bluuebunny/crossref_metadata_2025 huggingface dataset:
MEG Dynamic functional connectivity as a longitudinal biomarker for Alzheimer’s Disease relatives
Authors: Carrasco‐Gómez Martín , García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Ramírez Federico , Cabrera Jesús , Fernández Ricardo Bruña , Santos Andrés , Maestú Fernando
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common cause of dementia. Although it presents a long preclinical period, treatment has yet to be found, and individuals at risk, like first‐degree relatives, are being studied to identify early detection markers to maximise the effectiveness of treatments. Functional connectivity changes have been observed even at this early stage (Ramirez‐Toraño et al., 2021), but most disregard its temporal dimension. This study investigates the value of a simple estimation of dynamic functional connectivity (dFC) in a longitudinal follow‐up of individuals with varying risk of the disease, as this parameter is expected to decrease across the disease continuum (Grieder et al, 2018).

Method

95 cognitively unimpaired participants with a family history of AD (FH+) and 39 without it (FH‐) underwent two longitudinal 5‐minute resting‐state magnetoencephalography recordings, approximately 3 years apart. FC in the low alpha band (8‐10 Hz) was estimated in 4‐second segments using phase locking value in the source space, and the standard deviation (STD) across epochs was calculated. Then, a STD ratio was derived dividing the STD values of the follow‐up session by those of the baseline session, and then averaged over nodes belonging to the same regions of the automatic anatomical labelling atlas. Left‐tailed t‐tests between the STD ratio of both groups in each ROI link (n_comparisons = 3160) were calculated and corrected for multiple comparisons with a false discovery rate using q = 0.20.

Result

13 links show a significantly lower dFC in the FH+ group than in the FH‐ group (Figure 1). Interestingly, these links involve regions where amyloid‐beta deposits early in the AD continuum (Mattsson et al., 2019), and are strongly related to the default mode network (Palmqvist et al. 2017).

Conclusion

This study suggests that a simple estimation of dFC like STD may be useful in early detection pathological patterns characteristic of AD, even in cognitively unimpaired individuals at risk. The fact that dFC decreases were detected in areas where amyloid deposits appear at an early stage might indicate that these changes are related to changes in the excitation/inhibition ratio, which will be further studied in upcoming investigations.
High risk of obstructive sleep apnoea is associated with higher baseline plasma glial fibrillary acidic protein and predicts decline in levels over time in cognitively unimpaired older adults
Authors: Pivac Louise N , Pedrini Steve , Chatterjee Pratishtha , Doecke James D , Villemagne Victor L , Dore Vincent , Brown Belinda M , Weinborn Michael , Sohrabi Hamid R , Gardener Samantha L , Asih Prita Riana , Bucks Romola S , Masters Colin L , Rowe Christopher C , Martins Ralph N , Rainey‐Smith Stephanie R
Published: December 2023

Background

Findings from animal studies report links between obstructive sleep apnoea (OSA) models and elevated glial fibrillary acidic protein (GFAP). In humans, elevated plasma GFAP, reflecting reactive astrogliosis, is considered an early event in the Alzheimer’s disease (AD) continuum. The current study investigated whether OSA risk predicts the slope of plasma GFAP in cognitively unimpaired older adults.

Method

Linear mixed effect model analyses were conducted on 70 cognitively unimpaired older adult (M = 73.1, SD = 5.2, 57.1% female) participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Individuals completed the well‐validated STOP‐Bang questionnaire to assess OSA risk (Low; Intermediate; High), and underwent positron emission tomography (PET) to quantify brain Aβ burden. Plasma GFAP was measured using the Simoa® platform over three timepoints (range 30.06 ‐ 99.45 months). The model included, a random intercept, a three‐way interaction between OSA risk, baseline brain Aβ status and time, adjusting for Apolipoprotein E (APOE) ε4 status, sex, baseline age, and baseline body mass index.

Result

High risk of OSA and high brain Aβ (>25 Centiloids) were independently associated with higher baseline plasma GFAP and forecast a negative longitudinal plasma GFAP trajectory.

Conclusion

These novel findings suggest that OSA mechanisms, independent of prior brain Aβ accumulation, may contribute to early reactive astrogliosis in cognitively unimpaired older adults. Additionally, a decline in plasma GFAP was observed during the preclinical period, both in those at high risk of OSA and those at greater risk of AD due to high brain Aβ.
The use of caffeine consumption in cognitive impairment and relationship with sleep disorders
Authors: Dewer Bethan , Blackman Jonathan , Gabb Victoria , Morrison Hamish , Coulthard Elizabeth
Published: December 2023

Background

The impact of caffeine on cognition and dementia risk remains unclear with previous studies demonstrating both detrimental and potentially protective effects. There is limited data on the role of caffeine consumption in prodromal and established dementia. We explored the relationship between sleep and caffeine in a population with and without dementia.

Method

Patients with a diagnosis of mild cognitive impairment or mild dementia due to probable Alzheimer’s disease (AD group, n = 8) or Lewy body disease (LBD group, n = 7) and age‐matched controls (HC group, n = 9) were recruited into an observational cohort study on sleep and memory. Caffeine consumption, sleep duration, and baseline demographics were collected at baseline via self‐reported questionnaires and used in a multiple linear regression to explore relationships between cognitive impairment/dementia, sleep, and caffeine.

