bluuebunny/crossref_metadata_2025 huggingface dataset:
Objective and subjective sleep quality in Amnestic and Non‐Amnestic Elderly Patients: is a subjective report from the patient an accurate?
Authors: Gumenyuk Valentina , Roth Thomas , Korzyukov Oleg , Miller Nicholas , Jones Tristan , Rizzo Matthew , Murman Daniel L
Published: January 2025

Background

Sleep disturbances and cognitive impairments, especially memory deficiency are one of the most common complications affecting everyday life in patient diagnosed with neurodegenerative disorder. Clinically evaluated, specific cognitive processes can be grouped into two categories: amnestic functions (AMN, clinically memory impairments) and non‐amnestic functions (n‐AMN, cognitive impairments non‐memory related). To date, no cure treatments are available for AMN / n‐AMN patients, therefore maintaining the well‐being and an adequate sleep quality of people who are in prodromal state (i.e., AMN or n‐AMN is a high priority for society general and for the patient / family specifical. In this study, we compared objective sleep results to self‐reported sleep in AMN and n‐AMN groups with respect to healthy matched controls to investigate whether the self‐reported sleep results are accurate

Method

Sleep disturbances and cognitive impairments, especially memory deficiency are one of the most common complications affecting everyday life in patient diagnosed with neurodegenerative disorder. Clinically evaluated, specific cognitive processes can be grouped into two categories: amnestic functions (AMN, clinically memory impairments) and non‐amnestic functions (n‐AMN, cognitive impairments non‐memory related). To date, no cure treatments are available for AMN / n‐AMN patients, therefore maintaining the well‐being and an adequate sleep quality of people who are in prodromal state (i.e., AMN or n‐AMN is a high priority for society general and for the patient / family specifical. In this study, we compared objective sleep results to self‐reported sleep in AMN and n‐AMN groups with respect to healthy matched controls to investigate whether the self‐reported sleep results are accurate

Result

Table summarizes all results found in the study. AMN group showed lower score in cognitive memory related processes (Craft story and Benson figure recall), as compared to n‐AMN and Healthy groups. Both patient groups overestimated their SE in self‐report data as compared to SE in objective actigraphy data. In healthy group, the SE was accurately self‐reported (see Figure).

Conclusion

Our results suggest that regardless of the severity of memory impairments objective measure of sleep should be implemented for clinical evaluation.
Initial symptoms in individuals with Alzheimer’s or mixed Alzheimer’s‐Lewy body dementia are noted at an older age and are more likely to be amnestic in African Americans than Whites
Authors: Beamon Quintasha , Zhu Audrey , Bena James , Leverenz James B , Pillai Jagan A.
Published: January 2025

Background

Amnestic initial symptoms are common in Alzheimer’s disease(AD). However initial non‐amnestic (language, executive or visuospatial) symptoms are seen in ∼20% and associated with faster progression. Given racial differences in clinical and biomarker characteristics in AD, we explored if initial cognitive symptoms differed by race of the participants among autopsy confirmed AD, Lewy body pathology (LBP) and mixed pathology (AD‐LBP).

Methods

A retrospective cohort study conducted among 2422 participants with confirmed ADP, LBP, or mixed ADP‐LBP meeting neuropathogy diagnostic criteria in National Alzheimer Coordinating Center (NACC) data from 2005 to 2019. Participants at initial visit had a Clinical Dementia Rating‐Global (CDR‐G) scale ≤1. Due to sparse data in some minorities, analysis was limited to racial groups that had participants with both amnestic and non‐amnestic symptoms. This limited analysis to 93 African American (AA) and 2,299 White participants. Statistical methods including two‐sample t‐tests and Fisher’s Exact tests and Firth’s logistic regression examined the impact of race, age, sex and education on initial symptoms.

Results

Initial cognitive symptoms in AA were noted at an older age compared to Whites (mean[SD] (71[10] vs 69[10] yrs, p = 0.04) and their age at death was older (83[10] vs 81[10] yrs, p = 0.04) across neuropathologies. When the groups were evaluated within neuropathologies, age at onset differences were significant only in mixed ADP‐LBP (71[9]vs 68[10] yrs, p = 0.029) although a similar trend was noted for other neuropathologies. AA participants were less likely to have initial non‐amnestic symptoms than Whites (7.5% vs 23.6% p<0.0001). Similar results were noted when the groups were evaluated within ADP and AD‐LBP(Only 6 AA participants with LBP limited analysis). AA also differed from Whites on initial MMSE (22 vs 24, p = 0.003), CDR‐Sum of boxes (4.5 vs 4, p = 0.047), female% (51.6% vs 39.7%, p = 0.024) and education (14 vs 16yrs, p<0.001), but no difference in APOE ε4 carriers were noted. Despite considering age, sex and education in the regression model, AA had higher odds, 3.06(95%CI 1.51‐7.92) for amnestic initial symptoms compared to Whites.

Conclusion

Initial cognitive symptoms in AA were reported at an older age than Whites in the NACC. Non‐amnestic initial symptoms were less common among AA than Whites.
Comparing effects of demographic variables on current and novel neuropsychological measures in older adults with and without Alzheimer’s disease
Authors: Reed Alexandra M. , Duff Kevin , Schaefer Sydney Y
Published: January 2025

Background

Neuropsychological assessments are often affected by demographic factors, such as age, education, and sex. These demographic variables frequently lead to differences in test scores between minorities and non‐minorities, lowering diagnostic accuracy of Alzheimer’s disease (AD) among minoritized groups. A new test (quick Behavioral Exam to Advance Neuropsychological Screening, or qBEANS) has been developed to assess early signs of AD. The current study compared the influence of demographic variables on qBEANS and other neuropsychological tests that are commonly used in the assessment of AD.

