bluuebunny/crossref_metadata_2025 huggingface dataset:
Posterior hippocampal redundancy: A marker of non‐pathological brain aging
Authors: Blujus Jenna K , Oh Hwamee
Published: December 2022

Background

Several neural mechanisms underlying brain resilience to Alzheimer’s disease (AD) have been proposed, including redundant neural connections between the posterior hippocampi and all other brain regions (pHipp‐redundancy), and global functional connectivity of the left frontal cortex (gLFC). It remains unclear whether these two mechanisms confer resilience to AD pathologies through similar or distinctive mechanisms. We examined if redundancy, measured through graph theory, underlies the neuroprotective effects of both pHipp‐redundancy and gLFC connectivity in the early stage of AD pathologies.

Method

From the ADNI database, 370 CN and MCI participants were utilized. Aβ‐positivity (Aβ+) was defined as PET AV45 SUVR normalized to cerebellum greater than 1.11. Resting state data were preprocessed using fMRIprep (v20.2.6). Network graphs were constructed with 263 functional ROIs as nodes and z‐transformed correlations between each node as edges. Redundancy was calculated by summing the direct and indirect paths (path lengths=1‐4) between each hippocampal region (i.e., anterior and posterior hippocampal regions, bilaterally and LFC) and its 262 connections. Group differences (Aβ‐status, diagnosis) were computed in R using non‐parametric ANCOVA models with 10,000 permutations. Regression analyses were conducted to examine if Aβ‐status and diagnosis moderated the relationship between SUVR and redundancy. Models covaried for age, sex, education, and APOE4.

Result

Across CN and MCI, Aβ‐ had higher bilateral pHipp‐redundancy than Aβ+ (p’s<.034). Diagnosis significantly moderated the relationship between SUVR and left pHipp‐redundancy (β=0.112, p=.042). CN exhibited a stronger negative relationship between SUVR and left pHipp‐redundancy than MCI (p<.001). Finally, in CN, Aβ‐status significantly moderated the relationship between SUVR and right aHipp‐redundancy (β=0.358, p=.012), showing that in Aβ‐ CN, redundancy decreased with higher SUVR (p=.01), while in Aβ+ CN, redundancy remained the same as SUVRs increased. No relationships between Aβ‐status and redundancy, and interactions between SUVR and Aβ‐status or diagnosis, were significant in LFC.

Conclusion

Together, these findings suggest that bilateral pHipp‐redundancy may reflect normal brain aging without Aβ, rather than resilience in pathological aging, and a distinctive mechanism of brain aging from that of gLFC connectivity in the progression of AD.
Hierarchical, multiclass prediction of Alzheimer’s clinical diagnosis using imputed, multimodal NACC data
Authors: Ren Yueqi , Shahbaba Babak , Stark Craig E.
Published: December 2022

Background

Early detection and diagnosis are critical for effective treatment of Alzheimer’s disease (AD). Statistical machine learning holds promise for disease prediction using large AD repositories, such as the National Alzheimer’s Coordinating Center (NACC) dataset. Past work has extensively explored binary classifications of AD diagnosis. Here, we extended this to address two major, remaining challenges: data imputation and multiclass classification (e.g., AD vs Mild Cognitive Impairment, MCI vs. Healthy Cognition, HC).

Method

For imputation, we tested single‐value (baseline), k‐NN, and Bayesian imputation on a subset of complete training data with artificially removed values (completely at random). Per modality of interest, a systematic search was conducted for the best input feature set to impute the missing values. The mean absolute deviation and mismatch rate between the imputed and true values were used to evaluate the methods on a held‐out test set. For classification, we then implemented both “flat” multiclass and hierarchical classification, an extension of multiclass classification that organizes classes into a tree, to predict clinical diagnosis using multimodal inputs. Several pipelines with combinations of imputation methods, classifiers, and input modalities were tested on different hierarchical classification strategies, e.g., HC vs [AD vs MCI], compared with the flat, multiclass baseline (AD vs MCI vs HC).

Result

Compared to the baseline methods for both imputation and classification, the proposed alternatives performed better, as measured by the predetermined imputation and classification metrics evaluated on the test set. For imputation, behavioral and neuropsychiatric features were more easily and accurately imputed while ApoE genotype was more difficult to impute. For classification, using a combination of classifiers and input features in the hierarchy outperformed the baseline method and support the notion that select biomarkers are better able to characterize AD subpopulations within the hierarchy.

Conclusion

Establishing a systematic imputation method tailored to AD biomarker modalities fills a critical gap in achieving more robust disease prediction. Building a hierarchical classifier parallels working through a differential diagnosis for AD, which offers greater translational value than binary classification of AD. In combination, these results form an important step toward developing reliable, holistic classifiers of AD disease status.
Incidence of Cognitive Decline 5 Years after Orthopaedic Surgery According to Method of Assessment
Authors: Atkins Kelly J , Evered Lisbeth A , Scott David A , Silbert Brendan S
Published: December 2022

Background

Older adults who undergo elective surgery may be at risk of an altered cognitive trajectory leading to long‐term decline. We investigated the incidence of cognitive decline in the elderly following elective non‐cardiac surgery five years post‐operatively and examined whether differences in classification criteria for cognitive outcomes resulted in different incidence rates.