Result

Multiple linear regression was used to test if age, sex, hours of sleep, anxiety or cognitive impairment was associated with caffeine consumption. On average, people in the AD/LBD groups had longer sleep duration and greater caffeine intake. After controlling for age, sex, and diagnostic group, there was a negative correlation between self‐reported hours of sleep and caffeine consumption (p = 0.004). The average reduction in sleep hours with increased caffeine intake was ‐1.35, 97.5% CI [‐2.21, ‐0.50]. After controlling for age, sex, there was a positive correlation for those with a diagnosis of AD/LBD having increased caffeine consumption (p = 0.007).

Conclusion

Our results suggest that those consuming more caffeine are likely to be sleeping for fewer hours, and those with cognitive impairment may be consuming more caffeinated drinks on average per day. An increase in caffeine consumption in the cognitively impaired may be used as self‐medication for daytime somnolence or as a cognitive stimulant. Recruitment continues and further analysis of actigraphy and napping data will add further insights.
Community Pharmacists expand access to cognitive function assessments with Cognivue Clarity™ device
Authors: Abubakar Amina , Sinclair Jessica , Kabisatpathy Saswat , Lutz Susan
Published: December 2023

Background

Most initial cognitive assessments are performed by primary care physicians (PCPs). With the growing senior population reaching the age of increased risk for Alzheimer’s (65 yrs), coupled with the projected shortage of up to 48,000 PCPs by 2034 (IHS Market Ltd. AAMC;2021), use of pharmacy‐based cognitive assessments can greatly expand access. Pharmacists are more accessible than PCPs (Tsuyuki et al. 2018) and are among the most trusted healthcare professionals.

Method

Member pharmacies of CPESN USA were selected to conduct standardized cognitive function tests using the Cognivue Clarity® device. Study participants were ≥65 yrs and had the ability to complete a survey about their cognitive screening history and PCP contact information. Site education and training were conducted by the Avant Institute and Cognivue. Sites were surveyed following data collection. Study was funded by the Davos Alzheimer’s Collaborative and occurred August 2022 ‐ December 2022.

Result

Nineteen CPESN pharmacy sites from 13 states, 10 within medically underserved or rural areas, submitted 425 eCare plans that were eligible for analysis. Less than 16% (67/425) patients reported having a previous cognitive assessment, with 81% (343/425) reporting this was their first cognitive assessment, and the remainder reported unknown. Approximately 73% (312/425) of patients had Cognivue clinical overall scores outside the normal range and were referred to their PCP. Site surveys post‐data collection showed that >83% and >72% of pharmacies rated ease of use of the Cognivue Clarity device, and education and training, to be an extremely significant or significant contributor to study success, respectively.

Conclusion

Pharmacists are often overlooked as a vital link to assessing the cognitive health of seniors. With two FDA‐cleared immunotherapies available, it is critical that seniors are aware of their cognitive status so they can seek research studies, further evaluations, and/or medications. This study showed that with training and use of Cognitive Clarity, pharmacists can easily provide seniors with an objective cognitive function assessment. Accordingly, widespread implementation of pharmacy‐based computerized cognitive testing could greatly expand access to meet the brain health needs of the growing senior population.
Hearing loss moderates cognitive‐motor dual‐tasking before and after combined exercise and cognitive training in older adults with mild cognitive impairment: Findings from the SYNERGIC and COMPASS‐ND studies
Authors: Downey Rachel , Petersen Berkley , Mohanathas Niroshica , Campos Jennifer L. , Montero‐Odasso Manuel , Bherer Louis , Pichora‐Fuller M. Kathleen , Phillips Natalie , Li Karen
Published: December 2023

Background

Age‐related hearing loss is associated with poor cognitive‐motor dual‐task performance and is a risk factor for dementia and mild cognitive impairment (MCI). Although different interventions have shown to improve dual‐task performance in older adults, it is currently unclear whether hearing ability affects training efficacy in individuals with MCI.

Methods

Secondary data analyses of 75 participants with MCI (Mage
= 73.66 ± 6.67) who completed the Canadian Consortium on Neurodegeneration and Aging SYNERGIC and COMPASS‐ND studies. We investigated how hearing ability (normal hearing (n = 56), hearing loss (n = 19)) moderated the efficacy of a 20‐week intervention (combined exercise and cognitive training (n = 32), exercise training alone (n = 31), control (n = 12)) on single‐ and dual‐task working memory performance (serial one or seven subtractions, semantic fluency) and spatio‐temporal gait characteristics.

Results

At baseline, participants with hearing loss had slower gait speed and higher step time variability while concurrently completing the semantic fluency task, compared to participants with normal hearing. Participants with hearing loss also had higher accuracy on the semantic fluency and serial seven subtractions tasks while dual‐tasking, compared to participants with normal hearing. Single‐ and dual‐task gait speed increased significantly following combined exercise and cognitive training, with greater improvements observed in participants with hearing loss compared to those with normal hearing. However, older adults with hearing loss showed a significant decrease in dual‐task serial seven subtractions and semantic fluency following combined exercise and cognitive training.

