bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling Vascular and Parenchymal Microenvironment Changes in Patients with Mixed CAA/AD Pathology: A Spatial Transcriptomic In‐Depth Analysis
Authors: Juarez Enrique Chimal , Garfe Nur Jury , Redding Javier , Troncoso Juan C , Johnson Travis S , Reeves Cristian A Lasagna
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA), defined as the accumulation of amyloid in cerebral blood vessels causing alterations in the blood brain barrier (BBB) and the gliovascular unit, occurs in over 85% of Alzheimer’s disease (AD) cases, positioning CAA as one of the strongest vascular contributors to age‐related cognitive decline. However, the specific mechanisms in the microvasculature that become altered due to amyloid deposition and its downstream effects on the brain are complex and incompletely understood. A spatial transcriptomic analysis comparing pathways affected in the gliovascular niche differently in the presence of vascular amyloid could provide critical insight into the mechanisms underlying cerebrovascular changes involved in the deposition of Amyloid in the cerebrovasculature.

Method

Using NanoString’s GeoMx Human Whole Transcriptome Atlas, which measures over 18,000 protein‐coding genes at each region of interest (ROI) in tissue sections, we evaluated mixed CAA/AD pathology patients. We evaluated and performed selected pair wise comparisons between 4 types of ROI:
1)
Astrocytes surrounding vascular amyloid,
2)
astrocytes surrounding amyloid‐free vasculature,
3)
astrocytes surrounding parenchymal amyloid, &
4)
astrocytes in an amyloid‐free parenchymal zone.

Result

Conducting pairwise comparisons among the four types of Regions of Interest (ROIs) unveiled distinctive transcriptomic signatures across ROI categories. Notably, gene expression profiles in regions of vasculature positive for Aβ‐amyloid differed significantly from those in amyloid‐free vasculature, showcasing pronounced gene expression changes. While the signatures corresponding to both Parenchymal amyloid and vascular amyloid have a similar transcriptional signature, they differ in certain pathways. Through meticulous data mining, we identified a co‐expression cluster of genes intricately linked to vascular amyloid deposition. Further analysis involved determining Differentially Expressed Genes (DEGs) based on ROI types, yielding a comprehensive list of potential targets indicative of the perturbations induced by vascular amyloid deposition versus parenchymal amyloid deposition.

Conclusion

In summary, the identified differential (parenchymal vs vascular) genes underscore a clear association with alterations in the neurovascular microenvironment, indicating a discernible shift in vasculature dynamics attributed to amyloid presence. This observation emphasizes the significance of comprehending the changes within the vascular unit to address Cerebral Amyloid Angiopathy (CAA) thoroughly to develop comprehensive strategies to tackle CAA‐related challenges.
Neuropsychiatric symptoms and brain aging in mild cognitive impairment and early dementia: A multicenter study
Authors: Sone Daichi , Beheshti Iman , Tagai Kenji , Kameyama Hiroshi , Takasaki Emi , Kashibayashi Tetsuo , Takahashi Ryuichi , Ishii Kazunari , Kanemoto Hideki , Ikeda Manabu , Shigeta Masahiro , Shinagawa Shunichiro , Kazui Hiroaki
Published: January 2025

Background

Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging‐derived brain‐age estimation by machine‐learning analysis has shown promise as an individual‐level biomarker. We investigated the relationship between NPS and brain‐age in amnestic mild cognitive impairment (MCI) and early dementia.

Method

Clinical data, including neuropsychiatric inventory (NPI), and structural brain MRI of 499 individuals with clinical diagnoses of amnestic MCI (N = 185), early Alzheimer’s disease (AD) (N = 258) or dementia with Lewy bodies (DLB) (N = 56) were analyzed. We established a brain‐age prediction model using 694 brain structural MRI scans of healthy subjects and support vector regression model and applied it to the patients’ data. Finally, the brain predicted age difference (brain‐PAD: predicted age minus chronological age) were calculated.

Result

All clinical diagnostic groups showed significantly increased brain‐PAD, and the median (IQR) brain‐PAD was 4.3 (5.4) years in MCI, 6.3 (6.2) years in AD, and 5.0 (6.5) years in DLB. The NPI scores were subdivided into the following four categories: (i) Agitation and Irritability, (ii) Depression and Apathy, (iii) Delusions and Hallucinations, and (iv) Euphoria and Disinhibition. We found a significantly positive correlation between brain‐PAD and the depression/apathy factor (Spearman’s rs = 0.156, FDR‐corrected p = 0.002), while no significance was shown in the other NPS factors.

Conclusion

Abnormal brain aging may be involved in depression and apathy symptoms presented in MCI to early dementia stages, and brain‐age analysis may be useful as a novel biomarker for assessment or monitoring of NPS.
Study on the correlation between leisure activities and cognitive impairment in middle‐aged and elderly people in High‐altitude environment
Authors: Zhu Aiqin , Chai Changbiao
Published: January 2025

Background

To explore the influence of leisure activities on cognitive function of middle‐aged and elderly people living in hypoxia environment.

Method

Using a cross‐sectional random sampling survey method, a total of people over 50 years old who have lived for more than 20 years (average altitude 3000m) in Qinghai plateau region were selected. Demography information, chronic medical history, economic and marital status, and 21 leisure activities (including entertainment, mobile phone use, games, sports, travel, social interaction and housework) were investigated. Cognitive domain assessment tool was from Beijing aging brain rejuvenation initiative (BABRI) Dementia Risk Assessment program.