Method

In this study, 165 participants (68 cognitively unimpaired; 52 amnestic Mild Cognitive Impairment; 45 mild AD) completed the Symbol Digit Modalities Test (SDMT), Hopkins Verbal Learning Test‐Revised (HVLTR); Brief Visuospatial Memory Test‐Revised (BVMTR); and Trails Making Test (TMT) A and B. Participants also completed the qBEANS, which involves spooning two raw kidney beans at once with the nondominant hand to one of three target cups in a simple sequence, with higher scores being worse performance. Effects of age, education, and sex on raw test scores were analyzed using multivariable linear regression, with p‐values adjusted for multiple comparisons. Fisher transformations were used to examine if current tests were more affected by demographic variables than qBEANS.

Result

Participants' are was 65‐91 years (mean = 74.1) and education was 12‐20 years (mean = 16), with 56.3% female. Significant age effects were observed for all tests except qBEANS (p = .10) and TMT‐A (p = .73), with older ages being associated with worse scores. Similarly, there were significant education effects for all tests except qBEANS (p = .41), TMT‐A (p = .73), and TMT‐B (p = .31), with fewer years of education being associated with worse scores. Only the HVLTR (total and delayed recall) showed a significant sex effect, with females performing better than males. The overall influence of age, education, and sex on qBEANS scores was significantly smaller than the SDMT, HVLTR, and BVMTR (no different with TMT‐A or TMT‐B).

Conclusion

Unlike most neuropsychological tests, qBEANS may be appropriate for screening diverse populations without controlling for demographic variables. Future research should consider populations with lower educational attainment, as well as race, ethnicity, and native language on qBEANS relative to other neuropsychological measures.
A Challenging Case of Lewy Body Disease in a Symptomatic Patient Negative for Phosphorylated Alpha‐Synuclein: Implications for Lewy Body Spectrum Disorders
Authors: Alhneif Mohammad , Cherukuwada Lakshmi , Keating Mallory , Corbett William Cole , Gonzalez Angelique D. , Ogunbona Oluwaseun , Bieniek Kevin F. , Seshadri Sudha , Etemadmoghadam Shahroo , Flanagan Margaret E
Published: January 2025

Background

Lewy bodies (LBs), characterized by intraneuronal inclusions of misfolded alpha‐synuclein (α‐syn) protein, are the pathological hallmark of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Because this protein is phosphorylated at serine‐129 in 90% of LBs, its phosphorylation is considered a crucial pathogenic event in LB formation and disease development. Here, we present a unique brain autopsy case of a DLB patient with widespread LBs that were negative for phosphorylated‐α‐syn, challenging traditional diagnostic criteria.

Method

An 86‐year‐old male with a history of agent orange exposure presented with cognitive decline, REM sleep behavior disorder, tremors, and visual hallucinations. Clinical workup was inconclusive, suggesting atypical Parkinsonism or possible DLB. Postmortem neuropathological examination of H&E slides revealed numerous LB‐appearing inclusions in the midbrain. To confirm their identity, immunohistochemical staining for pSYN64, an antibody against phosphorylated‐α‐syn, was performed which showed negative staining (with an appropriately positive control slide which verified that the stain worked). Further immunohistochemistry with antibodies against P62, LB509, and anti‐nitro‐α/β‐synuclein as well as pSYN64 in other brain regions was performed. P62 is regarded as a surrogate marker of α‐Syn inclusions and LB509 is known to stain total α‐syn. Anti‐nitro‐α/β‐synuclein detects nitrated synuclein.

Result

The LB‐like inclusions in all brain regions including the midbrain showed positive staining for P62 and LB509, confirming their α‐synuclein content, but pSYN64 was consistently negative. Anti‐nitro‐α/β‐Synuclein showed scattered staining. The LB disease in this case was neocortical stage, which explains the patient’s cognitive impairment. Additionally, brainstem involvement justifies his parkinsonism during life.

Conclusion

This case challenges the long‐held notion that phosphorylated‐α‐syn is an essential component of LBs especially needed to cause clinical symptoms. The absence of phosphorylated‐α‐syn LBs in a symptomatic patient suggests that additional proteins, or alternative mechanisms of abnormal protein accumulation may be involved in disease pathogenesis. This report highlights the complexity of LB pathology and emphasizes the need for continued research to unravel the diverse protein aggregates and mechanisms underlying LB formation and neurodegeneration. By expanding our understanding of LB spectrum disorders, we can enhance diagnostic procedures and facilitate the development of targeted therapies for patients with these diverse and debilitating conditions.
Preliminary Findings from EMPOWER: Evaluating Memory as Part of Women’s Routine Care
Authors: Joyce Jillian L. , Cosentino Stephanie , Rizer Sandra , Dargie Samantha A. , Chapman Silvia , Mora Laura , Libon David J. , Tom Sarah E. , Marder Karen , Rosser Mary
Published: January 2025

Background

Despite evidence that Alzheimer’s disease (AD) related pathological changes occur earlier in women than men, women are diagnosed later. To address this care disparity, the Evaluating Memory as Part of Women’s Routine Care (EMPOWER) program was established to integrate cognitive screening into routine gynecological well‐woman visits. Recent work has demonstrated the feasibility of conducting subjective cognitive screening at the well‐woman visit. The extent to which such subjective screening maps onto objective cognitive screening is critical. Here we outline preliminary results from the EMPOWER program, where both a subjective memory screener and a novel digital cognitive assessment were used to screen cognition.

