
Published: December 2023

Background

The rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning.

Methods

The current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows.

Results

RUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural.

Conclusions

Additional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.
Interaction between DNA methylation and neighborhood disadvantage may impact risk for cognitive decline among Mexican Americans enrolled in the Health and Aging Brain Study – Health Disparities (HABS‐HD) Cohort
Authors: Housini Mohammad , Zhou Zhengyang , Kind Amy J. , Reid Danielle M , Daniel Ann Abraham , Silzer Talisa , O'Bryant Sid E. , Phillips Nicole , Barber Robert , Pathak Gita
Published: December 2023

Background

Literature continues to indicate that social exposome factors such as neighborhood disadvantage, measured by the area deprivation index (ADI), is associated with cognitive decline, total brain volume, hippocampal volume and AD neuropathology. We hypothesize that epigenetic markers are implicated in the effect of neighborhood disadvantage on neurodegenerative biomarkers among Mexican Americans. We used existing Illumina EPIC Methylation chip and ADI data from 32 Mexican American participants enrolled in the Heath & Aging Brain Study ‐ Health Disparities (HABS‐HD) cohort to test whether differentially methylated sites and regions moderate a portion of the effect of ADI on risk for implicated AT(N) biomarkers.

Method

This study included Mexican American participants with information on DNA methylation, ADI, and Neurofilament Light (NfL), who were part of the Health and Aging Brain Study – Health Disparities (HABS‐HD). We considered 25 targeted epigenetic markers, which were previously identified to be associated with MCI or NfL from our group. We conducted preliminary analysis to assess associations between ADI and NfL using whole data (n = 812), and whether such association is moderated by one of the aforementioned targeted epigenetic markers using data with DNA methylation information (n = 32). Linear regression models were conducted to test the above effects and adjust for covariates.

Result

Results of the linear regression models showed that ADI was significantly positively associated with NfL among Mexican Americans (p = 0.007) using whole data, but the moderation analysis revealed no significant moderating effects on such association for any of the targeted epigenetic markers. However, one CpG site, cg07413251, showed marginally significant interaction effects with ADI on the association with NfL (p = 0.056). The cg07413251 site maps to a CpG island located at chr3p24.1. The biological implications of differential methylation at this site are unknown and remain under investigation.

Conclusion

The lack of significant results for moderation effects of the targeted epigenetic markers in our pilot study were likely due to the small sample size. In our future work, we will expand samples size significantly, improving power to better understand the role of disadvantaged neighborhoods in influencing cognitive function. Investigations into other biomarkers are underway.
Prognostic prediction of the longitudinal cognitive trajectory of amyloid‐positive patients with mild dementia
Authors: Devanarayan Viswanath , Charil Arnaud , Sachdev Pallavi , Ye Yuanqing , Koyama Akihiko , Reyderman Larisa , Hampel Harald , Irizarry Michael C. , Dhadda Shobha , Kramer Lynn D
Published: December 2023

Background

Prediction of longitudinal cognitive decline for patients with mild dementia using baseline characteristics will be useful for designing optimal clinical trials and real‐world patient monitoring. This can be accomplished via machine‐learning models using baseline clinical characteristics. Adding plasma pTau181 and brain region volumes may improve the predictions.

Method

The training cohort (TC) included 905 amyloid‐positive (A+) patients with mild dementia from two clinical trials. The validation cohort (VC) included 230 A+ patients from another clinical trial. Over 85% of these patients had MCI. The longitudinal cognitive decline was defined by the change from baseline in CDR‐SB at months 3, 6, 9, 12, 15, and 18. Plasma pTau181 was measured using Simoa assay in a subset of 159 patients in TC.

Structural brain network (SBN) modules and hubs were derived using 207 regional volumetric MRI measures in TC via an algorithm from genomics called “multiscale embedded gene co‐expression network analysis”. A signature for predicting longitudinal cognitive trajectory for each patient was first derived using baseline cognitive assessments and demographics within TC via the Stochastic Gradient Boosting algorithm. The added value of SBNs and plasma pTau181 was then evaluated within this framework. Prediction performance was evaluated in VC via the correlation between predicted versus observed cognitive trajectory.

Result

Predictions of the longitudinal cognitive trajectory using baseline cognitive assessments achieved 43.4% and 42.5% correlation with observed values at months 12 and 18 respectively. Key baseline cognitive function predictors were ADAS‐Cog‐14, CDR‐SB, and sub‐scores such as ideational praxis and word recall.

Adding baseline SBNs significantly improved the correlation between predicted versus observed cognitive trajectory to 46.3% and 49.7% at months 12 and 18 respectively (p<0.05). Key baseline SBN predictors were middle and inferior temporal, inferior parietal, and superior frontal cortex, along with a module comprising the entorhinal cortex and temporal pole. Adding baseline plasma pTau181 to cognitive assessments yielded similar improvements, but adding both pTau181 and SBNs did not improve the predictions further.