Result

Among the 500 cases studied, there were 193 cases of cognitive impairment (CI) (38.6%), including 110 (22%) mild cognitive impairment and 83 (16.6%) Alzheimer’s disease. The CI group showed a significant increase in women, older age, workers and farmers, lower education, divorce and widowhood, living alone/with children, lower monthly income, smokers and drinkers (P<0.05); while reading (newspapers, magazines and books), playing chess and card activities (chess, poker and mahjong), watching TV, using mobile phones (Tiktok, Kwai and chatting), performing aerobic (walking, jogging, cycling and swimming) and resistance exercise (dumbbells, sandbags and pullers), traveling, visiting friends /relatives significantly decreased compared with the normal cognitive group (P<0.05). Multivariate binary regression analysis showed that women (OR = 1.787, 95% CI = 1.137‐2.808, P = 0.012), advanced age (OR = 1.066, 95% CI = 1.040‐1.093, P<0.001), occupation as workers (OR = 2.640, 95% CI = 1.263‐5.519, P = 0.010), and farming (OR = 2.420, 95% CI = 1.351‐4.333, P = 0.003) were risk factors for CI. Living with a spouse (OR = 0.211, 95% CI = 0.081‐0.548, P<0.001) and stop drinking (OR = 0.275, 95% CI = 0.093‐0.813, P = 0.020) were protective factors for CI. In leisure activities, aerobic endurance exercise (OR = 0.811, 95%CI = 0.676 ‐0.973, P = 0.024) and resistance exercise (OR = 0.625, 95%CI = 0.442 ‐0.883, P = 0.008) were protective factors for CI, while mobile phone use (OR = 1.185, 95% CI = 1.003‐1.339, P = 0.046) is a risk factor for CI. Mobile phone use (OR = 1.185, 95% CI = 1.003‐1.339, P = 0.046) was a risk factor for CI.

Conclusion

Aerobic and resistance exercise have a protective effect on cognitive function, while long‐term mobile phone watching Tiktok, Kwai and chatting may lead to CI in middle‐aged and elderly people in hypoxia environment.
Comparing Dual and Single‐Task Postural Performance in Older Adults with a Fall‐Related Chronic Mild Traumatic Brain Injury
Authors: Sommer Amaya , Okrah Albert K , Parada Stephen A , Jirau‐Rosaly Wanda D , Bursey Max , Reynolds Bradford , Ohamadike Chijioke , Jehu Deborah A
Published: January 2025

Background

Fall‐related mild traumatic brain injuries (mTBI) are prevalent among older adults and are a predictor of dementia. Delays in diagnoses lead to prolonged symptoms and impairments. Dual‐task posture may be more sensitive to detecting impairments compared to single‐task posture, but research is limited. The objective of this study was to characterize single and dual‐task postural performance in older adults with a fall‐related chronic mTBI.

Methods

We included community‐dwelling older adults who were seeking medical attention and/or still experiencing ongoing symptoms of a fall‐related chronic mTBI in this cross‐sectional study (n = 3; Age: 68.6 ± 8.1 years, Montreal Cognitive Assessment = 23 points, 67% Female). Dementia was an exclusion criterion. Participants stood on an AMTI force platform for 60 seconds and completed two repetitions of single‐tasks (standing with feet apart) and dual‐tasks (standing with feet apart while silently counting backwards by 3’s). Variables assessed were the 95% confidence area (m2), center of pressure (COP) path length (m), COP velocity (m/s), and mean frequency (Hz). A two‐way Condition (single, dual) by Measure (95% confidence area, COP path length, COP velocity, mean frequency) repeated measures analysis of variance was performed to compare single and dual‐task postural performance.

Results

There was a significant Condition by Measure interaction (F(3,6) = 11.53, p<0.01, ηp
2 = 0.85). Post hoc comparisons revealed a trend for greater path length (t(2) = ‐3.38, p = 0.08; single‐task: 0.80 m, dual‐task = 0.84 m) and velocity (t(2) = ‐3.38, p = 0.08; single‐task: 0.133 m/s, dual‐task = 0.139 m/s) during dual‐tasking compared to single‐tasking. No differences were shown in the 95% confidence area or mean frequency (p>0.05).

Conclusion

The trend towards greater COP path length and COP velocity during dual tasking highlights that increased attention demand likely provokes postural instability. These measures may be sensitive to detecting impairments in dual‐task postural control; however, these findings will be confirmed as we enroll further participants in this ongoing study. Refined screening protocols for fall‐related mTBIs may the improve time to diagnosis, prevent reinjury, and mitigate long‐term impairments, including the potential onset of dementia. Future research is needed to determine if cognitive impairment is a risk factor for fall‐related mTBIs in older adults, as all our participants had mild cognitive impairment.
Baseline regional amyloid distribution in relation to subsequent self‐ and informant‐rated apathy scores in community‐dwelling older adults
Authors: Munro Catherine E
Published: January 2025

Background

Apathy is a common neuropsychiatric symptom of Alzheimer’s disease (AD) and has been linked to greater levels of AD biomarkers (i.e., global cortical amyloid burden and regional tau levels) in preclinical individuals. However, it is unclear whether there are regional influences of amyloid on these relationships and if these relationships differ between self‐ and informant‐rated apathy. We sought to examine whether initial baseline levels of amyloid in brain regions linked to apathy in AD could predict self‐ and informant‐rated apathy at follow‐up.