Method

Women 50 and older appearing for routine gynecological well‐woman visits at the Columbia University Integrated Women’s Health Center were eligible to participate in this study. Participants completed a subjective cognitive survey, the Screener for Cognitive Problems in Everyday Life (SCOPE), as well as a digital cognitive task, the Linus Health Core Cognitive Evaluation (CCE). The SCOPE scores range from 0‐5, and endorsement of any item is considered a positive screen. The CCE comprises a digitized version of the Mini‐Cog (three‐word recall and clock‐drawing). CCE performance ranges from 0‐5 points, with 4‐5 as Normal, 2‐3 as Borderline, and 0‐1 as Impaired.

Result

Of 130 eligible women, 71 (55%) were recruited. Table 1 provides descriptive demographic and cognitive data. Total number of items endorsed on the SCOPE was associated with total CCE performance (Table 2). Additionally, women that screened SCOPE positive were more likely to perform in the borderline/impaired category of the CCE (Table 3).

Conclusion

Integrating cognitive screening into the routine gynecological well‐woman exam can identify midlife and older women experiencing cognitive difficulties, a critical step in addressing the care disparity. The current study demonstrates the validity of a subjective cognitive screener for detecting early cognitive dysfunction. A limitation of the study is the lack of ethnic and racial diversity, especially groups that are at increased risk for AD. Ongoing work is expanding EMPOWER to clinics that serve a more sociodemographically diverse patient population. Future work should include longitudinal monitoring to assess both subjective and objective cognitive changes over time.
Exploring the Intersection Between Seizures, Traumatic Brain Injury, and the Risk of Incident Cognitive Impairment in Cognitively Normal Older Adults
Authors: Babulal Ganesh M. , Trani Jean‐Francois , Zhu Yiqi
Published: January 2025

Background

Seizures, traumatic brain injury (TBI), and dementia increase in prevalence with age. However, the role of seizure and TBI on cognitive impairment risk (CI) is unclear. This study investigated how a diagnosis of seizures and TBI was associated with the progression to CI and assessed the role of medications.

Method

We analyzed data from the National Alzheimer’s Coordinating Center (NACC) (June 2020 data‐freeze). Inclusion criteria required participants 1) aged 65 years or older at their first visit, 2) cognitively normal at baseline (Clinical Dementia Rating [CDR] score of 0), and 3) complete information on race, age, gender, and education. 8,139 participants were included and followed until dropout or the first instance of CI progressing CDR 0 to 0.5. Seizure and TBI were determined by the clinician’s judgment based on medical history and the participant’s annual visits. Medication categories were derived by NACC using Ultum/Lexi‐Comp© therapeutic drug categories. Age, sex, race/ethnicity, and education were included as control variables. Cox proportional hazards model examined the associations between the diagnosis of seizure, TBI, or both and the progression of cognitive impairment measured by CDR. To account for selection bias, we applied propensity score weighting (PSW) with the inverse probability treatment weighting (IPSW) technique.

Result

Unadjusted survival models found a diagnosis of seizures significantly increased the hazard ratio (HR) of CI progression by 58% (p < 0.05), while the diagnosis of TBI increased the HR by 28% (p < 0.05). After applying IPSW to reduce the selection biases, the diagnosis of seizures increased the HR for CI by 39% (p < 0.05), TBI increased it by 25% (p < 0.001), and having both seizure and TBI diagnoses increased the risk of CI by 56% (p < 0.05). The use of antipsychotic, anxiolytic, sedative, or hypnotic agents and angiotensin‐converting enzyme (ACE) inhibitors was found to reduce the risk of CI significantly.

Conclusion

The presence of seizure or TBI was significantly associated with the increased risks of CI. Antipsychotic, anxiolytic, sedative, or hypnotic agents and angiotensin‐converting enzyme (ACE) inhibitors were associated with a reduced risk, emphasizing the importance of early treatment.
Impact of smell dysfunction of Covid‐19 in older adults on cognition and quality of life
Authors: Velayudhan Latha , Mitchell James , Pickering Ellie , Palmer Abbie , Richards Megan , Khan Zunera , Corbett Anne , Ballard Clive G , Aarsland Dag
Published: January 2025

Background

Smell dysfunction has been one of coronavirus disease 2019 (Covid‐19) symptoms. Identification of those with these symptoms are important as olfactory impairment in general has been studied to have increased mortality, poor quality of life, increased incidence of depression and risk for dementia. Smell dysfunction related to Covid‐19 in older adults and its impact is lesser studied. We evaluated impact of covid‐19 infection and smell dysfunction on cognition and quality of life in older adults above 50 years of age.

Methods

A longitudinal online survey, Smell and Taste Function in Older Adults in the Covid‐19 Pandemic (STAP) was added as a sub‐study to the ongoing remote wider study‐ Platform for Research Online to investigate Genetics and Cognition in Ageing (www.protect.org.uk). A separate ethics approval was sought for STAP (Reference LRS‐19/20‐18549). Interested participants of PROTECT study within the UK completed online questionnaire following consent, on a quarterly basis for a year. Information on Covid‐19 symptoms, testing, diagnosis, re‐infections, vaccinations and management was collected as part of the questionnaire in addition to socio‐demographic details, medical and lifestyle history and quality of life.