Method

We prospectively studied older adults following orthopaedic surgery, alongside non‐surgical control participants. All participants completed a battery of neuropsychological tests before surgery and again five years postoperatively. We classified Postoperative Cognitive Dysfunction (POCD), (a change‐based construct historically used in anesthesiology and surgery) as a decline of two standard deviations (SD) on two or more cognitive tests compared to controls. We also assessed Neurocognitive Disorders (NCD) relative to change in controls, a term recently introduced to align cognitive disorders with community medicine. Major NCD was defined by a decline of two SD on any test, accompanied by a subjective memory complaint and observed decline in instrumental activities of daily living. Mild NCD was classified as a memory complaint and a decline of one SD on at least one test.

Result

From an initial 300 participants enrolled, 227 participants (surgical = 199, non‐surgical control = 34) completed the five year follow‐up. Average (SD) follow‐up age was 74.8 (6. 6) years and 154 (67.8%) were female. We identified POCD at five years in 28 (14.2%), and major NCD in 38 (19.3%) participants. Mild NCD was more common, occurring in 81 (41.1%) participants. Cognitive decline five years postoperatively was associated with increasing age, whereas education history and anesthetic technique (spinal or GA) were not significantly associated. Further analyses will determine the role of cardiovascular risk factors.

Conclusion

We found both overlap and differences in the incidence rate of cognitive decline according to the criteria used for classification. Regardless of classification criteria and nomenclature, we found higher rates of cognitive decline amongst non‐cardiac surgical patients compared to rates reported in the general population. Our findings provide support that even elective, non‐cardiac surgical procedures under anesthesia are associated with a faster rate of cognitive decline amongst older adults. Possible pathophysiological mechanisms, including cardiovascular factors, will be discussed.
Examining the Moderating Roles of Social Isolation and Social Technology Use in Health Disparities of Cognitive Impairment
Authors: Byrne Kaileigh A
Published: December 2022

Background

There are profound racial disparities in cognitive impairment and dementia. Black and rural older adults are nearly twice as likely to develop dementia compared to White and urban‐dwelling older adults, respectively. However, the way social factors affect these racial and rural‐urban disparities in dementia prevalence remains poorly understood. Social isolation is associated with poorer cognitive outcomes among older adults, yet social technology use may provide a means to reduce social isolation. This research examines how two social factors—social isolation and social technology use influence racial and rural disparities in cognitive impairment and dementia.

Method

Data was extracted from the 2014 to 2018 waves of the Health and Retirement Study (N = 5,358). Participants (aged 50‐102) completed survey measures of social isolation, loneliness, and frequency of online social communication (e.g., use of Facebook, Skype). The modified Telephone Interview for Cognitive Status was used to operationalize dementia. The validated TICS classification system was used to classify scores with a cognitive status of dementia (scores ≤6), cognitive impairment (score of 7‐11), or cognitively normal (scores ≥12). Data was analyzed using structural equation models.

Result

Across all groups, frequency of social technology use moderated the negative relationship between social isolation and cognitive impairment, controlling for age, education, gender, wealth, and general computer usage. More frequent social technology use was associated with cognitively normal status among older adults who reported greater degrees of social isolation. In terms of health disparities, the results revealed racial, but not rural‐urban, differences in the relationship between frequency of social technology use and cognitive status. Frequent social technology use was associated with improved cognitive status in Black American older adults but not White older adults, irrespective of their level of social isolation.

Conclusion

Social technology may offer a means to mitigate cognitive decline; the potential benefit of such technology may be particularly promising among Black older adults.
Racial/Ethnic Disparities in Risk and Protective Factors of Dementia in the United States
Authors: Ferdows Nasim B. , Aranda Maria P.
Published: December 2022

Background

Recent population‐based studies show decline in dementia incidence and prevalence in high‐income countries, suggesting that improved population cardiovascular health and rising levels of education in the past 25 years were associated with reduction of dementia risks. However, in the US, there is a variation in changes over time of educational attainment, prevalence and management of chronic diseases, and behaviors associated with poor cardiovascular health among racial/ethnic groups. This study examines the risk and protective factors associated with dementia and decomposes racial/ethnic disparities in factors associated with cognitive functioning.

Method

We performed a retrospective analysis of 3,495 older individuals (65+) in 2016 who participated in Harmonized Cognitive Assessment Protocol, linked to Health and Retirement Study to trace the individuals back to 2000. Using Mini‐Mental State Examination (MMSE), individuals were classified as demented vs normal. Risk factors included were cardiovascular factors, hearing loss, and history of being uninsured in midlife, and current smoking, depression, and physical inactivity. Protective factors included were educational attainment. Using Oaxaca‐Blinder decomposition, the relative contribution of different variables in explaining racial/ethnic disparities in cognitive functioning was evaluated.