Conclusion

These findings help clarify the relationship between hearing loss, cognition, and mobility in old age and inform training recommendations for persons with MCI based on hearing ability. Combined exercise and cognitive training appears to have increased attentional and physical resources, allowing participants with hearing loss to shift postural prioritization strategies while dual‐tasking from a posture‐second strategy to a posture‐first strategy. Thus, combined exercise and cognitive training may be particularly beneficial for older adults with both MCI and hearing loss, in order to improve safe walking behaviours while multi‐tasking and mitigate further decline.
Association between known Alzheimer’s disease risk loci and in vivo brain amyloid pathology in a Korean Cohort
Authors: Ahn Hyejin , Byun Min Soo , Yi Dahyun , Jung Gijung , Huang Yen‐Ning , Griswold Anthony J. , Pericak‐Vance Margaret A. A , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Kang Koung Mi , Lee Jun‐Young , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young
Published: December 2023

Background

Most genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have been conducted in populations of European ancestry. It is important to determine if known AD‐related variants from these studies are associated with AD biomarkers. Therefore, we investigated the association between known AD risk loci and in vivo brain Aβ deposition in older Korean adults.

Method

Participants (n = 503) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were analyzed. Older adults who were cognitively normal (CN), had mild cognitive impairment (MCI) or AD dementia (264 CN, 148 MCI, 91 AD) underwent comprehensive assessments including 11C‐PiB‐PET/MRI and blood sampling. Among 76 AD‐related target single nucleotide polymorphisms (SNPs) with genetic evidence compiled by the AD Sequencing Project (ADSP), 38 SNPs with minor allele frequency (MAF)>1% were extracted from TOPMed‐based imputed GWAS genotyping data in KBASE. We employed exploratory univariable logistic regression analysis with Aβ positivity as the dependent variable for each SNP. Then, SNPs with a significance level of p<0.05 were subjected to confirmatory multivariable logistic regression analysis, adjusting for age and sex, with Bonferroni correction.

Result

In the first step of exploratory analyses, we discovered significant differences in Aβ positivity rates between carriers and noncarriers of minor allele of several loci, including rs16824536 in MME, rs11218343 in SORL1, rs4985556 in IL34, rs4277405 in ACE and rs3851179, located in the intergenic region between EED and PICALM. The subsequent confirmatory analysis found an association between these variants and Aβ positivity after adjusting age and sex (Table 1). Notably, the negative association of rs3851179 with Aβ positivity remained significant after correcting for multiple comparisons and after controlling for APOE4 carrier status, age, and sex (OR 0.529, 95% CI 0.345–0.813).

Conclusion

We identified associations between several known AD risk loci and Aβ positivity on PET. rs3851179, demonstrated a robust association with in vivo brain Aβ positivity that was independent of APOE4 status. Our findings suggest that rs3851179 may be protective for in vivo Aβ accumulation. Additionally, the findings are needed to be replicated in other populations with different ancestries.
Brain Iron in Aging Signature Regions Relating to Long‐Term Cognitive Decline in Older Adults
Authors: Wang Yingzhe , Li Rui , Lu Heyang , Chen Xingdong , Cui Mei
Published: December 2023

Background

Brain iron accumulation has been linked to cognitive decline in Alzheimer’s disease (AD), which is often associated with cerebral atrophy in AD‐specific brain regions. However, it remains unclear whether there is a selective pattern of brain iron deposition associated with cognitive aging or age‐related brain atrophy compared to AD. Therefore, this study aimed to investigate the relationship between brain iron level, atrophy, and cognitive decline in a Chinese population‐based cohort and explore the spatial distribution of brain iron deposition associated with individual cognition functions.

Method

A total 770 community‐dwelling participants from Taizhou Imaging Study (mean age 62.0 ± 4.93 years, 57.5% women) underwent brain MRI examination, and among them 219 participants accepted neuropsychological tests at a mean follow‐up of 2.68 years. Brain iron deposition was evaluated using quantitative susceptibility mapping (QSM), while global atrophy, cortical thickness and subcortical volumes were analyzed using surface‐based techniques. Global cognition function was assessed using the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), and domain‐specific cognitive scores were obtained from subscores of MoCA. Regional analyses were performed on the cortical and 3 signature regions: Aging‐specific, Aging and AD signature meta‐ROIs (Figure 1).

Result

Iron levels were negatively correlated with classic MRI markers of cortical atrophy (cortical thickness, gray matter volume, local gyrification index) in total, Aging‐specific, and Aging signature cortical regions (all P < 0.05). Participants in the upper tertile of the cortical and Aging‐specific signature QSM showed worse global cognitive function compared to those in the bottom tertile after adjusting for gray matter atrophy. Among 219 participants who underwent follow‐up, higher brain iron levels in all ROIs predicted accelerated deterioration in the rate of cognitive decline in global cognition, attention, and visuospatial function (Table 1 and Table 2, all P < 0.05). These associations remained significant even after the including cortical thickness of each ROI as a covariate.

Conclusion

The present study demonstrates that aging and AD‐selective iron deposition is associated with atrophy and cognitive decline in elderly individuals, suggesting the brain iron deposition has the potential to be used as an imaging biomarker for tracking cognitive aging.
Prevalence of geriatric syndromes among older outpatients with dementia
Authors: Nguyen Thanh Xuan , Vu Huyen Thi Thanh , Nguyen Tam Ngoc , Nguyen Thu Thi Hoai , Nguyen Huong Thi Thu , Tran Luc Viet , Nguyen Anh Trung , Pham Thang
Published: December 2023

Background

The occurrence of geriatric syndromes in people with dementia may result in worsening of independence and autonomy.