Results

Of the 3725 participants who took part in the baseline survey since June 2021, 1017 participants completed the follow up survey with the addendum questionnaire on re‐infections, vaccination history and other symptoms including self‐reported cognitive problems. The mean age was 66.65 years (7.87) and 80.5% were women. Of the 437 of the participants who reported having had Covid‐19 infection, 116 participants (26.5%) had partial or total smell loss. Olfactory impairment caused by Covid‐19 was associated with poorer quality of life especially social activities, diet and mood. People with Covid‐19 related smell impairment had significantly higher mental fatigue, attention and concentration problems, difficulties with memory, planning and organising, word and name finding difficulties and making decisions.

Conclusions

Older adults with smell dysfunction related to Covid‐19 infection had poorer quality of life and cognitive abilities affected. Further research is needed not only to understand the longitudinal course of smell impairment related to Covid‐19 and cognition, but also important to devise interventions to support these individuals to improve their well‐being.
Uncovering Molecular Features that Contribute to Tau Spread and Aggregation
Authors: Rauch Jennifer
Published: January 2025

Background

Tauopathies are a class of neurodegenerative diseases marked by tau protein spread and aggregation. Recently, our group described the cellular receptor Low‐density lipoprotein Receptor‐related Protein 1 (LRP1) as a regulator of tau spread. Knockdown of LRP1 halts tau spread in human induced pluripotent stem cell‐derived neurons and the mouse brain, indicating potential therapeutic implications. However, a comprehensive understanding of the tau‐LRP1 molecular complex remains elusive.

Method

Our research focuses on elucidating the tau‐LRP1 structural interface and investigating how tau aggregate structure influences LRP1 processing. We are using covalent‐labeling mass spectrometry to map the tau‐LRP1 interface in vitro and in cells. We are isolating brain‐derived tau oligomers from various tauopathies and measuring their dependence on LRP1 using cell culture models of tau propagation.

Result

Our results have identified residues critical for the interaction between tau and LRP1. Further, we have determined that brain‐derived tau oligomers utilize LRP1 for their endocytosis and that this is potentially dependent on structural elements of tau oligomers.

Conclusion

Our work provides insights into the structural aspects underlying tau‐LRP1 interactions and lays the groundwork for the design of potential disease therapeutics.
Comparison of skin carotenoid content and dietary intake between cognitively normal older adults and older adults with Alzheimer’s Disease: an updated matched‐pair analysis
Authors: Keller Jessica E , Sullivan Debra K , Taylor Matthew K , Burns Jeffrey M , Swerdlow Russell H
Published: January 2025

Background

Alzheimer’s Disease (AD) is a systemic metabolic disease with a variable number and type of clinical symptoms mostly impacting the brain. Skin carotenoid content (SCC) is an objective measure of carotenoid‐containing fruit and vegetable intake that has been validated in diverse populations. Our previous findings suggest SCC scores differ between older adults with and without AD regardless of dietary intake of carotenoids. Therefore, our objective was to investigate this correlation across a larger sample of matched pairs.

Method

Baseline data from two dietary interventions (NCT03860792, NCT03841539) were analyzed. Pairs are exact matches for sex, race/ethnicity, and education and are matched within three years of age and 5 kg/m2 body mass index. Each pair (n = 26 pairs) includes one cognitively normal (MMSE > 25), community dwelling older adult (‘CN’) and one community dwelling older adult with AD (‘AD’). Baseline self‐reported dietary intake data (3‐day food records) were collected, reviewed, and entered into the Nutrition Data System for Research (NDSR 2019) database by a Registered Dietitian. SCC scores were collected through pressure‐mediated reflection spectroscopy via VeggieMeter® (Longevity Link Corporation, Holladay, UT). Paired samples t‐tests were used to compare differences in SCC scores and dietary intake (IBM SPSS, version 29). Significance was set at p = 0.05.

Result

SCC scores were different between matched pairs (SCC scores: AD 194.62, CN 281.50, p = 0.002). There was no difference in dietary intake between AD and CN pairs for daily energy (1768 vs 1824kcal/day; p = 0.75), fat (75.6 vs 78.7g/day; p = 0.71), carbohydrate (196.7 vs 190.0g/day; p = 0.73), or protein (74.3 vs 76.3g/day; p = 0.77), respectively. Both groups had similar food group intake (p‐value range 0.18‐0.84), including all fruit and vegetable groups except CN had higher intake of non‐citrus fruit (p = 0.03; +0.59 servings/day). Individual carotenoid intake was not different between groups (total vitamin A, p = 0.31; beta‐carotene, p = 0.31; alpha‐carotene, p = 0.41; beta‐cryptoxanthin, p = 0.54; lutein+zeaxanthin, p = 0.32; lycopene, p = 0.42).

Conclusion

This updated analysis suggests that individuals with AD have lower skin carotenoid content compared to matched cognitively unimpaired individuals. These differences are not explained by differences in diet suggesting that AD may be associated with disease‐associated biochemical features that are metabolism‐related and not limited to the brain.
Lifetime stressor exposure and cognition in community‐dwelling older Latino adults from the Boston Latino Aging Study
Authors: Martinez Jairo E. , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Martinez Lusiana , Munera Diana , Vila‐Castelar Clara , Giudicessi Averi , Schwab Nadine A , Gomez Liliana A Ramirez , Gatchel Jennifer R. , Saldana Daniel G , Catalan Marta Gonzalez , Slavich George M , Tompson Martha , Cronin‐Golomb Alice , Quiroz Yakeel T.
Published: January 2025

Background

Stressors occurring over the lifespan (i.e., lifetime stressor exposure) are hypothesized to contribute to greater risk of cognitive decline and dementia. There is a higher prevalence of Alzheimer’s disease and related disorders in Latinos compared to non‐Latino Whites. Relative to non‐Latino Whites, Latinos report higher levels of stress, but few studies have examined lifetime stressor exposure in Latinos. To address this gap, we used the Stress and Adversity Inventory for Adults (Adult‐STRAIN) translated into Spanish to examine lifetime stressor exposure and its relation to cognition in community‐dwelling older Latino adults.