Result

Accounting for sociodemographic, mid‐, and later‐life characteristics, Blacks have higher odds of having dementia, following Hispanics and Whites. Higher levels of education and wealth were associated with lower odds of dementia. History of stroke and hearing loss during mid‐life, and depression and physical inactivity in late‐life were associated with higher odds of dementia. The decomposition shows that about 32% of Blacks and Whites difference in MMSE score was explained by demographics and later‐life characteristics, while nearly 68% of the difference remains unexplained. Comparing Whites and Hispanics, 70% of the difference in MMSE score was explained by demographics and later‐life characteristics, while nearly 30% of the difference remains unexplained.

Conclusion

Blacks and Hispanics are found to have a higher risk of dementia compared to whites. Accounting for demographics, mid‐ and later‐life risk and protective factors explain only one‐third of the difference in cognitive functioning between Blacks and Whites and nearly two‐thirds of the differences between Hispanics and Whites.
Longitudinal changes in brain glucose metabolism, astrocyte biomarkers and behavior in an APP/PS1 rat model
Authors: da Rocha Andreia Silva , Machado Luiza Santos , Soares Carolina , Ferreira Pamela C.L. , Bellaver Bruna , Kunach Peter , Rosa‐Neto Pedro , Green Kim N , Zimmer Eduardo R. ,   Model AD Consortium
Published: December 2022

Background

Imaging and fluid biomarkers have helped to reconceptualize Alzheimer’s Disease (AD) as a continuum. However, the biological interpretation of each AD biomarker remains under investigation. In this context, animal models that mimic the AD dynamic biomarkers cascade model present high translational value and can be used to refine our interpretation of biomarker findings. In light of this, we longitudinally evaluated [18F]FDG‐PET imaging, cerebrospinal fluid (CSF) glial and immune biomarkers, and behavior in the TgF344‐AD rat, a model harboring human APP/PS1 mutations.

Methods

TgF344‐AD rats and wild‐type littermates were longitudinally evaluated at 3, 6, 9, and 12 months of age. Rats underwent [18F]FDG‐microPET scans, behavioral tasks (Y‐maze and novel objective recognition) and CSF samplings. The [18F]FDG SUVr was calculated with pons as the reference region. CSF glial and immune markers were measured by multiplex ELISA. A cross‐sectional cohort was used to measure cortical glutamate uptake (ex‐vivo slices) at the same time points. Further examination of astrocyte proteins immunocontent was conducted at 9 months of age.

Results

At 3, 6 and 12 months, no changes in [18F]FDG metabolism were found. At 9 months of age, we identified a significant cortical hypermetabolism in the TgF344‐AD and a decline in alternance during the Y‐maze task. CSF GFAP levels were elevated at 6 and 9 months of age, while CSF S100B was decreased at 9 months of age. Additionally, the cortical and hippocampal glutamate uptake and GFAP cortical immunocontent were increased at 9 and 12 months of age. The recognition memory and CSF inflammatory markers (sTREM2, IL‐6, TNF‐α, IL‐10) were not altered in any of the ages evaluated.

Conclusion

Our results suggest that the TgF344‐AD rat model is suitable for studying astrocytic adaptations during early stages of amyloidosis in the rat brain. These adaptations include cortical glucose hypermetabolism, fluid biomarker evidence of reactive astrogliosis, and spatial memory impairment with concurrent abnormalities in astrocyte glutamate uptake in the cortex and hippocampus. Due to the critical role of astrocytes in brain glucose handling, our findings suggest that astrocyte reactivity could be driving glucose hypermetabolism and memory impairment early in the disease course.
Characterization of chromosome 5q35 risk locus in African Ancestry population.
Authors: Nuytemans Karen , Rajabli Farid , Jean‐Francois Melissa , Adams Larry D. , Starks Takiyah D. , Whitehead Patrice L. , Kunkle Brian W. , Caban‐Holt Allison M , Cuccaro Michael L. , Vance Jeffery M. , Haines Jonathan L. , Reitz Christiane , Byrd Goldie S. , Beecham Gary W. , Vance Margaret A. ,   The NIA‐LOAD Family‐Based Study
Published: December 2022

Background

As part of the Research in African American Alzheimer Disease Initiative (REAAADI) and Late‐Onset AD Family Study (LOAD), genotyping array and whole genome sequencing (WGS) data were generated for 51 families (160 affected and 318 unaffected). Multipoint linkage analyses identified a peak LOD score on chr5q35 (HLOD=3.20). Additionally, a suggestive locus flanking the 1‐LOD score was previously identified in an AA GWAS study (p‐value=2.6×10‐6) (Kunkle et al, 2019). Here, we further characterize this locus and its role in AD.

Method

We performed region‐wide association analysis in an independent REAAADI dataset of ∼240 cases and ∼650 controls to fine map the signal in the locus. Additionally, we analyzed the WGS data to prioritize variants in the consensus regions based on segregation with disease among affected individuals and rarity (MAF<0.01). All variants were annotated for putative function including protein changes for coding variants and evidence for regulatory activity (ENCODE, RoadMap Epigenome) and chromatin interactions (publicly available HiC and promoter capture C) for noncoding variants.