Method

A cross‐sectional study was conducted on outpatients with dementia aged ≥ 60 years old. Dementia was diagnosed by neuropsychiatrists following DSM‐5 criteria.. The geriatric syndromes includes nutritional status (Mini Nutritional Assessment Scale‐Short Form), polypharmacy, comorbidities, alcohol use, symptom of depression (Quality of Life in Alzheimer Disease), physical functional (Barthel Index, Instrumental Activities of Daily Living), lower body strength (30 seconds stand chair test), high risk of fall (Time Up and Go test ≥ 13.5 seconds), hearing loss (Whisper test), low visual acuity (Snellen test) and poor quality sleep (The Pittsburg Sleep Quality Index).

Result

A total of 87 participants was recruited in the study (mean age: 76.8±1.2 years; female: 65.5%). The median number of geriatrics syndrome per participant was 5 (IQR = 2). The most common geriatric syndromes were loss of independence (96.6% impariment in ≥1 IADL task score), reduced lower body strength (86.2%), risk of malnutrition (78.2%), low speed (74.7%) and risk of falls (67.8%). The prevalence of alcohol use, risk of malnutrition, loss of independence and reduced lower body strength were consistently increase linearly with the severity of dementia.

Conclusion

The presence and co‐incidence of geriatric syndromes is common among outpatients with dementia. This finding could have important clinical implications in the clinical work‐up and service delivery in Vietnam. We have begun to think about how we can develop our primary to provide comprehensive, multidisciplinary approaches to screening, recognition, and treatment of people with dementia
Hand grip strength, anthropometrics and cognitive decline
Authors: McGuinness Bernadette , Passmore Anthony Peter , Holmes Clive , Patterson Christopher , Linden Gerry , McEvoy Claire T , McAlinden Michael , McKay Gareth J , Farsi Dominic , Teeling Jessica
Published: December 2023

Background

Hand grip strength is a well validated measure of physical strength, while anthropometric measures such as weight, waist, hip and mid upper arm circumference, are well validated to determine physical health. The present analysis investigated the relationship between hand grip strength, anthropometric measures and dementia incidence in 70–90‐year‐old men residing in Northern Ireland (NI).

Method

The PRIME‐COG study is nested in PRIME (Prospective Epidemiological Study of Myocardial Infarction), a cohort study of men in NI. In the most recent follow up for PRIME‐COG, men underwent a comprehensive cognitive assessment from which a consensus diagnosis of normal cognitive function, MCI or dementia was made by experienced clinical researchers. Hand grip strength and anthropometrics measures were also recorded. Logistic regression models were performed to assess the association between hand grip strength and anthropometric measures and cognitive endpoints.

Result

The analysis identified that low hand grip strength was associated with dementia and/or MCI, although this did not reach statistical significance (OR 1.39, p = 0.18). In the anthropometric measures, a significant relationship was observed between hip circumference and dementia and/or MCI at PRIME‐COG follow up (OR 0.93, p = 0.01), whereas BMI was non‐significantly associated (OR 1.22, p = 0.58). The remaining anthropometric measures investigated were not found to hold any significant relationships with the cognitive outcomes.

Conclusion

Within a cohort of older men residing in NI, low hand grip strength was associated with a 39% increased risk of dementia or MCI, although this was not statistically significant. In anthropometric measures, hip circumference was found to be significantly negatively associated with a 7% reduced risk of dementia or MCI, while BMI was associated with a 22% increased risk, which again was not of statistical significance. The present study helps further contribute to the evidence base that physical well‐being is associated with cognitive function.
Estimating Braak stage from [18F]MK6240 PET scans
Authors: Whittington Alex , Porat Lily , Christian Bradley T. , Devanand Devanand P. , Hostetler Eric D. , Johnson Keith A. , Johnson Sterling C , Klunk William E , Lao Patrick J. , Rowe Christopher C , Devanarayan Viswanath , Reilhac Anthonin , Reyderman Larisa , Irizarry Michael C. , Charil Arnaud , Gunn Roger N
Published: December 2023

Background

[18F]MK6240 is a second‐generation radiotracer for imaging tau pathology in vivo. Regional thresholds that allow for an assessment of Braak stage have yet to be established and importantly may vary between regions. In this work we use a Z‐score approach to define regional thresholds and estimate Braak stage in Alzheimer’s Disease.

Method

All static MK6240 images used were downloaded from the Lantheus/Cerveau database, spatially normalised into MNI space using DARTEL and SUVR images were computed using an inferior cerebellum reference region. Three Braak meta‐ROIS, Braak I/II, Braak III/IV and Braak V/VI (Figure 1), were applied to 275 amyloid negative healthy control images to define regional thresholds for positivity in each ROI at the level of mean SUVR + 2 SD. These thresholds were then applied to 232 scans from subjects across the AD spectrum with associated MMSE data (88 healthy control, 68 MCI and 76 AD: 131 Aβ+ / 101 Aβ‐).