Method

110 participants from the Boston Latino Aging Study (BLAST) were included (mean age = 68.7 [SD = 8.4] years, mean 10.5 [SD = 5.3] years of education, 85 females, 28 with mild cognitive impairment). The Adult STRAIN was used to assess lifetime stressor exposure and severity. The Preclinical Alzheimer’s Cognitive Composite‐5 (PACC5), adapted for Spanish speakers, was used to assess cognitive performance (z‐scores) across five measures (Mini‐Mental State Examination [MMSE]; Wechsler Adult Intelligence Scale‐4th edition Coding; Free and Cued Selective Reminding Test; NEUROPSI Atención y Memoria: Logical Memory; and Category Fluency [Animals]). Linear regressions examined associations between lifetime stressor exposure, stressor severity, age, sex, education, and cognition.

Result

On average, participants reported 27.7 (SD = 13.8, range = 5‐85; possible range = 0‐166) total lifetime stressors with a total severity score of 65.0 (SD = 35.7, range = 4‐162; possible range = 0‐265) or the equivalent of an average severity rating between “moderately” and “quite” stressful for each stressor. Older age was associated with fewer total lifetime stressors (β = ‐.39, p = .01) and lower total stressor severity (β = ‐1.34, p = .008). There were no associations between education or sex and total lifetime stressor exposure or total stressor severity (ps>.09). Neither PACC5 nor MMSE performance alone was associated with total lifetime stressor exposure or total stressor severity after adjusting for age (ps>.52).

Conclusion

Older Latino adults reported moderately severe stressors across their lifetime. With age, older Latinos reported fewer lifetime stressors and lower stressor severity, perhaps due to cohort effects or positivity bias. Future studies with larger samples are needed to elucidate the impact of lifetime stressors on older Latinos. The Adult‐STRAIN may be a useful tool in characterizing this relation.
Validation Study of A Novel VR‐Based Cognitive Assessment Tool: Influences of Demographic Characteristics
Authors: Yerlikaya Deniz , Arsoy Erdil , Sükuti Murat , Baytimur Meliha Beste , Özbilgen Eda , Şenyer Seray , Baytimur Emre , Sarıdede Dilek Betül , Bayatlı Simay , Duru Adil Deniz
Published: January 2025

Background

Emerging technologies paves the way for the development of novel cognitive assessment approaches. Virtual reality (VR) has high ecological validity, increases participant engagement, and allows the assessment of functions that are challenging to evaluate with traditional methods. The present study aimed to validate a novel cognitive assessment tool and investigate the effects of demographical variables.

Method

A total of 575 healthy individuals aged between 18‐66 years were included in the study. A subgroup of the participants (n = 326) attended the verbal and visual versions of the computerized N‐back task. All participants underwent the modified version of NORA VRx™ ‐ Core experience. Seven metrics were calculated from working memory, attention, and information processing tasks during the experience. The relative contributions of the age, education and gender variables on the VR‐based metrics were assessed with multiple linear regression analysis. The concurrent validity was investigated by the correlation between VR‐based scores and N‐back scores using the Pearson Correlation.

Results

Age, gender, and education were significant predictors of the working memory scores, whereas only age and education were the significant predictors for the information processing scores. All the calculated cognitive scores worsened with the increasing age and lower education levels. Male had better scores in working memory and attention measures than female. The correct answer number at the verbal and visual N‐back tasks showed moderate correlations with the VR‐based scores. The working memory scores showed the strongest correlations with the 2‐ and 3‐back conditions (p<0.001 for all).

Conclusion

The present study introduces a novel and valid cognitive assessment tool. The sample was stratified according to age and education and norm values were prepared accordingly. In the future studies, it is important to determine the characteristics of the population aged 50 years and older and to examine the discriminatory power of the novel tool among various patient groups.
Sleep complaints associates with anxiety in individuals with Subjective Cognitive Decline from a South‐Brazilian cohort
Authors: Rivas Gabriela Raquel Paz , Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , de Paula Leonardo Martins , Giordani Manuella Edler Zandoná , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L. Fagundes , Zimmer Eduardo R. , Castilhos Raphael Machado
Published: January 2025

Background

Subjective cognitive decline (SCD) is defined by the presence of cognitive complaints in cognitively unimpaired (CU) individuals. Despite being part of the continuum of a neurodegenerative disease, the cause of the cognitive complaint is quite heterogeneous. Sleep disturbances may be associated with cognitive complaints and even objective cognitive decline. Therefore, our aim is to analyse sleep complaints in patients with SCD evaluated in a south‐Brazilian SCD (BRASCODE) cohort.