Result

Region‐wide association analysis identified two regions of rare (MAF∼0.01) variants downstream (p=3.0×10‐8) and upstream (p=3.7×10‐6) of the 1‐LOD linkage region. Segregation analysis using WGS data identified 111 rare variants (MAF<0.01) segregating with disease in the AD individuals of the family with the highest LOD score contributing to the linkage peak. These include a 3’UTR and synonymous variant in INSYN2B/FAM196B as well as a promoter variant in WWC1/KIBRA. Interestingly, four other AA families contributing to the chr5 linkage signal harbor different within‐family shared variants located in INSYN2B’s promoter or in enhancer regions with evidence for interaction with INSYN2B’s promoter. WWC1, expressed in astrocytes, was previously reported in AD context, whereas novel candidate INSYN2B encodes an inhibitory synaptic factor active in oligodendrocytes and neurons.

Conclusion

Our initial analyses provide evidence for two candidate genes contributing to AD genetics in the AA population. Additional work for functional validation of these candidates for AD is ongoing. This AA population‐specific finding shows the importance of diversifying population‐level genetic data to better understand the genetic determinants of AD on a global scale.
Trajectories of plasma Aβ42/40 among African Americans: Preliminary results from the African American Fighting Alzheimer’s in Midlife (AA‐FAIM) study
Authors: Van Hulle Carol A. , Zuelsdorff Megan , Koscik Rebecca Langhough , Ennis Gilda E. , Bouges Shenikqua , Fischer Barbara L. , Wyman Mary F. , Lambrou Nickolas H. , Johnson Adrienne L. , Umucu Emre , Salazar Hector , Chin Nathaniel A. , Meyer Matthew R. , Holubasch Mary S. , Kirmess Kris , Verghese Philip B. , West Tim , Venkatesh Venky , Yarasheski Kevin E. , Gleason Carey E.
Published: December 2022

Background

African Americans (AA) are under‐represented in Alzheimer’s disease (AD) biomarker research. Blood‐based biomarkers for AD offer the promise of greater diversity in research studies, but little is known about the performance of these biomarkers within an AA cohort. We examined the association between modifiable and non‐modifiable risk factors on the trajectory of plasma measures of Aβ42/40 in a large well‐characterized AA cohort.

Method

N=318 AA participants enrolled in in African Americans Fighting Alzheimer’s in Mid‐Life (AA‐FAIM) provided 690 plasma samples. The ratio Ab42/40 was calculated from plasma Aβ40 and Aβ42 quantified by C2N Diagnostics (PrecivityAD™; Figure 1). Age range was 39 ‐ 87 years at baseline (see Table 1); 52% of the cohort provided ≥2 plasma samples. Mixed‐effects linear models were used to test for longitudinal change in Aβ42/40 where years since baseline was the measure of time (M= 4.13 years, range = 1 to 16 years). To determine if risk factors modified Aβ42/40 trajectory, we tested the interactions between time and the following AD risk factors: APOE genetic risk, cardiovascular factors measured at baseline plasma sample (blood pressure, BMI, total cholesterol), and amyloid PET positivity.

Result

Raw Aβ42/40 values plotted against time are shown in Figure 2. None of the risk factors modified the trajectory of Aβ42/40 (p values ranged .22 to .84), which declined by approximately 1% per year over baseline (p <.001; Table 2). After accounting for longitudinal trajectory, Ab42/40 was 3% lower among APOE ε4 carriers, while higher baseline total cholesterol was associated with higher Aβ42/40. In a subset of participants with PiB‐PET visual ratings (N=35), amyloid positive participants (N=10) had 12% lower plasma Aβ42/40 values than amyloid negative participants (p<.001) after accounting for longitudinal trajectory.

Conclusion

These initial analyses conducted exclusively in African Americans suggest that clinical risk factors (total cholesterol, APOE) can influence brain amyloid pathology, as determined using plasma Aβ42/40. More research is needed to fully characterize AD pathology and dementia risk in AAs. This research is imperative in light of the disproportionate burden of dementia in the AA community and the increasing use of biomarkers in research and clinical practice.
The regional relationship between CSF VEGF and white matter microstructural integrity in older adults: A voxelwise DTI study
Authors: Tubi Meral A , Hare Evan , Nir Talia M , Sagare Abhay P , Wang Xinhui , Schneider Lon S. , Joe Elizabeth B , Toga Arthur W. , Harrington Michael G , Zlokovic Berislav V , Chui Helena C , Braskie Meredith N
Published: December 2022

Background

Both white matter (WM) micro‐ and macro‐ structural abnormalities occur in Alzheimer’s disease (AD) with micro‐structural abnormalities likely preceding macrostructural changes in the AD cascade. Diffusion tensor imaging (DTI) fractional anisotropy (FA) ‐ which is sensitive to factors such as myelination, fiber coherence, and fiber density‐ within an MRI voxel may be used to detect AD‐specific deficits. However, mechanisms driving loss of WM microstructural integrity in AD are poorly understood. Vascular endothelial growth factor (VEGF) is a multi‐function vascular protein linked to early AD brain and cognition biomarkers. VEGF provides neurotrophic support via glia and is also secreted by glial cells essential for maintaining myelin. However, in humans, the relationship between VEGF and WM microstructural integrity has yet to be mapped. We evaluated whether cerebrospinal fluid (CSF) VEGF levels were associated with voxelwise WM FA in older adults without dementia.