Result

[18F]MK6240 showed similar mean values and low variability across all ROIs in the amyloid negative healthy controls (Figure 1). The regional SUVR cut‐off values were estimated as: Braak I/II = 1.29, Braak III/IV = 1.15 and Braak V/VI = 1.15. When these cut‐offs were applied to subjects across the AD spectrum with MMSE data (Figure 2), 118 out of 232 were negative for Braak pathology. These subjects were predominantly healthy controls and their mean MMSE was 27.3. For subjects that demonstrated Braak positivity in at least one region, 104 subjects demonstrated an ordering consistent with Braak staging whilst 10 subjects had an atypical ordering consistent with hippocampal sparing. 64 subjects were positive in all Braak regions with a mean MMSE of 23.4 and all but one of these subjects was either MCI or AD.

Conclusion

Analysis of [18F]MK6240 images with thresholds that allow for the determination of Braak stage status provides data that are consistent with clinical status and MMSE score. This approach may be useful in natural history studies and clinical trials.
Childhood self‐reported socioeconomic status modifies the genetic risk of Alzheimer’s on mid‐ and late‐life cognitive decline in a population‐based study
Authors: Xu Yuexuan , Engelman Corinne D.
Published: December 2023

Background

Childhood socioeconomic status (c‐SES) and genetic risk of Alzheimer’s disease (AD) contribute to an individual’s risk of developing AD in later life. A better understanding of the interactions between these risk factors can help design policy interventions to eliminate AD disparities at the earliest possible stage in life. In this study, we investigated whether global and domain‐specific c‐SES index modified the effect of genetic predisposition to AD on mid‐to‐late life cognitive decline.

Methods

We evaluated longitudinal associations of cognitive aging with validated global and domain‐specific c‐SES index, including childhood financial, human, and social capital domains. In the Health and Retirement Study, we separately tested interactions between the global and domain‐specific c‐SES index and a non‐APOE polygenic risk score (PRS) and APOE. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation. Inverse probability weighting is used to adjust for selection mortality in the genetic sample.

Results

Self‐reported overall and domain‐specific c‐SES index can significantly modify the age‐related effect of non‐APOE PRS on longitudinal global cognition, particularly among APOE ε4 carriers. After FDR correction, model parameters predicted that statistically significant PRS‐related differences in simple slopes between people with high (1 SD+ from population mean) and low (1 SD‐ from population mean) global and domain‐specific c‐SES index started showing after people reached age ∼77, with individuals who have low c‐SES bearing greater detrimental effect from the currently known combined effect of non‐APOE common variants as they age, and greatest among people who are also APOE ε4 carriers.

Conclusion

Self‐reported childhood SES can modify the association between non‐APOE PRS and longitudinal cognition decline.
Depression amplifies the association between age and amyloid burden in an at‐risk cohort
Authors: Nelson Alexis R , Edmunds Kyle J , Brach Talia L. , Planalp Elizabeth M. , Christian Bradley T. , Betthauser Tobey J , Johnson Sterling C , Asthana Sanjay , Okonkwo Ozioma
Published: December 2023

Background

Older age is associated with increased risk for Alzheimer’s disease (AD), as well as amyloid‐beta (Aβ) deposition in key cortical regions associated with age‐related cognitive decline. Depression—especially late‐life onset—may influence the association of age on cortical amyloidosis. However, evidence is mixed in literature, making this association unclear. This study assesses whether depressive symptoms exacerbate the relationship between age and Aβ burden in an older cohort at‐risk for AD.

Method

Clinical Core participants (n = 238, mean ± SD age 68 ± 8.4 years, 63.9% females, 85.3% White, 8.8% Black or African American, 5.9% American Indian or Alaska Native, and 40% APOE‐ε4 carriers) from the Wisconsin Alzheimer’s Disease Research Center (WADRC) were included in this study. Aβ accumulation was quantified using Pittsburgh compound B positron emission tomography (PiB‐PET) DVR maps with a cerebellum gray matter reference region. Mean DVR values were extracted from the left and right precuneus. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cross‐sectional linear regression models were assembled in a moderation framework to test the interaction between age and GDS scores. Variables in the models included GDS scores, age at GDS data collection, sex, APOE‐ε4 carriage, and the difference between age at GDS data collection and age at PiB‐PET exam. An age x GDS interaction test was followed up with simple main effects analyses, testing the within‐group associations of age and PiB‐PET Aβ load at increasing levels of GDS scores.

Result

GDS scores were largely normal (M = 1.29, SD = 1.61). Older age was associated with higher PiB‐PET binding (β = 0.01, p<0.01). The age x GDS interaction was significant (β = 0.003, p = 0.03). Conditional effects of the moderator were assessed at ±1SD from the mean GDS score, revealing progressively stronger associations between age and PiB‐PET binding across GDS groups (‐1SD GDS: β = 0.012, p<0.01; Mean GDS: β = 0.016, p<0.01; +1SD GDS: β = 0.021, p<0.01).

Conclusion

Our results suggest that greater depressive symptoms significantly amplify the association of age with Aβ deposition. Given AD’s increasing prevalence, it appears crucial to enhance treatment of late‐life depression, as that might lead to higher resilience against Aβ burden and subsequent dementia.
Single Molecule Detecting Amyloid Beta Oligomers In Human Cerebrospinal Fluid With Buoyant‐Antigen‐Magnetic Assay
Authors: karimpourkalou zahra , wang chuanlie , Viola Kirsten L. , Klein William L. , Anker jeffrey N
Published: December 2023

Background

Alzheimer’s Disease is a progressive neurodegenerative disorder that lacks a definitive treatment and affects an estimated 6.5 million Americans. Several lines of evidence suggest that Amyloid Beta Oligomers (ABOs) in cerebrospinal fluid (CSF) may be a cause of Alzheimer’s Disease and could be a biomarker for disease diagnosis/prognosis, and effectiveness of ABO modulating therapies. ABOs have been shown to target neuronal synapses, affect memory in cell and animal studies, and can be reversed in animal studies using antibodiesThere is also evidence that CSF ABO concentration is higher in Alzheimer’s patients, but these are reportedly found at very low levels.