Method

We included CU individuals aged > 65 years‐old with cognitive complaints from the BRASCODE cohort. Exclusion criteria were uncontrolled psychiatric/clinical illness, cerebrovascular disease, and the use of psychotropic drugs. We applied the Memory Complaint Scale (MCS) (in both participant and informant), Geriatric Anxiety Inventory (GAI) and Geriatric Depression Scale (GDS), Pittsburgh Sleep Quality Index (PSQI), Mini Mental State Examination (MMSE), Mild Behavioral Impairment (MBI) and Neuropsychiatric Inventory (NPI) questionnaires. For this analysis we used the data collected in the 12‐month follow‐up only.

Result

Forty‐seven participants completed the 12‐month evaluation between March, 2022 and November, 2023. Of these, 74.5% (n = 35) were women, median age of 71 (69‐74.5) years‐old and 16 (11‐18) years of formal education. Their median interquartile range (IQR) on SCD‐patient and SCD‐informant scale was 8 (6‐9.5) and 4 (2‐6), respectively. The remaining scale’s ‐median and IQR scores‐ were the following: PSQI, 7 (4‐9); GAI, 6 (3‐9); GDS 2 (1‐4), MMSE, 29 (28‐30); NIP,1(0‐4); MBI‐patient, 3 (0.75‐6); and MBI‐informant, 3 (1‐9). The analysis showed that the PSQI scale only had correlation with GAI (p‐value = 0.02841, rho = 0.3466809). There was no association with the MCS‐participant and MCS‐informant scales, nor with MMSE, age, education and behavior scales, MBI or NPI.

Conclusion

This result obtained for the PSQI score suggests that poor sleep quality in SCD individuals from a south‐Brazilian cohort may be associated with anxiety symptoms. Larger sample may provide additional information about the relationship of cognitive, anxiety and sleep complaints.
A systems‐biology approach to identify candidate genes associated with composite brain pathology scores in the Adult Changes of Thought (ACT) and the Religious Orders Study and Memory and Aging Project (ROSMAP) autopsy cohorts
Authors: Dutta Aheli , Broome Jai , Sinha Sagnik , Gibbons Laura E. , Shade Lincoln MP , Katsumata Yuriko , Travaglini Kyle J , Gabitto Mariano I , Zhao Zijie , Lu Qiongshi , Schneider Julie A. , Latimer Caitlin S , Keene C Dirk , Crane Paul K. , Fardo David W. , Mukherjee Shubhabrata
Published: January 2025

Background

Previously, we developed a co‐calibrated and harmonized brain pathology score (BPS) across prospective cohort studies with research brain donation that incorporates multiple forms of postmortem neuropathology, using confirmatory factor analysis. We sought to identify genetic loci associated with BPS using a systems‐biology approach, combining data from participants in the Adult Changes in Thought (ACT), the Religious Orders Study, and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.

Method

We used PLINK in each cohort separately for genome‐wide association studies (GWAS) of BPS using HRC imputed data from European ancestry participants, adjusting for age at death, sex, and population substructure. We performed meta‐analysis using the adaptively weighted Fisher’s approach in METAL. We performed gene‐wide analysis using the meta‐analyzed results which we then integrated into the human protein‐protein interaction (PPI) network using a dense module searching (DMS) method to identify network hub genes for BPS. We interrogated the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD) dataset on the middle temporal gyrus to determine which cell types both hub genes were expressed in and how they differed across donors with higher degrees of AD pathology (i.e. along AD pseudo‐progression).

Result

The sample size consisted of 1,848 brain donors (Table 1). The quantile‐quantile plot and genomic inflation (λ = 1.005) for GWAS meta‐analyses showed no bias (Figure 1a), with the Manhattan plot in Figure 1b. Apart from significant SNPs around the APOE region, we identified two candidate loci a) (Chr 9: rs1332179; MAF = 0.1; P_meta = 8.7 × 10‐8) and b) (Chr 17: rs11078196; MAF = 0.34; P_meta = 1.9 × 10‐7). Regional association plots for these two loci are shown in Figure 1c. The PPI network analysis identified VCP and IQCB1 as hub genes (Figure 2a). While both hub genes were expressed broadly across cell types, IQCB1 was specifically higher with higher degrees of AD pathology in Microglia and VCP was lower with higher degrees of AD pathology in several neuronal populations (Figure 2b).

Conclusion

We identified two potentially useful candidate loci associated with BPS using a systems‐biology approach. Further functional enrichment analysis is needed to determine whether these novel loci may identify targets for interventions to ameliorate AD.
Primary progressive aphasia in sporadic and familial (type 8) amyotrophic lateral sclerosis ‐ A longitudinal study
Authors: de Araujo Caroline Martins , Machado Thais Helena , Collares Mariana Asmar Alencar , de Paula França Resende Elisa , de Souza Leonardo Cruz
Published: January 2025

Background

Language is frequently affected in patients with sporadic amyotrophic lateral sclerosis (sALS), with reduced performance in naming, syntactic comprehension, grammatical expression, and orthographic processing. In a previous study, we demonstrated that the language profile of patients with familial type 8 ALS (ALS8), linked to p.P56S VAPB mutation, is similar to sALS. From a neuropsychological standpoint, there appears to be an overlap between primary progressive aphasia and ALS (PPA‐ALS) even in phases of the disease with little functional impairment. We aimed to investigate whether language decline has prognostic value in patients with ALS.