Method

We evaluated 72 older adults without dementia from the USC Alzheimer’s Disease Research Center (ADRC) (mean age 65.7; 47‐82 years old) with a clinical dementia rating (CDR) score of 0 (n=56) or 0.5 (n=16) who had both CSF VEGF‐A levels and a 3 T diffusion MRI scan (64‐direction (b=1000 s/mm2) DWI volumes). MRI scans were pre‐processed to reduce artifacts related to motion, distortion, eddy currents, bias field, and susceptibility artifacts. Tract‐based spatial statistics, using FSL software, was implemented to derive skeletonized FA maps along WM tracts. The association between VEGF and voxelwise FA WM integrity was evaluated using FSL’s general linear model tool. We covaried for age, sex, and CDR. FA significance cluster maps were corrected for voxelwise multiple comparisons.

Result

Higher CSF VEGF levels were associated with lower DTI FA, indicative of poorer WM microstructural integrity, in the left and right superior longitudinal fasciculus, left anterior thalamic radiation, and left inferior frontal occipital fasciculus (p<0.05) (Figure 1).

Conclusion

These results demonstrate for the first time in humans that VEGF levels are related to WM microstructure in older adults without dementia, primarily in long range association fibers connecting temporal, parietal, and frontal lobes. These pathways are essential for memory, language, attention and emotional control.
Amyloid, tau, cerebrovascular disease, neurodegeneration, and cognition in middle‐aged adults from a racially and ethnically diverse, community‐based study
Authors: Lao Patrick J. , Lippert Rafael , Benavides Andrea , Berroa Joncarlos , Igwe Kay C , Schupf Nicole , Mayeux Richard , Manly Jennifer J , Brickman Adam M.
Published: December 2022

Background

Alzheimer’s disease (AD) pathophysiology (i.e., amyloid‐induced tau) and cerebrovascular disease drive neurodegeneration and cognitive impairment. Our objective was to investigate moderation and mediation pathways among amyloid PET, tau PET, vascular MRI, and structural MRI in a middle‐aged, racially and ethnically diverse sample.

Methods

In an ongoing study, participants (n=63; 61±6 years old, 68% women, 13±4 years of education, 12% Non‐Latinx White/25% Non‐Latinx Black/63% Latinx) underwent amyloid PET (weighted average Florbetaben SUVR in Thaal phase regions), tau PET (average MK‐6240 SUVR in Braak stage I), vascular MRI (white matter hyperintensity (WMH) volume), and structural MRI (AD‐signature cortical thickness) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease. Serial parallel mediation was used to assess two pathways from age to neurodegeneration (i.e., age to amyloid to tau to neurodegeneration; age to WMH to tau to neurodegeneration).

Results

Older age was associated with greater amyloid (7E‐3 [3E‐3, 0.01], p=0.001), which was in turn trend level associated with greater tau (0.55 [‐0.1, 1.2], p=0.09); tau was not associated with cortical thickness (‐6E‐3 [‐0.09, 0.08], p=0.88). The total indirect effect of this amyloid pathway was not significant (‐2E‐5 [‐3E‐4, 3E‐4], p=0.88). Older age was associated with greater WMH (0.01 [2E‐4, 0.02], p=0.048), but WMH was not associated with tau (0.01 [‐0.20, 0.22], p=0.91) or cortical thickness (‐8E‐3 [‐0.08, 0.06], p=0.82). The total indirect effect of this vascular pathway was not significant (‐9E‐7 [‐2E‐5, 2E‐5], p=0.93). The direct effect from age to neurodegeneration, given both indirect pathways, was significant (‐5E‐3 [‐9E‐3, ‐1E‐3], p=0.005).

Conclusions

In midlife, there is evidence of age‐related increases in cerebrovascular disease and amyloid‐induced tau, but the two pathways do not have an effect on neurodegeneration in this age group. Older age is the strongest predictor of neurodegeneration, but AD and cerebrovascular pathology may become stronger predictors later in the AD continuum.
Teleneuropsychology in the memory clinic setting: evidence for reliability and usability of videoconference‐based neuropsychological testing
Authors: Butterbrod Elke , Zevenhoven Pia , Waterink Lisa , van Leeuwenstijn Mardou , van der Flier Wiesje M. , van den Heuvel Dominique M.J. , Sikkes Sietske A.M.
Published: December 2022

Background

Remote neuropsychological assessment through video teleconferencing (VTC) can improve accessibility to dementia care, even beyond the COVID‐19 pandemic. Evidence for the usability and reliability of VTC is still limited in a memory clinic population, particularly for tests assessing non‐memory and non‐verbal functions. This study aims to investigate stability of performances on neuropsychological tests across in‐person and VTC modality, as well as VTC user experiences, in memory clinic patients.