Method

We are developing a single molecule counting assay using buoyant and magnetic beads that are functionalized with monoclonal antibodies specific to ABOs. A buoyant‐antigen‐magnetic (BAM) sandwich complex is formed when buoyant and magnetic particles both bind with ABOs. Unlabeled magnetic particles and buoyant beads are initially collected using magnetic force, while unlabeled buoyant particles separate and rise to the top. Removal of the magnet frees BAM complexes to rise away from the non‐labelled magnetic particles, where they can be observed and counted based on their intense scattering for light from a flashlight. The recorded video of BAMs movement is analyzed to determine the number of BAMs rising, which is correlated to the concentration of ABOs in the sample (McNaughton BH 2017).

Result

The procedure uses 20 microliter of CSF and takes 40 minutes and could be speeded up in future if needed. Rapid mixing via buoyancy bead motion provides a higher capture efficiency. The orthogonal forces from magnetophoretic and buoyancy separation ensure complete separation. Preliminary results show its capability to identify spiked synthetic ABOs at 20 fM in both cerebrospinal fluid and plasma samples (n = 20), although work is ongoing.

Conclusion

Overall, BAM assays provide a simple and elegant approach for isolating, detecting, and studying ABOs in CSF and plasma.
Characterization of data‐driven cognitive and amyloid‐beta phenotypes in older Veterans
Authors: Thomas Kelsey R. , Clark Alexandra L , Weigand Alexandra J. , Durazo Alin Alshaheri , Membreno Rachel , Luu Britney , Rantins Peter , Ly Monica T. , Rotblatt Lindsay J , Bangen Katherine J.
Published: December 2023

Background

Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer’s disease (AD), military‐related exposures leading to vascular disease (e.g., agent orange), posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI) may also impact cognition. This study aimed to derive groups based on objective cognition, subjective cognition, and amyloid burden, and then compare groups on demographic, clinical, and biomarker characteristics.

Method

A hierarchical cluster analysis was conducted on 233 Vietnam‐Era Veterans without dementia from the Department of Defense‐Alzheimer’s Disease Neuroimaging Initiative. Variables entered in the cluster analysis included: immediate and delayed memory, language, and attention/executive functioning domain scores; subjective cognitive decline (SCD) severity; and cortical amyloid PET SUVR. A discriminate function analysis (DFA) tested the extent to which the individual variables predicted cluster‐group membership. ANOVAs and chi‐squared tests examined demographic, clinical, and biomarker characteristics by group.

Result

Cluster analysis identified 4 groups: Group 1 with high cognition, low SCD, and average amyloid (n = 41); Group 2 with average cognition, average SCD, and low amyloid (n = 121); Group 3 with low attention/executive functioning, average SCD, and high amyloid (n = 28); and Group 4 with low memory/language, high SCD, and average amyloid (n = 43; Figure 1). The DFA correctly classified 88.8% of participants. Group 3 had the greatest proportion of APOE ε4 carriers and individuals with TBI, highest tau burden, and lowest hippocampal volume. Group 4 had the fewest years of education, highest proportion of Hispanic/Latino participants, PTSD, and worst sleep quality. Groups did not differ on age, depressive symptoms, hypertension, or substance use (Table 1).

Conclusion

Within Vietnam‐Era Veterans, there were high and average cognition groups (Groups 1 and 2), both with low amyloid burden. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans’ co‐morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. Group 4 had the worst cognitive scores and highest SCD despite low amyloid; education, PTSD symptoms, sleep quality, and perhaps sociocultural factors may be contributing to this profile. Future work will investigate longitudinal cognitive and functional declines by group.
Volume of contrast‐based Substantia Nigra segmentation is decreased in dementia patients compared to healthy controls
Authors: Krohn Friedrich , Teipel Stefan , Spottke Annika , Düzel Emrah , Jessen Frank , Ziegler Gabriel , Betts Matthew
Published: December 2023

Background

The substantia nigra (SN) is susceptible to neurodegeneration in Alzheimer’s disease. Automatic segmentation of the SN using MRI permits in vivo morphological assessment of the SN in cohort studies. Here we evaluate the multi‐brain segmentation (MB, Brudfors, 2020) to learn a probabilistic tissue prior of the SN using neuromelanin‐sensitive MRI while systematically studying effects of (A) SN tissue contrast; and (B) volumetric differences between healthy subjects and memory patients.

Method

We studied 50 3T single‐site T1w FLASH MRI from cognitively healthy older adults from the DZNEDELCODE cohort and a second ageing cohort in Magdeburg and 25 multi‐site diagnosed memory patients (MCI or AD). We quantified local SN signal contrast and image noise as a quality metric (obtained from CAT/SPM toolbox). We learnt tissue priors for each 10, 20, 30 and 50 older adults with the highest SN tissue contrast. For each tissue prior, we obtained model‐based SN tissue segments and calculated (integrated) SN volume. We compared SN volume between tissue prior segmentations and correlated it to age and quality. We coregistered all patients to the N = 50 tissue prior and compared volumetric differences between healthy adults and patients using voxel‐based morphometry (VBM).