Method

202 participants who were cognitively unimpaired and nondepressed at baseline (mean age = 72.6) were included from the longitudinal Harvard Aging Brain Study cohort. MRI/PiB‐PET were performed at baseline and self‐ and informant‐rated apathy levels were obtained cross‐sectionally using Apathy Evaluation Scale (AES; lower scores indicating greater apathy) scores at their most recent visit (mean years follow‐up = 7.8). Regional PiB DVR values were calculated using FreeSurfer‐defined bilateral regions of interest (ROI) implicated in apathy: inferior temporal (IT), entorhinal, anterior cingulate (ACC), precuneus, supramarginal, and medial and lateral orbitofrontal (mOFC, lOFC) cortices, and the thalamus and amygdala. Separate linear regression models assessed whether regional baseline PiB levels predicted self‐ and informant‐rated apathy at follow‐up for each ROI, covarying for age, sex, education, and time‐to‐follow‐up, adjusted for multiple comparisons.

Result

Higher baseline PiB levels in the IT, precuneus, supramarginal, ACC, and mOFC were associated with lower informant‐rated AES scores (indicating greater apathy) at follow‐up (Figure 1). Baseline PiB levels in any ROIs were not predictive of future self‐rated AES scores (Table 1). Results lost significance when examining only individuals who had a Clinical Dementia Rating score of 0 at follow‐up, indicating results were driven by those who progressed to cognitive impairment.

Conclusion

In a cohort of older adults who were cognitively unimpaired and nondepressed at baseline, higher initial cortical amyloid levels in the IT, precuneus, supramarginal, ACC, and mOFC regions were associated with greater informant‐rated, but not self‐rated, apathy approximately 8 years later. These results shed light on the neurobiology of apathy in older individuals and preclinical AD and emphasize the importance of obtaining both self‐ and informant‐report when assessing new or worsening neuropsychiatric symptoms.
Associations among mild behavioral impairment symptoms, brain pathology and cognition in individuals with autosomal‐dominant Alzheimer’s disease: Findings from the Colombia‐Boston (COLBOS) biomarker study
Authors: Vasquez Daniel , Aguillon David Fernando , Baena Ana Y , Langella Stephanie , Munera Diana , Zubiri Victoria , Ramos Claudia , Alvarez Sergio , Ochoa‐Escudero Martin , Kaplan Elizabeth , McDowell Celina F. Pluim , Martinez Jairo E. , Giudicessi Averi , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Vila‐Castelar Clara , Gomez Liliana A Ramirez , Lopera Francisco , Gatchel Jennifer R. , Quiroz Yakeel T.
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) are common in early stages of Alzheimer’s disease (AD) and may be early markers of cognitive decline and dementia in older individuals. The Mild Behavioral Impairment Checklist (MBI‐C) was developed to capture new‐onset transdiagnostic NPS in individuals at risk of dementia. We sought to determine whether mild behavioral impairment symptoms are elevated in non‐demented Presenilin‐1 (PSEN1) E280A carriers, who are genetically determined to develop dementia by their 50s. We hypothesized that those with higher MBI‐C total scores would have worse memory performance and greater brain pathology.

Method

A total of 25 mutation carriers (mean age = 36.3±7.23; 56% females; 18 cognitively‐unimpaired, 7 impaired) and 30 non‐carriers (70% females) from the Colombia‐Boston (COLBOS) Biomarker study were included. All participants completed cognitive testing, the MBI‐C (self‐reported), and florbetapir (amyloid), flortaucipir (tau) PET, and structural magnetic resonance imaging. We used Mann‐Whitney Test to examine group differences, and Spearman’s correlation and linear regression to examine associations among MBI‐C total score, Geriatric Depression Scale‐15 (GDS), Mini‐Mental State Examination (MMSE), CERAD word list learning delayed recall, cortical amyloid burden, regional tau, and hippocampal volume. In sensitivity analyses, we restricted carriers to the 18 unimpaired.

Result

MBI‐C total scores were similar between carriers and non‐carriers (p = 0.09). Compared to non‐carriers, carriers had greater amyloid burden (r = 0.55; p = 0.004) and lower hippocampal volume (r = ‐0.43; p = 0.034). Among all carriers, higher MBI‐C total scores were associated with lower hippocampal volume (r = ‐0.44; p = 0.034), greater amyloid burden (r = 0.5; p = 0.011), and worst memory performance (r = ‐0.36; p = 0.021). There were no associations with tau pathology (p‐values>0.05). Sensitivity analyses were consistent with previous results except for hippocampal volume (r = ‐0.4; p = 0.08).

Conclusion

Findings suggest that NPS captured by MBI‐C are associated with pathology and memory in a Colombian kindred with autosomal dominant AD, years before the median age of dementia onset in this cohort. This underscores the importance of behavioral symptoms in preclinical and prodromal ADAD. Follow‐up analyses with larger samples and longitudinal assessments are needed to characterize neuropsychiatric symptom evolution as an early marker and target for intervention.
Subjective Cognitive Decline‐Plus: Longitudinal Assessment and Risk for Cognitive Impairment
Authors: Kang Moonil , Li Clara , Mahajan Arnav , Spat‐Lemus Jessica , Durape Shruti , Chen Jiachen , Gurnani Ashita S. , Devine Sherral A. , Auerbach Sanford H. , Ang Ting Fang Alvin , Sherva Richard , Qiu Wei Qiao , Lunetta Kathryn L. , Au Rhoda , Farrer Lindsay A. , Mez Jesse
Published: January 2025

Background

Subjective cognitive decline (SCD) is recognized to be in the Alzheimer’s disease (AD) cognitive continuum. An international working group known as the SCD‐initiative recently proposed “SCD plus” features, including report of memory problems, recent SCD relative to conversion, SCD over age 60, and consistent SCD over time, that increase the risk for future objective cognitive decline. These have not been fully assessed in a large community‐based setting.