Method

Patients were included at the Alzheimer Center Amsterdam between August 2020 and February 2021. Patients underwent in‐person neuropsychological assessment, and subsequently through VTC within 4 months. Stability of performances on all tests across assessments was investigated with intraclass correlations coefficients/percentage agreement and independent samples t‐tests/Wilcoxon signed‐rank tests. Rank order stability was investigated with Pearson or Spearman correlation/Chi‐square tests. For each test, we converted standardized (T‐)scores into seven performance classes (see Figure 1) and described the proportion of patients showing a clinically relevant difference in performance class. Furthermore, we described stability of patients’ overall assessment performance (no impairment, single‐domain impairment, multi‐domain impairment). User friendliness and system usability were assessed with questionnaires by patients and neuropsychologists. Scores were set against previously defined acceptability cut‐offs, and compared across diagnostic groups (subjective cognitive decline [SCD] vs. MCI/dementia) with independent samples t‐tests.

Result

Thirty‐one patients (62±6.7 years, 55% male, 58% SCD, 42% MCI/dementia) completed VTC assessment. Intraclass correlation coefficients ranged from moderate (0.5; TMT index) to excellent (>0.9; RAVLT, LDST), see Table 1.Significant differences in mean performances were observed for Digit span and Stroop test (SCD group only). For all tests, the majority of patients showed no clinically relevant difference in performance (Figure 1, 61%‐100% stable). Nineteen patients (61%) had the same overall assessment performance across modalities (Figure 2). User friendliness (mean total scores patients/psychologists:164/143) and usability (mean item scores patients/psychologists:3.0/3.0) reached acceptability and did not differ between diagnostic groups.

Conclusion

VTC assessment may serve as an accessible and user friendly method to test cognitive functioning in the memory clinic, with largely similar reliability coefficients as in‐person assessments. Implications of VTC assessment for the evaluation of impairment severity, and possibly diagnosis, should be further investigated.
Default‐mode connectivity mediates the association between cardiovascular and metabolic risks and cognition: a pilot study
Authors: Rashid Barnaly , Glasser Matthew F. , Nichols Thomas , Van Essen David , Juttukonda Meher R , Schwab Nadine A , Yacoub Essa , Lovely Allison , Terpstra Melissa , Harms Michael P , Bookheimer Susan Y. , Ances Beau M , Arnold Steven E. , Salat David H
Published: December 2022

Background

Prior studies have linked increased vulnerability to cognitive decline later in life with exposure to cardiovascular and metabolic disease risk factors. Further, these classic risk factors are associated with alteration to brain structure and function. This project investigates whether altered default‐mode network (DMN) functional connectivity (FC) mediates the association between cardiovascular and metabolic (CVM) health and cognition.

Method

Structural, Resting‐state fMRI, and fieldmap scans were collected in a large sample of 930 healthy volunteers aged 36 to 90+ years old (mean ± SD: 61.6 ± 16 years; female= 55.6%) from the Human Connectome Project in Aging (HCP‐A) study. Data were preprocessed using the currently recommended HCP‐A pipelines, including precise spatial preprocessing, multi‐modal cross‐subject alignment, and selective temporal denoising. FC values were computed using full correlation with FSLNets amongst the neocortical brain areas of HCP‐A’s multi‐modal parcellation and standard FreeSurfer subcortical structures and converted to z‐scores with the Fisher transform. A composite CVM index (CVMI) was computed with variables related to general CVM health, and a cognitive composite index (CCI) encompassed measures of general cognition, memory, processing speed, and executive functioning. Figure 1 presents the mediation model implemented using MATLAB. The mediation effects were assessed in the full sample (FDR corrected, p<0.05), as well as separately in ‘younger’ participants below 65 years (n = 546) and ‘older’ participants aged 65+ years (n = 384) with and without sex stratification (uncorrected).

Result

Figure 2 highlights an indirect effect between CVMI and CCI that is mediated by DMN FC. In the full sample, the CVMI shows a significant negative direct effect on CCI (b=‐0.54, p<.001). This effect is mediated by DMN FC as seen in Figure 2(a), which is well‐replicated in the sex‐stratified analyses. Similar overlapping effects are observed in the younger and older groups. Figure 3 presents an example of connectivity and age association differences between low and high CCI groups.

Conclusion

Our results indicate that cardiovascular and metabolic health impacts cognitive functioning, and that this is, at least in part, mediated by DMN FC.
Functional fitness predicts global cognition scores
Authors: Gray Michelle , Paulson Sally , Gills Joshua L. , Jones Megan , Campitelli Anthony , Rodgers Charles , Madero Erica N. , Myers Jennifer Rae , Glenn Jordan M. , Bryk Kelsey Nicole
Published: December 2022

Background

Alzheimer’s disease (AD) is the 5th leading cause of death and the 6th most burdensome disease among US older adults. Given the concern with public health, understanding modifiable risk factors contributing to cognitive decline is imperative. With preliminary symptoms of cognitive decline occurring long before diagnosis, the ability to identify modifiable risk factors is key to primary prevention and maintenance of cognition. Often among individuals with AD, physical function is concurrently impaired. Thus, the primary aim of the present investigation is to determine the ability to predict global cognition scores from commonly used physical function assessments.