Result

The template‐space N = 50 SN prior (in red) was visually larger than all other priors (Fig 1A). Patients visually had a lower SN volume than healthy from N = 50 (Fig 1B). The N = 50 native space SN tissue prior volume was significantly higher than all other tissue prior volumes (p>0.01, Fig 2A). SN volume correlated with quality for N = 50 (p = 0.02, Fig 2B). The N = 50 sample SN contrast (Fig 2C) did not differ between patients and healthy adults. Patients had a decreased volume in a cluster overlapping with the SN (N = 268, pFDR corrected = 0.02 (Fig 2D).

Conclusion

Here we demonstrate that model‐based learning of a probabilistic SN tissue prior using intensity‐based generative approach to segmentation is feasable in a heterogenous cohort. Additionally, using this prior, we showed that while there is no difference of the SN contrast, there is a significant decrease in SN volume consistent with previous analyses (Krohn et al 2022).
Plasma ADRD Biomarkers are Altered in COVID‐19 ICU Survivors
Authors: Risacher Shannon L , Khan Babar A. , Dage Jeff L. , Clauss Matthias , Twigg Homer , Russ Kristen A. , Leary Erika L , Saykin Andrew J. , Wang Sophia
Published: December 2023

Background

Long Covid, which features cognitive symptoms in some people, affects an estimated 23.3 million Americans. Older adult survivors of COVID‐19‐associated critical illness are more likely to experience the cognitive symptoms of Long Covid, including deficits in attention, memory, and executive functioning. We sought to evaluate Alzheimer’s disease and related dementia (ADRD) plasma biomarkers in pilot study of older ICU survivors of COVID‐19‐related critical illness and non‐COVID critical illness.

Method

17 ICU survivors (13 COVID‐19, 4 non‐COVID) underwent clinical and cognitive testing, a blood sample, and a structural MRI approximately 2 months after ICU discharge. Plasma from the blood sample was extracted, and SIMOA assays were used to measure Aβ42, Aβ40, glial fibrillar acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (pTau181). Structural MRI scans were processed using Freesurfer version 6 to measure brain atrophy (mean global cortical thickness). Plasma analyte values over three standard deviations outside the mean of the whole group were excluded (1 NfL and 1 pTau). Two‐sample t‐tests were used to compare plasma analytes between ICU groups. Pearson or Spearman correlation models were used to evaluate the relationship of target analytes with brain volumes. Covariates were tested but did not change the results.

Result

Significantly lower Aβ42/40 ratio and Aβ42 levels were observed in COVID‐19 ICU survivors relative to non‐COVID ICU survivors (Figure 1). Across all participants Aβ42/40 ratio was not associated with mean global cortical thickness, while NfL and GFAP levels were negatively associated with cortical thickness (Figure 2). However, when limited to only the COVID‐19 ICU survivors, a more ADRD‐like pattern was observed, with a trend for a positive association of Aβ42/40 ratio with cortical thickness and negative association of GFAP and NfL with cortical thickness (Figure 3).

Conclusion

Cognitive impairment in COVID‐19 critical illness may be related to ADRD pathophysiology. Future studies in larger samples of COVID‐19 ICU survivors, as well as those with Long Covid symptoms with a history of mild to moderate COVID‐19 infection are needed to better understand these relationships.
Circadian sleep regulation and brain tissue microstructure in cognitively unimpaired older adults
Authors: Deantoni Michele , Reyt Mathilde , Dourte Marine , De Haan Stella , Lesoinne Alexia , Vincenzo Muto , Hammad Grégory , Christina Schmidt , Baillet Marion
Published: December 2023

Background

Circadian dysfunction increases with age, leading to changes in the circadian regulation of physiological and biological rhythms, including sleep. Actigraphy studies demonstrated that altered 24‐h rest‐activity patterns, an estimate of circadian sleep‐wake regulation, is related to cognitive decline and tightly linked to Alzheimer’s disease progression. Here, we assessed whether circadian sleep regulation, measured during a multiple naps protocol, is related to brain microstructural integrity in a group of cognitively unimpaired older adults.

Method

Eighty‐six retired older individuals (mean age [SD] = 69.9 ± 5.2 y.o., 32 females, Table 1) with no major sleep disorders or medical condition, underwent an in‐lab 40‐h multiple naps protocol and brain structural magnetic resonance imaging. As rapid eye movement (REM) sleep is under strong circadian control, circadian REM sleep amplitude was computed by fitting a Gaussian curve on REM sleep duration (% of total sleep time) measured for each nap opportunity. The multiparametric mapping protocol was used to derive indices of brain tissue microstructure using magnetization transfer saturation (MTsat), R1 and R2* maps (hMRI toolbox v0.2.2). Statistical models were adjusted for age, sex, education, and for additional covariates related to sleep architecture and its circadian modulation, including mean REM% and sleep efficiency (SE), the accumulation of REM sleep and sleep need (slope of a fitted first‐order polynomial curve), and circadian SE amplitude.