Method

Participants from all cohorts of the Framingham Heart Study who were ≥ 60 years with normal cognition at analytic baseline were included. SCD was assessed longitudinally using a single question. We treated SCD as a time‐varying variable and considered SCD to be present if it was endorsed at the last cognitively normal visit. If SCD was endorsed during two or more consecutive visits, including the last valid visit, it was considered to begin at the first of the consecutive visits. Outcomes included consensus‐diagnosed mild cognitive impairment (MCI), AD, and all‐cause dementia. Survival analyses were performed on time‐to‐event data obtained between 2005 and 2019 with up to 12 years of follow‐up. Models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS) excluding the APOE region.

Result

3,735 participants (mean baseline age: 68.0 years, women: 55.1%, non‐Hispanic Whites: 91.6%, SCD: 44.5%, APOE ε4 carriers: 21.5%) were included. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all‐cause dementia by 6.9 years. APOE ε4 and tertiles of AD PRS status did not significantly differ between SCD and non‐SCD groups. SCD was significantly associated with survival time to MCI (HR = 1.57; 95% CI = 1.22−2.03; P = 4.79×10−4), AD (HR = 2.98; 95% CI = 1.89−4.70; P = 2.80×10−6), and all‐cause dementia (HR = 2.14; 95% CI = 1.44−3.18; P = 1.82×10−4). After adjustment for APOE and AD PRS, the effects of SCD were largely unchanged.

Conclusion

In a community setting, SCD reflecting “SCD plus” features increased the risk of future MCI, AD, and all‐cause dementia with about the same HR estimated in clinic‐based settings. SCD may be an independent clinically expressed risk factor for preclinical AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.
Association of CSF AD biomakers and lifestyle factors with neuropsychiatric symptoms among non‐demented older persons
Authors: Soldan Anja , Truesdell Valerie , Pettigrew Corinne , Moghekar Abhay , Zipunnikov Vadim , Spira Adam P. , Albert Marilyn S. ,   BIOCARD RESEARCH TEAM
Published: January 2025

Background

Higher level of cognitive reserve (CR), measured using proxies such as years of education or literacy, is associated with reduced risk of Mild Cognitive Impairment (MCI) and dementia. Little is known about how CR and other lifestyle factors impact non‐cognitive outcomes, including depression and other neuropsychiatric symptoms (e.g., agitation, delusions, anxiety, etc.). This study examined whether factors that influence cognition among non‐demented older adults (i.e., CR, demographics, vascular risk, sleep quality, physical activity, ApoE4 genetic status) are also associated with depression and other neuropsychiatric symptoms, and whether these associations vary by AD pathology levels.

Method

Depression and other neuropsychiatric symptoms were assessed using the Geriatric Depression Scale (GDS) and Neuropsychiatric Inventory (NPI), among 181 non‐demented BIOCARD Study participants (mean age = 72.6y, including 152 cognitively unimpaired and 29 with MCI). Total volume of physical activity and sleep efficiency were measured using actigraphy. Level of CR was based on a composite of years of education, vocabulary, and reading ability. A subset of participants (n = 125) had cerebrospinal fluid measures of amyloid and tau (Fujirebio Lumipulse G1200 assays), with AD pathology levels summarized as the ratio of p‐tau181/(AB42/AB40). Linear regressions evaluated the cross‐sectional relationship between the risk and protective factors with total GDS and NPI scores, and interactions with AD‐pathology levels.

Results

For depression, greater total physical activity (p<0.004) and greater sleep efficiency (p = 0.006) were associated with lower GDS scores, independent of CR, age, sex, vascular risk, and ApoE4 status, which were not associated with GDS scores. The strength of this association was reduced among participants with higher AD‐pathology levels (p<0.05 for interactions of ptau181/(Ab42/Ab40 with physical activity and sleep efficiency. For neuropsychiatric symptoms, higher CR scores were associated with lower NPI scores and this association was independent of p‐tau181/(AB42/AB40) levels, but greater among those with poor sleep efficiency and among men.

Conclusion

These results suggest that level of cognitive reserve, sleep quality, and physical activity levels are associated with depression and other neuropsychiatric symptoms among non‐demented older adults. Moreover, these associations differentially depend on AD‐biomarker levels, suggesting that individualized approaches to the treatment of neuropsychiatric symptoms among older adults are likely most successful.
Neurobehavioral, and Cytoarchitecture Evaluation of the Therapeutic Potential of n‐butanol fraction of Phoenix dactylifera L. on lead acetate triggered neurodegenerative changes in Wistar rats
Authors: Lazarus Stephen S , Musa Sunday Abraham , Agbon Abel Noserenme , Sunday B Oladele
Published: January 2025

Background

Lead, a pervasive and toxic environmental pollutant, of particular concern is its impact as a trigger for neurodegenerative diseases. Phoenix dactylifera (date palm), has garnered attention due to its pharmacological properties: antioxidant and anti‐inflammatory, attributed to its rich flavonoid content. This assessed the therapeutic potentials of n‐butanol fraction of P. dactylifera (BFPD) on the behavioral and histomorphology of hippocampus lead acetate (PbA)‐induced neurotoxicity in Wistar rats.