Conclusion

Longitudinal cognitive decline of A+ patients with mild dementia can be predicted using baseline cognitive assessments. Adding specific structural brain networks or plasma pTau181 significantly improves the predictions.
Longitudinal change of plasma biomarkers with incident mild cognitive impairment or Alzheimer’s disease in a multi‐ethnic cohort
Authors: Honig Lawrence S. , Kang Min Suk , Sanchez Danurys , Reyes‐Dumeyer Dolly , Lantigua Rafael A. , Dage Jeff L. , Brickman Adam M. , Manly Jennifer J. , Mayeux Richard , Gu Yian
Published: December 2023

Background

The utility of plasma‐based Alzheimer’s biomarkers in differentiating cognitively healthy individuals from those with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) has been widely investigated in cross‐sectional studies. There are fewer data on longitudinal change of these biomarkers over time, particularly in multi‐ethnic cohorts.

Method

Based on a community‐based, multi‐ethnic cohort study, the Washington Heights Inwood Columbia Aging Project, we included 610 cognitively normal individuals with three plasma samples collected over a mean period of 6.7 years. We used AD biomarkers, including Aβ40, Aβ42, tau, phosphorylated tau‐181 (P‐tau181), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL), and two calculated ratio measures (Aβ42/Aβ40, P‐tau181/Aβ42). During the follow‐up, 156 individuals developed MCI, 50 developed AD, and 404 remained cognitively unimpaired. We used generalized estimating equations to examine whether those who developed MCI and AD had different rates of change in plasma biomarkers than controls. Analyses were adjusted for age, years of education, sex, race and ethnicity, and APOE ɛ4 status. Similar analyses were performed to examine whether the rate of biomarker change differed by race and ethnicity, sex, and APOE ɛ4 status.

Result

The initial mean age of individuals was 73.1 (SD = 5.6) years, 419 (69%) were women, and 25.9% carried APOE e4. Individuals self‐identified as non‐Hispanic White (28.9%), non‐Hispanic Black (25.4%), or Hispanic (45.7%). Compared to controls, individuals with incident MCI had an accelerated increase in P‐tau181 (b = 0.029, p = 0.048), NfL (b = 0.027, p = 0.010), GFAP (b = 0.029, p = 0.002), and a more rapid decrease in Aβ42/Aβ40 ratio (b = ‐0.015, p = 0.033). Individuals with incident AD also had a greater increase in NfL (b = 0.041, p = 0.027) and GFAP (b = 0.04, p = 0.006) than controls. Hispanics had a faster increase in NfL (b = 0.033, p = 0.002) and GFAP (b = 0.034, p<0.001), and Black participants had a faster increase in NfL (b = 0.028, p = 0.023), compared to Whites. Neither sex nor APOE ɛ4 genotype affected rates of biomarker changes.

Conclusion

Longitudinal change in plasma biomarkers may have clinical utility, since incident MCI and AD are accompanied by faster increases in P‐tau181, NfL, and GFAP, and a faster decrease in Aβ42/ Aβ40 ratio. The trajectories of AD biomarker change may also vary by race and ethnicity.
History of infections is associated with smaller hippocampal volume in older women
Authors: Ukraintseva Svetlana , Popov Vladimir , Duan Hongzhe , Yashkin Arseniy , Akushevich Igor , Arbeev Konstantin , Yashin Anatoliy
Published: December 2023

Background

Accumulating evidence suggests that infections can play a major role in Alzheimer’s disease (AD), however, mechanism is unclear as multiple pathways may be involved. One possibility is that infections might contribute to AD directly by promoting neuronal death and neurodegeneration.

Method

We investigated the relationship between history of infectious diseases (a potential AD risk factor) and brain hippocampal volume, HV (a biomarker of neurodegeneration and AD neuropathology) in a subsample of the UK Biobank participants with respective information. Infectious disease diagnoses were based on ICD‐10 codes. The left/right HV was measured by the MRI. Analysis of variance (ANOVA) and Welch Two Sample t‐test were used to examine the statistical significance.

Result

The HV was significantly lower in older women (age 65+) with prior history of infections, compared to the same age women without such history (p‐value = 0.014 and 0.029, for the left and right HV, respectively). The effect size increased with age, and this increase was faster for the right vs. left HV. The difference in HV between male subjects with and without history of infections was not statistically significant.

Conclusion

In this study, prior infections were significantly associated with the lower left/right HV in women aged 65+, which supports the role of infectious diseases in neurodegeneration and preclinical AD pathology in females. The effect size increased with age, in line with the increase in brain vulnerability to stressors due to aging. The faster increase for the right vs. left HV might indicate that females’ verbal memory declines faster with age compared to visual‐spatial memory, following the exposure to infectious disease, which deserves further investigation. The observed sex differences may reflect a higher vulnerability of the female brain to infection‐related factors, which in turn might contribute to the higher risk of AD in women compared to men.