Results

Whole‐brain voxel‐based quantification analysis revealed that low circadian REM amplitude was related to low MTsat, R1 and R2* values in several white matter regions mostly located around the lateral ventricles (Figure 1A). In addition, a significant association was observed between low circadian REM amplitude and low R1 values in two grey matter clusters encompassing the hippocampus, entorhinal cortex, thalamus and hypothalamus (Figure 1B).

Conclusion

Our findings provide first evidence that changes in circadian sleep regulation is associated with microstructural changes in key brain regions sensitive to the aging process and involved in sleep‐wake regulation. These results further emphasize the relevance of monitoring circadian sleep regulation for the early detection of individuals at risk for neurodegeneration and cognitive decline.
Errors and repetitions on tests of language, verbal learning, and memory in cognitively unimpaired adults at increased risk for Alzheimer’s disease
Authors: Mueller Kimberly D , Basche Kristin E , Bruno Davide , Frost Casey Michelle , Christian Bradley T. , Betthauser Tobey J , Johnson Sterling C , Hermann Bruce P , Langhough Rebecca E
Published: December 2023

Background

Errors and repetitions on verbal fluency and list learning tasks have been found to predict progression to MCI and differentiate between healthy aging, MCI, and dementia. This study examined whether errors and/or repetitions on verbal measures were cross‐sectionally associated with amyloid pathology in baseline cognitively unimpaired (CU) adults, and provided additional information beyond traditional total score measures.

Method

We included 437 participants from the Wisconsin Registry for Alzheimer’s Prevention who completed comprehensive neuropsychological testing and amyloid (Ab) positron emission tomography (PET) scans using Pittsburgh Compound‐B (PiB). Ab(+/‐) status was determined using an established threshold average distribution volume ratio(DVR) >1.19 across several brain regions. From the most recent testing visit, we extracted the total number of errors and repetitions from the Rey Auditory Verbal‐Learning Test (AVLT), animal fluency, and letter fluency; these were summed to form error and repetitions composites. We ran ANCOVAs with Ab(+/‐) as predictor; age, sex, and WRAT‐3 reading were covariates. Cohen’s D effect sizes characterized strength of relationships, where higher errors = negative effect sizes, and higher total scores = positive effect sizes. Sensitivity analyses examined errors and total scores from individual tests, and removal of participants who progressed to MCI.

Result

Sample characteristics are presented in Table1. Relationships between error, repetition and total score variables are shown in Figure1. Ab(+/‐) was a significant predictor of the error composite (p = .001) but not the repetition composite. Ab(+/‐) was significantly associated with AVLT learning total (p = .01), but not with animal or letter fluency totals. Secondary analyses revealed that AVLT errors alone were associated with Ab(+/‐) (p<.0001); effect sizes were greatest for AVLT errors (d = ‐.46) than for the error composite (d = ‐.39) or for AVLT total score (d = .39) (Figure 2). Removal of impaired participants yielded similar effect sizes.

Conclusion

Findings from this CU sample suggest that AVLT errors may be more sensitive to early AD pathology than traditional total score measures. Errors on list‐learning may represent other cognitive and/or sensory processes (e.g., auditory processing, hearing, attention, inhibition) that are sensitive to AD but are not represented in total scores. Future research includes examining longitudinal and additional error composites’ relationships with AD pathology to develop more sensitive cognitive measures.
The Role of Apolipoprotein E4 Allele in the Gut Microbiome of Puerto Ricans with Alzheimer’s Disease
Authors: Olivieri‐Henry Gerianne , Sepulveda Vanessa , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Pérez‐Luzunaris Fabián J. , Herrero‐Rivera Carlos , Godoy‐Vitorino Filipa
Published: December 2023

Background

Alzheimer’s disease (AD) causes dementia, a debilitating disorder that gradually declines mental function and ends with death. Evidence suggests that the apolipoprotein E (ApoE) gene influences Alzheimer’s risk. Allele E2 is neuroprotective, E3 is neutral, and E4 is associated with a higher genetic risk for AD. Our main goal was to study the gut microbiome of Puerto Ricans with AD compared to unimpaired cognitive controls and its association with ApoE allele variants. We hypothesized that people with AD and does with less protective alleles have reduced microbial diversity.

Methods

We present the preliminary results of forty eight participants (n = 48), 24 with AD and 24 controls, with clinical and cognitive assessments. Fecal samples were collected for genomic DNA extractions followed by 16S rRNA genes (V4 region) amplification and ApoE genotyping was done at the PR‐INBRE CRI genomics core, using real‐time PCR TaqMan‐BHQ probes.

Results

Controls, even with a single E4 allele, showed higher abundance of Ruminococcus bicirculans, absent in AD patients. Clostridium leptum was in higher abundance in controls with neuroprotective alleles E2E3 and in considerably reduced abundance in AD patient with E3E4 phenotype. Methanobrevibacter was in higher abundance in participants with any E4 allele than those with either E2 or E3 alleles. Faecalibacterium and Bacteroides were in higher abundance in controls compared to AD patients. Faecalibacterium, Ruminococcus, Clostridium and Bacteroides are anti‐inflammatory taxa and butyrate producers. Methanobrevibacter could favor metabolizing acetate to methane and thus antagonize the health‐directed butyrate benefits.

Conclusion

Participants with any ApoE E4 allele have decreasing butyrate‐producing gut bacteria. This developing study area may open the possibility for preventive microbiome‐based therapies that could result in a clinical benefit for patients with and without AD.