Method

Forty‐two rats were categorized into seven groups (n = 7). Two experimental phases were employed: Toxicity‐phase, and Treatment‐phase. Toxicity‐phase: all rats received PbA (120 mg/kg), for 14 days, except group one (control); Treatment‐phase: group II (sacrificed), group III (Natural recovery), while groups (IV‐VII) received (500 mg/kg, 750 mg/kg and 1000 mg/kg) n‐BFPD and (100 mg/kg) vitamin C (as reference antioxidant). Treatment was via oral route, which lasted for 28 days. Therapeutic properties of n‐BFPD were assessed using Neurobehavioral assessment: Morris water maze performance and Novel object recognition test for (spatial memory, learning, and cognition); Oxidative stress biomarkers were assay using Malondialdehyde [MDA], and Superoxide dismutase [SOD], and microscopic hippocampus examination (CA1 and CA3) using histological and histochemical staining techniques and quantification of Nissl substance stain intensity using a computer running image analysis software (imageJ).

Result

PbA‐treated group revealed neurodegenerative changes as remarkable (p<0.05) memory, learning and cognition impairment, elevation MDA levels and decrease in antioxidant enzymes (SOD), and cytoarchitectural distortions evidenced by necrotic nuclei, vacuolation and pyknosis, compared to the control. However, treatment with n‐BFPD revealed cognitive improvement in memory and learning; decreased MDA levels and increased SOD activities. Mild distortion‐to‐relatively normal neuronal cytoarchitecture relative to the control was also observed with n‐BFPD treatment.

Conclusion

n‐BFPD possesses potential therapeutic properties against PbA‐induced neurobehavioural and cognitive deficit and pathological changes which are indicator of neurodegenerative diseases.

Keyword: cytoarchitecture, cognition, neurodegeneration
Pathological Associations with Rate of Progression of Frontotemporal Dementia
Authors: Magee Rogan , Ohm Daniel T , Rhodes Emma , Massimo Lauren , Wolk David A , Lee Eddie B , McMillan Corey T , Irwin David J
Published: January 2025

Background

There is considerable variability in the rate of clinical progression among individuals with frontotemporal dementia (FTD) and prognostic markers are lacking. Moreover, due to the rarity of postmortem data, the relationship between rate of progression and postmortem tau and TDP‐43 proteinopathy is understudied.

Method

To explore the pathologic underpinnings of differences in clinical progression of FTD, we used clinical data collected by the Penn Center for Neurodegenerative Disease Research from 130 patients with autopsy‐confirmed frontotemporal lobar degeneration (FTLD‐tau = 62, FTLD‐TDP = 68) across six domains (age at onset, survival in years, first Clinical Dementia Rating [CDR] scale score, first Mini‐Mental State Examination [MMSE] score, annual change in CDR, annual change in MMSE). We used principal components analysis to scale and collapse these data into two dimensions, and k means to automatically select three clusters based on silhouette width. We used automated digital pathology to measure mean percent area occupied (AO%) by TDP‐43 pathologic inclusions in up to 17 distinct autopsied brain regions.

Result

PCA (Fig 1A) Cluster 3 progressed relatively fastest and was enriched for FTLD‐TDP cases and GRN mutation carriers (Table 1). Among FTLD‐TDP cases, TDP type E was enriched in cluster 3 (3 of 4) and type C was enriched in cluster 1 (13 of 16). Among FTLD‐tau cases, progressive supranuclear palsy was overrepresented in cluster 1 (19 of 20). Principal component 1 (PC1) negatively correlated with independent measures of functional outcomes extracted from the clinical record, including the time to develop incontinence and complete dependence in activities of daily living (Figure 1B, C). PC1 correlated with the average pathologic TDP‐43 AO% in FTLD‐TDP cases (Figure 2).

Conclusion

Taken together, these results suggest that increased rate of clinical progression may relate to increased burden of TDP‐43 observed postmortem. The heterogeneity in the prognosis of FTLD may be driven by biological factors, such as disease activity. Further, FTLD‐TDP (especially FTLD‐GRN) may associate with faster progression. Biomarkers of FTLD‐TDP and/or improved access to mutation testing may improve prognostication in the care of FTD.
Classification of Microglia in Human Alzheimer’s Disease Postmortem Cases
Authors: Stephen Terri‐Leigh , Nguyen Kenneth , Hawes Debra , Breningstall Bayla M , Bienkowski Michael S
Published: January 2025

Background

Microglia undergo varying regional dependent functional changes, which can exacerbate cognitive decline in Alzheimer’s disease, but the full clinical relevance remains unclear. Ramified microglia survey the micro‐environment and inert/amoeboid microglia engulf debris. A third morphological type; rod microglia, have been observed in a number of pathological conditions, but are relatively understudied. It has been suggested that they form after acute neurological insult and understanding their anatomical distribution across brains with Alzheimer’s disease may provide useful information regarding disease progression.

Method

University of Southern California Alzheimer’s Disease Research Center (USC ADRC) post‐mortem hippocampal and prefrontal cortical sections were immunostained with 4G8 for amyloid, AT8 for neurofibrillary tau tangles and Iba1 for microglia and imaged using an Olympus VS120 slide scanning microscope. 20 Alzheimer’s disease cases and 10 control cases were selected to best represent population demographics (balanced for sex and ApoE genotype). We utilized Ilastik machine learning toolkit to classify amyloid pathology (dense, diffuse, and amyloid precursor protein), neurofibrillary tangles, neuritic plaques and microglia (rod, inert and ramified) within stained tissue section images. These classifications were then overlaid within manually segmented region maps (aligned with the Allen Human Brain Atlas) using the Quantitative Imaging Toolkit (QIT).