Method

First, we performed a cross‐sectional evaluation. We included two groups of participants: 1) patients with sALS (n = 17); 2) patients with familial ALS8 (n = 22). The groups were matched for age, sex, and education level. All participants underwent a comprehensive language battery, including the Boston Diagnostic Aphasia Examination, the reduced Token Test, letter fluencies (FAS), categorical fluency (animals), word definition from the Cambridge Semantic Memory Research Battery, and a narrative discourse analysis. We also applied the Addenbrooke’s Cognitive Exam ‐ Revised Version (ACE‐R), the Hospital Anxiety and Depression Scale (HADS), and the ALS Functional Rating Scale‐Revised (ALSFRS‐R). The patients were reassessed 10‐65 months after the baseline visit with ALSFRS‐R, to follow up the progression rate of the disease.

Result

We observed that the memory item of the ACE‐R test was able to predict functional declining in the fine motor domain in patients with sALS (F (1,16) = 19.443, R2 = 0.549, p<0,001).. The use of phonological cues in patients with ALS8 was able to predict global functional declining in this group (F (1,20) = 21.361, R2 = 0.516, p<0.001).

Conclusion

Our data suggest that language decline may have prognostic value in cases of sALS and ALS8.
Toxic Interplay Between Small Dipeptide Protein Repeats and Tau in Tauopathies
Authors: Bhatt Nemil , Puangmalai Nicha , Jerez Cynthia , Shchankin Nikita , Kayed Rakez
Published: January 2025

Background

Tauopathies, including Alzheimer’s Disease and Frontotemporal Dementia, are characterized as intracellular lesions composed of aggregated tau proteins. Soluble tau oligomers are shown to be one of the most toxic species and are responsible for the spread of tau pathology. Recent studies have found that several proteins such as amyloid b, a‐synuclein, and TDP‐43 can aggregate tau. In this study, we investigated the ability of small metabolites like C9orf72 associated dipeptide protein repeats (DPRs) to interact with and aggregate tau to form toxic soluble tau oligomers.

Method

We have developed various models which express dipeptide protein repeats to understand the interaction between short peptides and tau. The dipeptide protein repeat induced tau aggregates were characterized using biophysical, as well as biochemical assays in vitro and in cellular models. Furthermore, we evaluated their toxicity, and seeding potency to understand the biological effects of this interaction.

Result

Our results suggest the propensity for DPRs, especially glycine‐arginine and proline‐arginine repeats to form oligomeric structures which interact and seed tau in a prion like fashion. This leads to the production of tau oligomers causing alterations in the microtubule dynamics in cell lines as well as primary neuronal culture systems.

Conclusion

Many studies have investigated the toxicity of small protein repeats, however, the role of DPR oligomers in inducing tau aggregation is still unclear. Thus, the ability to understand the toxic interplay between small peptide repeats and tau oligomers has great potential to further the understanding of tau progression and aid in the development of targeted therapeutics.
Altering ApoE in mice expressing human amylin in the pancreas exacerbates brain amyloid pathology and behavior deficits
Authors: Leibold Noah S , Viswanathan Velmurugan Gopal , Radulescu Laura , Kotiya Deepak , Verma Nirmal , Despa Florin
Published: January 2025

Background

The APOE ε4 allele is the most prominent genetic predisposition for sporadic Alzheimer’s disease (AD). Amylin, a neuroendocrine hormone co‐secreted with insulin from the pancreas, is increased in blood in AD and readily forms neurotoxic homo‐ and hetero‐oligomers with β‐amyloid in AD. Previously, we showed that intravenously infused ApoE4 in rats expressing human amylin specifically in the pancreas led to increased brain amylin accumulation. Further, we showed increased blood levels of human amylin disrupts β‐amyloid efflux. Therefore, we investigated whether mice humanized for amylin and ApoE demonstrate ApoE isoform‐specific alterations in cerebrovascular amylin deposition and β‐amyloid homeostasis.

Methods

Six‐month‐old male mice humanized for ApoE3 or ApoE4 and amylin (ApoE3HIP and ApoE4HIP) and mice humanized for amylin without ApoE expression (ApoE‐KO‐HIP) were tested for behavior deficits before brain microvessel isolation and amylin quantification by ELISA. β‐amyloid was quantified using the MesoScaleDiscovery platform. GFAP‐amylin colocalization in the brain was quantified using immunohistochemistry (IHC) while double‐immunofluorescence (double‐IF) and STORM imaging were used for amylin‐ApoE colocalization. Immunoprecipitation experiments were conducted to confirm brain amylin‐ApoE binding interactions.

Results

ApoE4HIP mice demonstrated worsened behavioral deficits when compared to E3HIP mice. IHC of ApoE4HIP and ApoE3HIP brains revealed significantly increased deposits of GFAP and amylin in ApoE4HIP mice. Amylin in brain parenchyma, but not capillaries, was higher in ApoE4HIP vs. ApoE3HIP mice (p<0.0001 and p = 0.4455) while ApoE‐KO‐HIP mice demonstrate reduced amylin in both fractions as measured by ELISA. β‐amyloid 40, but not 38 or 42, levels were significantly higher in ApoE4HIP brain and microvessels (p<0.0001 and p = 0.0123) vs. ApoE3HIP. Analysis of double‐immunofluorescence, STORM, and immunoprecipitation experiments is ongoing.