Method

Community‐dwelling adults 60 years and older completed all assessments. Global cognition (percentile score) was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). All participants were free from mild cognitive impairment, dementia, and probable dementia. Physical function variables included maximal hand grip strength (average of right and left hands), lower‐body peak force development during a sit‐to‐stand task, and 10‐mfast walking time. Linear regression analysis was performed to determine the proportion of variance accounted for by the independent variables (sex, hand grip strength, peak force, 10‐meter walk time). Semi‐partial correlations were performed to determine the unique contribution from each independent variable.

Result

27% of the variance in global cognition was accounted for when including all independent variables. Semi‐partial correlations revealed the largest unique contribution was from the 10‐meter fast walking time, accounting for 19% of the variance (p < .001). Lower‐body peak force production accounted for 9% (p < .001). Sex accounted for 2.6% (p =.04) and hand grip strength accounted for 2% (p = .055).

Conclusion

The current investigation provides support for the predictive capabilities of physical function assessments on cognitive ability—in particular, the time to complete a 10‐meter walk. This is paramount to future efficacious treatments with the inconsistent nature of current cognitive testing and implementation, primarily because of difficulties accessing qualified neuropsychological professionals. The physical function assessments presented here are cost effective and may serve as an early warning sign to cognitive decline.
Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study.
Authors: Gordon Elizabeth , Cavedo Enrica , dos Santos Clarisse Longo , Samper‐González Jorge , Schwarz Adam J. ,   the MEMENTO Study Group
Published: December 2022

Background

Neuroanatomical atrophy profile is increasingly recognized as a valuable characterization in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.

Method

1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age=70.6 (8.2), 60% female, CDR‐SB=0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z<‐1.64) [1,2]: no/minimal atrophy [N‐] (n=1,012), limbic predominant: LP (n=37), hippocampal sparing: HS (n=84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n=20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐=114, LP=8, HS=21 and TD=2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.

Result

At month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102=N‐, 18=LP, 15=HS, and 8=TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p<0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p<0.001) particularly for orientation and global CDR.

Conclusion

Early atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.

[1] Planche et al., (2020)

[2] Schwarz et al., (AAIC2022)
Assessing a Network‐Specific Polygenic Risk Score for Alzheimer’s Disease in the Midwestern Amish and Across Diverse Ancestries
Authors: Osterman Michael D. , Song Yeunjoo E. , Wheeler Nicholas R. , Laux Renee A. , Adams Larry D. , Caywood Laura J. , Prough Michael B. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Lynn Audrey , Bartlett Jacquelaine , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Dorfsman Daniel A. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Bush William S. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. ,   Alzheimer's Disease Sequencing Project (ADSP)
Published: December 2022

Background

Alzheimer’s disease (AD), the most common type of dementia, has a complex etiology with a strong genetic component. Many genetic risk variants for AD have been identified including APOE, the largest known genetic risk factor. However, most of this research has examined only broad populations of individuals with European ancestry and there is mounting evidence that effect sizes vary by population. Here, we investigate the transferability of polygenic risk scores (PRSs), including a network‐specific PRS, in the midwestern Amish and across diverse ancestries.

Method

Data from 1,091 Amish adults with AD diagnosis by consensus were considered for analysis from the Collaborative Amish Aging & Memory Project. Genotype data (Illumina GSA and MEGAEX) were imputed using the Haplotype Reference Consortium panel. We also analyzed 15,745 individuals from the Alzheimer’s Disease Sequencing Project (ADSP) r3 with three predominant race/ethnicity groups: African American (AA; n=2,937), Hispanic (n=3,047), and non‐Hispanic White (NHW; n=9,708). An AD network‐specific PRS was constructed by including variants from AD‐implicated molecular networks in the Kyoto Encyclopedia of Genes and Genomes. A comprehensive pruning and thresholding PRS considering all variants was calculated for comparison. Effect estimates from Kunkle et al. (2019) were used. PRS‐only models, sex and age covariate‐only, and full models were constructed for each group and the full ADSP data.

Result

We observed that PRS‐only predictive ability was similar between the comprehensive PRS (AUC=0.56) and the network‐specific PRS (AUC=0.55) in the full ADSP r3 data. Network‐specific PRS performance was similar in the Amish (AUC=0.55). However, we observed better predictive ability with the comprehensive PRS compared to the network‐specific PRS in each of the subgroups (Amish AUC: 0.61 vs. 0.55; NHW: 0.70 vs. 0.53; AA: 0.56 vs. 0.53, Hispanic: 0.61 vs. 0.56). These trends were consistent after inclusion of sex and age covariates.