Result

Our findings revealed elevated rod and inert microglial staining in Alzheimer’s disease cases compared to controls alongside an increase in pathology burden across disease stage. Ramified microglia were reduced in Alzheimer’s disease cases compared to controls. Iba1 was correlated with amyloid pathology, specifically in the dentate gyrus (DG) of the hippocampus. Rod microglia were significantly more elongated with more processes in Alzheimer’s disease cases compared to controls. In general ramified had more processes, inert tended to be smaller with rod falling in between.

Conclusion

Regional variations in microglia morphology and function in Alzheimer’s disease could reflect differences in Alzheimer’s disease cell type susceptibility and have implications for understanding the disease progression.
Validating a measure of diminished motivation across the lifespan: Preliminary findings.
Authors: Scott Bonnie M , Rana Amtul‐Noor , Hilsabeck Robin C.
Published: January 2025

Background

Motivational disturbances are a major harbinger for dementia, being associated with a two‐ to seven‐fold higher conversion rate from mild cognitive impairment. However, there are currently no objective assessment methods for identifying motivational disturbances in older adults (OA). Here, we present preliminary findings from a larger study which aims to validate an objective behavioral measure of effort in OAs by investigating the effects of age, risk, and reward (gain vs. risk trials), and effort type (physical vs. cognitive) on motivated decision‐making.

Method

Two modified versions of the Effort Expenditure for Rewards Task (EEfRT) were developed, including one requiring physical effort (i.e., finger tapping: P‐EEfRT) and one requiring cognitive effort (i.e., working memory: C‐EEfRT). Both tasks included an equal number of gain and loss trials in which participants could choose to expend greater effort to either win or avoid losing points on each trial. Five younger (YA: ages 19‐22) and six older (OA: ages 67‐78) adults completed these tasks along with a cognitive screener and self‐report symptom inventories.

Result

YAs and OAs did not differ in cognitive status nor accuracy scores on the experimental tasks. A significant main effect and interaction of risk/reward magnitude and outcome valence (gain/loss) was found for the frequency of hard task selections on both the P‐EEfRT and C‐EEfRT, suggesting that the decision to exert greater physical and cognitive effort was significantly influenced by the combination of these task parameters in both age groups. A significant age group X outcome valence effect was also observed for both tasks, with YAs exhibiting considerably greater effort expenditure on trials with the possibility of gaining vs. losing points while OAs exhibited a similar pattern of performance for medium to large outcomes on the P‐EEfRT but failed to modulate their responses across task conditions on the C‐EEfRT. Finally, greater self‐reported symptoms of fatigue, apathy, and anhedonia were associated with lower cognitive and physical effort expenditure in the OA group and with slower decision‐making reaction times in the YA group.

Conclusion

Findings suggest that the influence of risk and reward on cognitive and physical effort‐based decision‐making varies across the lifespan.
Vascular health influences the correspondence between self‐report of physical activity and activity measures obtained with a smartwatch
Authors: Chaturvedi Riya , Holmqvist Sophia L. , Kaplan Marina , Simone Stephanie M. , Tassoni Molly B. , Mckniff Moira , Giovanetti Tania
Published: January 2025

Background

Greater physical activity (PA) is associated with better cognitive and vascular health, but accurate assessment of PA is challenging. Self‐report questionnaires of PA may be compared against objective measures from smartwatch sensors; the correspondence between measures may be influenced by a variety of factors such as cognition or age. The focus of this study was to identify baseline participant characteristics (vascular risk, cognition) that influence the association between self‐reported PA and PA measured with a Garmin Vivosmart 4 smartwatch in a racially diverse sample of older adults.

Method

32 older adults (M age = 68.53); 32% Black/African American) with healthy cognition (n = 26) or mild cognitive impairment (n = 6) completed the International Physical Activity Questionnaire (IPAQ) to assess PA (moderate and vigorous intensity, walking; metabolic equivalent [MET] minutes) and the Framingham Stroke Risk Profile (FSRP) to assess vascular risk. A cognitive composite was evaluated as an average of t scores from several neuropsychological tests. PA was also measured over a 30‐day period in which participants wore a Garmin Vivosmart 4 smartwatch for 23 hours/day that captured duration of moderate and vigorous intensity PA and daily steps. Smartwatch measures were averaged across the 30‐day monitoring period. Discrepancy scores between the three Garmin PA metrics and three corresponding self‐reported PA measures were computed as the difference between sample‐based z‐scores. Relations between discrepancy scores and demographics/clinical characteristics were analyzed using Spearman correlations or independent samples t‐tests.

Result

Greater overreporting of self‐reported walking PA was significantly related to lower education (ρ = ‐.440, p = .012) and greater vascular risk (ρ = .433, p = .013). There were no significant relations between overreporting of moderate/vigorous intensity PA and participant characteristics. There were no significant relations between cognition or sex and overreporting of PA.

Conclusion

Vascular health was associated with overreporting of PA on self‐report measures relative to objective measures obtained with a smartwatch, but vascular health influenced only one of three measures (i.e., step count). Cognitive abilities and sex were not associated with discrepancies between subjective and objective measures of PA. Further work is needed to determine whether vascular heath biases either self‐report or sensor measures of daily steps in older adults.
Cognitive Flexibility in Bilinguals and Multilinguals and Its Implications for Dementia
Authors: Akkunje Preetie Shetty , Ramesh Keerthana , Archa Sasi Kumar , Hegde Prasanna Suresh , Thaut Michael H.
Published: January 2025

Background

Verbal fluency (VF) is crucial for language processing and cognitive flexibility, involving selective attention, inhibition, set shifting, response generation, and self‐monitoring. VF assessment includes two distinct tasks, i.e., phonemic and semantic VF. It assesses long‐term verbal semantic memory, phonological awareness, lexical–semantic access, and executive function. Semantic VF is mainly based on generating semantic associations, whereas phonemic VF is based majorly on executive functions instead of lexicon–semantic networks. Even though the VF involves several neural substrates majorly is coordinated by superior frontal lobe and temporal lobe for phonemic and semantic VF, respectively. This study aims to assess VF in linguistically diverse young adults of bilingual and multilingual individuals and its contributing insights into language‐cognition interplay.