Conclusions

Our data suggest ApoE may function as a transporter of amyloid‐forming amylin in the brain with amylin binding ApoE4 stronger than ApoE3. The increased affinity of amylin for ApoE4 coincides with worsened brain amyloid pathology, disrupted β‐amyloid homeostasis, increased astrogliosis suggesting neurodegenerative insult, and functional impairments due to elevated amylin amyloid burden. These data may implicate the amylin‐ApoE interaction as a mechanism underlying ApoE4‐specific neuropathology. Additional studies to delineate the mechanisms by which amylin and ApoE interact at the BBB interface and alter amyloid deposition are needed.
Amylin vasculopathy impairs cerebral Aβ efflux through altering cerebral vasodilation
Authors: Davargaon Ravichandra S , Leibold Noah S , Verma Nirmal , Powell David K , Despa Florin
Published: January 2025

Background

Impaired interstitial fluid drainage in the brain is indicated by the presence of perivascular β‐amyloid (Aβ) deposits and is attributed to alterations in contractility and relaxation of vascular smooth muscle cells (SMCs). The brain microvasculature in Alzheimer disease (AD) accumulates amyloid‐forming amylin secreted from the pancreas. Here, we tested the hypothesis that cerebrovascular amylin deposits perturbs cerebral Aβ efflux by impairing cerebral vasodilation.

Methods

Using transgenic rats expressing amyloid‐forming human amylin in the pancreas (HIP rats) (aged 16‐months) and wild‐type (WT) littermates that express non‐amyloidogenic rat amylin, we conducted comparative analyses of cerebral blood flow (CBF), pressure myography in isolated pial arteries and vascular SMC oxidative stress experiments.

Results

Longitudinal brain MRI measurements revealed consistent structural alterations that progressed more rapidly with aging in HIP vs. WT rats, leading to 14.9% reduction in CBF in HIP rats. Plasma nitrite and nitrate, stable nitric oxide (NO) end products, were increased in HIP vs. WT by 84.7% and 24.87%, respectively. Pressure myography experiments using pial arteries showed that both WT and HIP arteries developed arterial tone (e.g. pressure‐induced constriction); however, arteries from HIP rats show significant elevations (56.9‐142.3%) in arterial tone compared to WT rats at physiologically‐relevant intravascular pressures (e.g. 60‐100 mmHg). Consistent with these results, vascular SMCs from HIP rats showed elevated (12.6% increase) lipid peroxidation, which was replicated in SMCs incubated with exogenous human amylin (29.6%). Increased lipid peroxidation contributes to oxidative stress in the vascular wall and reduces NO bioavailability, altering vasodilatory function. Both arginase activity and expression (of Arginase 1 and 2) were increased in brain microvascular lysates from HIP rats compared to those from WT by 17.6%, 63.9%, and 57.8%, respectively, suggesting arginase‐NO dysregulation. A possible impact of increased blood amylin concentration on cerebrovascular arginase‐NO regulation was further tested in brain microvascular lysates from rats intravenously injected with amyloid‐forming human amylin (55.0% reduction in arginase activity).

Conclusion

Our results indicate perivascular Aβ deposits in the setting of AD are potentially linked to amylin vasculopathy and altered spontaneous contraction/relaxation of cerebrovascular SMCs. Future experiments will focus on delineating molecular markers of amylin‐induced alterations of SMC contractile phenotype.
Second‐Generation Epigenetic Clocks and Socioeconomic Status Predict Midlife Cognitive Status
Authors: Bell Sophie A. , Beam Christopher R. , Finkel Deborah , Barna A. Cevelle , King Ariel , Sikes Kendra , Ryan Lesa , Davis Deborah Winders , Turkheimer Eric
Published: January 2025

Background

DNA methylation (DNAm) age measures, or ‘epigenetic clocks’, surpass chronological age in their ability to predict age‐related morbidities and mortality. The Louisville Twin Study (LTS) presents an opportunity to clarify the role of early life environmental exposures and development in biological and cognitive aging in midlife. We expect that second‐generation DNAm age measures trained to predict age related outcomes and death, independent of chronological age, will be sensitive to cognitive ability in midlife.

Method

Data collection of the midlife phase of the LTS is ongoing. This study utilizes data from 281 middle‐aged twins, including 56 monozygotic and 41 dizygotic complete twin pairs (mean age 51.9 years ± 7.03). Midlife cognitive ability (IQ) was measured using the Wechsler Adult Intelligence Scale Fourth Edition. DNAm age acceleration was calculated using five clock algorithms: Horvath 1, Horvath 2, Hannum, GrimAge, and PhenoAge. We conducted an exploratory factor analysis to identify common factors as latent variables among the five clocks. Composite scores for factors were calculated, and genetically informed, quasi‐causal regression models were fitted in which adult IQ was predicted from childhood socioeconomic status (SES), DNAm factor composite score, and the interaction between DNAm age and SES.

Result

Factor analysis produced a two‐factor structure: first‐generation clocks (Horvath 1, Horvath 2, and Hannum) and second‐generation clocks (PhenoAge and GrimAge). As predicted, childhood IQ and childhood SES predict adult IQ. Acceleration in the second‐generation factor predicts lower midlife cognitive ability (b = −0.15, SE = 0.068, p <.05). Additionally, there is an interaction in the second‐generation model such that people raised in higher SES families show a less negative relationship between DNAm age acceleration and adult IQ (b = 0.092, SE = 0.036, p <.05). However, there is no significant effect of the first‐generation factor on adult IQ, and no SES interaction effect.

Conclusion

Second‐generation DNAm age measures show promise in their predictive value for cognitive aging processes. Moreover, the longitudinal twin design of the LTS serves as a quasi‐experimental framework to investigate hypothesized causal effects of DNAm on cognitive aging. Finally, our findings related to childhood SES suggest that the epigenome is malleable and responsive to early‐life stressors.