Conclusion

We demonstrated that a network‐specific PRS performed similarly to a comprehensive PRS in a combined diverse population and the Amish but confers less predictive ability when investigating individual subgroups. Thus, the network‐specific PRS has potential as a component of a risk model in diverse populations because it may successfully account for effects that are consistent across subgroups.
The M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) VU0453595 and M4 PAM VU0467154 Normalize Sleep‐Wake Architecture Deficits in Aged Mice
Authors: Russell Jason K , Bubser Michael , Ingram Shalonda , Newhouse Paul A , Lindsley Craig W , Jones Carrie K
Published: December 2022

Background

Declining basal forebrain cholinergic integrity has been associated with disturbances in sleep‐wake architecture in Alzheimer’s Disease (AD). Acetylcholinesterase inhibitors (AChEIs) provide symptomatic treatment for the cognitive deficits in AD through nonselective enhancement of cholinergic signaling. Additionally, AChEIs promote wakefulness, but reduce NREM sleep quality and produce dose limiting side effects through nonselective activation of peripheral muscarinic acetylcholine receptors (mAChR). Selectively targeting different mAChRs with positive allosteric modulators (PAMs) provides an alternate approach. In the current study, we assessed the effects of the M1 PAM VU0453595 and the M4 PAM VU0467154 on sleep‐wake architecture and arousal following dosing across the circadian cycle in aged mice.

Methods

Young (3‐4 month‐old, n = 13‐14 per group) and aged (19‐21 month‐old, n = 14 per group) C57/BL6 mice were implanted with HD‐X02 telemetry devices (DSI) for electroencephalography (EEG) recording. The M1 PAM VU0453595 (3‐30mg/kg IP) or the M4 PAM VU0467154 (1‐30mg/kg IP) were dosed 2‐hours into the active or inactive phases of the circadian cycle. EEG was recorded for 24‐hours, with sleep stages scored in 5‐second epochs. Arousal was assessed through changes in gamma power during wake, and sleep quality was measured through changes in delta power during NREM sleep. Statistical comparisons involved repeated measures one‐ or two‐way ANOVAs as appropriate, with Dunnett’s or Sidak’s multiple comparisons applied in all cases.

Results

The M1 PAM VU0453595 increased wakefulness and arousal with inactive phase dosing in young and aged mice. During the active phase, VU0453595 increased wakefulness and arousal only in aged mice. The M4 PAM VU0467154 increased NREM sleep in young and aged mice when dosed in both phases. In the inactive phase, suppression of REM sleep in young and aged mice is also observed. During NREM sleep, VU0467154 increased delta power in young and aged mice.

Conclusion

These findings suggest that M1 and M4 PAMs may be valuable as treatments in AD at different phases of the circadian cycle. M1 PAMs could be beneficial with morning dosing in clinical populations as they enhanced wakefulness and arousal. M4 PAMs could be advantageous with evening dosing in clinical population as they enhanced NREM sleep quantity and quality.
Depression and anxiety during the two waves of the COVID‐19 pandemic in two large, prospective, aging cohorts in rural and urban India.
Authors: Sundarakumar Jonas S. , Lingegodwa Abhishek Mensegere , Hameed Shafeeq K Shahul , Ravindranath Vijayalakshmi ,   SANSCOG & TLSA Study Teams
Published: December 2022

Background

India was severely impacted by both the first and second waves of COVID‐19 in 2020 and 2021. We aimed to estimate proportions of depression and anxiety disorder during both waves, among rural and urban Indians, and to compare depression trends during four distinct periods before and after the pandemic.

Method

Aging adults (≥45 years) from two, parallel, harmonized cohorts in rural (SANSCOG) and urban (TLSA) sites in India, underwent telephonic assessments for depression (GDS‐7) and anxiety (GAD‐7) during both waves of COVID‐19. Utilizing prior data from depression assessments (GDS‐30) during regular evaluations pre‐ pandemic and during an interim period between the two waves, we compared trends in overall proportions of depression between the two cohorts during four periods: pre‐COVID (684 rural, 317 urban); post‐COVID first wave (733 rural, 297 urban); post‐COVID interim period (458 rural, 204 urban); post‐COVID second wave (611 rural, 305 urban).

Result

Overall proportion of depression among rural subjects during both waves was 28.8%. Corresponding numbers for anxiety disorder were 5.5% and 3.9%. Among urban subjects, 6.5% and 15.1% were depressed, whereas 1.7% and 0.66% had anxiety disorder, during the first and second waves, respectively. Depression trends during the four periods mentioned above were starkly different between rural and urban Indians. Sub‐analysis of the same subset of rural subjects with pre‐COVID and post‐COVID (both waves) data, revealed that subjects ≥ 65 years and those with comorbidities had significantly higher depression (36.8% vs. 25.3% and 32% vs. 15.7%, respectively) during the first wave only.

Conclusion

Multi‐fold increase in depression among aging, rural Indians during both waves, with alarmingly high depression among subjects ≥ 65 years and those with comorbidities during first wave, is seriously concerning. Urgent public health measures are needed to address this added mental health burden and prevent further potential adverse consequences.