Method

A prospective cross‐sectional research study recruited 120 participants, divided into two groups: bilinguals (proficient in at least two languages;n = 60) and multilinguals (proficient in at least three languages;n = 60), identified through the Language Experience and Proficiency Questionnaire. Inclusion criteria encompassed participants aged 20‐50, of both genders, with standard education up to graduation. Participants with neurological or psychiatric language disorders and those scoring ≤25 on the Montreal Cognitive Assessment were excluded from the study. Research‐specific assessments, including Spontaneous speech of Western Aphasia Battery, Addenbrooke’s Cognitive Examination‐III for cognitive functions and VF tests (phonemic & semantic VF, phonemic & semantic switching tasks, alternating language task, controlled semantic association task), were conducted in L1, L2 for bilinguals and L1, L2, and L3 for multilinguals. Statistical evaluation was done using SPSS‐version‐29.0.10, utilizing descriptive statistics, Likelihood ratio, Chi‐square, and Independent sample t’‐tests.

Results

Participants recruited showed no significant difference between groups for age, gender and education highlighting linguistic‐diversity of participants which is essential for comprehending potential variations in research findings and their general applicability. The results revealed that bilinguals outperformed multilinguals in semantic VF tasks while multilinguals outperformed bilinguals in phonemic verbal VF tasks.

Conclusion

The adaptability in switching between semantic fields and linguistic‐dimensions of temporal lobe, particularly evident in bilinguals, underscores the cognitive advantages of bilingualism. These findings are crucial for formulating targeted interventions tailored to the unique needs of linguistically‐diverse dementia patients, to strengthen neural‐networks which can account for the principles of neuroplasticity.
Remote digital memory assessment in middle‐aged and older adults: Feasibility, reliability, and construct validity
Authors: Clark Lindsay R. , Basche Kristin E , Peterson Amanda , Rosario Hannah , Johnson Sterling C. , Düzel Emrah , Berron David
Published: January 2025

Background

Frequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). Our objective was to evaluate the feasibility, reliability, and construct validity of repeated remote memory assessment in late middle‐aged and older adults.

Method

Participants were recruited from longitudinal aging cohorts to complete medial temporal lobe‐based memory paradigms (Object‐In‐Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT‐OS], Complex Scene Recognition [CSR]) using the neotiv application on a smartphone or tablet at repeated intervals over one year. Participants were randomized to a task schedule (biweekly or bimonthly burst) for a total of 24 ten‐minute remote sessions. Feasibility metrics included participation, retention, compliance, and acceptability. Intraclass correlation coefficients (ICC) assessed test‐retest reliability over an 8‐week period. Analysis of covariance (ANCOVA) models including covariates of demographics, device type, and task schedule were used to evaluate relationships between neotiv baseline performance and traditional memory scores (Rey Auditory Verbal Learning Test [RAVLT]; Preclinical Alzheimer’s Cognitive Composite [PACC]).

Result

Of 280 potentially eligible adults, n = 180 consented (64% participation rate). Of 180 consented, n = 133 completed at least one session and n = 119 completed or nearly completed all sessions (retention rate = 66% for all consented and 89% for all completed 1+ session). Delayed retrieval sessions were completed within expected timeframes in 72% of sessions. Greater than 90% of respondents felt the application was easy to use, instructions were understood, and the frequency and length of remote sessions were appropriate. 60% enjoyed completing the tasks (34% felt neutral) and 40% preferred mobile tests to traditional cognitive testing (42% felt neutral). Test‐retest reliability was moderate (ICC = 0.54‐0.70). RAVLT and PACC were significantly associated with MDT‐OS, CSR, and ORR performance (p’s <.001).

Conclusion

Challenges to participation occurred primarily during enrollment; future studies may allocate additional support facilitating registration and initial task completion within the application. Acceptability of the mobile tasks was high. The mobile memory paradigms exhibited moderate test‐retest reliability and were significantly related to gold‐standard cognitive tests. Overall, findings support preliminary feasibility, reliability, and validity of the neotiv tasks in assessing memory function in cognitively healthy adults enriched for AD risk.
Attention‐deficit/hyperactivity disorder impacts the development of neuropsychiatric symptoms in Alzheimer’s disease
Authors: Leffa Douglas Teixeira , Bellaver Bruna , Povala Guilherme , Ferreira Pamela C. L. , Ferrari‐Souza João Pedro , Lussier Firoza Z , Soares Carolina , Zalzale Hussein , Bauer‐Negrini Guilherme , Abbas Sarah , Karikari Thomas K , Rohde Luis Augusto , Molina Brooke , Pascoal Tharick Ali
Published: January 2025

Background

Recent studies have shown that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). Increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with a more severe AD presentation, including worse cognitive function and higher tau pathology. Neuropsychiatric symptoms (NPSs) are common in AD and are hypothesized to occur with disease progression. It is unclear whether ADHD predispose individuals to the development of NPSs.

Method

We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate the associations between ADHD‐PRS and the development of NPSs in cognitively impaired (CI, including MCI and AD) subjects who had brain amyloidosis at baseline. NPSs were assessed with the NPI or NPI‐Q and divided into four syndromes: hyperactive (agitation, disinhibition, irritability, and aberrant motor behavior), psychosis (delusions, hallucinations, and night‐time behavior disturbances), apathy (apathy and appetite and eating abnormalities), and affective (depression and anxiety). Additionally, we tested the specificity of our findings by analyzing the association between the genetic risk for depression, bipolar disorder (BD), schizophrenia, and autism spectrum disorder (ASD) with the development of NPSs. Data were represented with Kaplan‐Meier survival curves, and analyses were performed with Cox proportional hazards regression models controlled by age, sex, and ancestry.

Result

We evaluated data from 852 participants (636 MCI [74.1%], 350 women [40.8%], mean [SD] age of 73.4 [7.3] years). ADHD‐PRS was associated with a higher risk of developing hyperactive (HR 1.41; 95% CI 1.04‐1.89) and apathy (HR 1.34; 95% CI 1.01‐1.77) symptoms, but not psychosis (HR 1.04; 95% CI 0.78‐1.41) or affective (HR 0.97; 95% CI 0.72‐1.32) symptoms. There was no association between the genetic risk for depression, BP, schizophrenia, or ASD with any neuropsychiatric syndrome.

Conclusion

Findings indicate that a higher genetic risk for ADHD may be a risk factor for the development of hyperactive and apathy symptoms in CI individuals. These effects were specific for ADHD and were not observed for other prevalent psychiatric disorders. Clinically, our results contribute to the literature that highlights the need for tailored assessments for CI individuals with ADHD histories.
Inflammatory changes underlying sepsis‐induced cognitive deficits in the Tau P301S mouse model of Alzheimer’s disease
Authors: Smith Camryn , Tienda Adriana , Harrison Fiona E.
Published: January 2025

Background

The prevalence of sepsis and delirium in the elderly is a risk factor for subsequent diagnosis of Alzheimer’s disease and related dementias (ADRD). Post‐sepsis impairments include changes in memory, attention, emotional function, and neuromuscular strength. Studies have shown a link between the prolonged activation of microglia after infection. However, the exact mechanisms remain unclear. Challenges in modeling delirium in animal models include use of young animals, short trial endpoints, and sickness behaviors that can confound behavioral assessments. We sought to address these challenges using animals with additional ADRD‐related neuropathology. We hypothesized that age and ADRD neuropathology will be associated with greater and prolonged microglial dysfunction, and poorer behavioral outcomes after sepsis.

Method

Male and female Tau P301S mice were used for this study at 5 months of age. These mice exhibit tau tangles, microgliosis and cell loss by 8 months of age. Mice of each genotype received either a polymicrobial cecal slurry injection to cause sepsis, or a vehicle control injection. Health scores of the mice were collected across the sickness timeline. Four days after infection, following recovery, behavior paradigms were conducted including y‐maze, fear conditioning, activity, rotarod, and nest‐building. The mice were then euthanized, and brains and plasma were collected to measure the progression of Alzheimer’s pathology and inflammatory response post‐infection.

Result

Male mice of both genotypes were more sensitive to the cecal slurry treatments than females as indicated by sickness scores and time to recover. In male mice, P301S mice were more sensitive to the chronic effects of sepsis with greater changes in locomotor activity and tests of learning and memory.

Conclusion

The data supports the link between poorer outcomes following sepsis in the presence of existing Alzheimer’s pathology and highlight a difference in the response to a systemic inflammatory challenge between male and female mice. These mice were tested prior to major development of ADRD‐related pathology to understand how additional inflammatory challenges may drive progression of ADRD pathology and behavioral changes. Future studies will confirm the range of neuropathological and neuroinflammatory changes in these mice.
A health intervention improves cognition in older adults at risk for Alzheimer’s Disease
Authors: Gray Michelle , Urbina Ray G , Jones Megan , Campitelli Anthony , Gills Joshua L , Paulson Sally , Glenn Jordan M.
Published: January 2025

Background

Alzheimer’s disease (AD) is the 7th leading cause of death and 6th most burdensome disease among US older adults. With pharmacological treatments for AD being predominantly ill‐effective, alternative, non‐pharmacological prevention and treatment strategies warrant exploration. Personal health coaching provides individualized strategies designed to improve physical, social, and emotional health leading to positive behavior changes that may improve cognitive ability. The purpose of the present investigation was to examine the effects of a health intervention on cognitive outcomes.

Method

Adults (n = 184), 60+ years, completed a 24‐month health intervention. All participants had their APOE4 status determined at baseline. Each participant completed either a monthly health coaching (HC) session or received bi‐weekly health education information email (HE). RBANS and ECOG‐12 were completed at baseline and 24 months. A repeated measures ANOVA was completed to determine changes in health intervention groups and APOE4 carrier groups over time.

Result

RBANS was significantly improved after HE for most tested RBANS cognitive paradigms (Language, Immediate and Delayed Memory, and Attention) among APOE4 non‐carriers. The HC intervention significantly improved Immediate Memory, and Attention among APOE4 non‐carriers. Among APOE4 carriers, HE improved Delayed Memory and the HC intervention improved Immediate Memory. ECOG‐12 values were significantly improved for both intervention groups, but only for APOE4 non‐carriers.

Conclusion

Both HC and HE produced significant improvements in many cognitive paradigms among APOE4 non‐carriers, though subjective cognitive decline was only improved in APOE4 non‐carriers. More information is needed to dissect the impetus for the changes in cognition.