bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of Antemortem Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Neuropathologic changes at Autopsy
Authors: Kurihara Masanori , Matsubara Tomoyasu , Morimoto Satoru , Saito Yuko , Kanemaru Kazutomi , Murayama Shigeo , Iwata Atsushi 
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) amyloid‐beta 42 (Aβ42) and tau phosphorylated at threonine 181 (p‐tau181) have been widely used as biomarkers for Alzheimer’s disease (AD). AT(N) classification even proposes each substance as a direct biomarker of amyloid (A) and tau (T) pathologies, respectively. However, recent studies suggest that increased CSF p‐tau181 may rather be associated with amyloid pathology. Although neuropathological evaluation at autopsy is the gold standard for assessing these changes, studies evaluating the association between CSF biomarkers and AD neuropathologic changes are limited.MethodWe retrospectively studied patients who underwent antemortem CSF AD biomarker measurement and neuropathological evaluation at autopsy at our institution from 1995 to 2021. CSF biomarkers were measured by ELISA (Fujirebio, Belgium). Neuropathological evaluation of AD was performed routinely regardless of diagnosis and Thal phase, Braak neurofibrillary tangle (NFT) stage, and CERAD score were assessed according to current guidelines.ResultThe mean age of the 119 patients was 76.2 ± 8.9 years; 49 were women. The duration from lumbar puncture to autopsy was median 2 years (0‐13 years). AD pathology was observed in 29 patients (24%). Other common pathologies were Lewy body disease and frontotemporal lobar degeneration. Antemortem CSF Aβ42 and p‐tau181 results were obtained in 119 and 68 patients, respectively. As expected, CSF Aβ42 decreased with increasing Thal phase and CERAD score. CSF p‐tau181 increased with increasing Thal phase, Braak NFT stage, and CERAD score. Even when the analysis was restricted to patients with Braak NFT stage 3 or less (n = 48), CSF p‐tau181 increased mildly with increasing Thal phase and CERAD score. In patients with moderate or severe amyloid pathology by Thal phase or CERAD score (n = 34), CSF p‐tau181 increased more highly at Braak NFT stage 5 or more.ConclusionThe results of this study, which directly compared antemortem CSF biomarkers with AD neuropathologic changes at autopsy, support the current theories that increased CSF p‐tau181 is caused by both amyloid and tau pathology related to AD while decreased CSF Aβ42 is associated with amyloid pathology.
Enlarged Perivascular Spaces in a Diverse Community‐based Sample. The Multi‐Ethnic Study of Atherosclerosis
Authors: Charisis Sokratis , Rashid Tanweer , Liu Hangfan , Ware Jeffrey B. , Jensen Paul N. , Austin Thomas R. , Li Karl , Fadaee Elyas , Hilal Saima , Chen Christopher Li‐Hsian , Hughes Tim M. , Romero Jose Rafael , Toledo Jon B. , Longstreth William T , Hohman Timothy J. , Nasrallah Ilya M. , Bryan Nick , Launer Lenore J J. , Davatzikos Christos , Seshadri Sudha , Heckbert Susan R. , Habes Mohamad 
Published: December 2023

AbstractBackgroundEnlarged perivascular spaces (ePVS) have been associated with small vessel disease of the brain (SVD). Nevertheless, the burden, correlates and significance of ePVS have been studied predominantly in White individuals, so the generalizability of these findings to other racial/ethnic groups remains uncertain. Herein, we present an investigation of ePVS in a large, multi‐ethnic, community‐based cohort.MethodePVS volumes were quantified in 1,026 participants (median age 71 years; 47% men) from the Multi‐Ethnic Study of Atherosclerosis, using a fully‐automated deep learning model with 82% lesion‐wise sensitivity. Based on previously‐described clinical rating systems, ePVS were grouped in four brain regions: basal ganglia, thalamus, frontoparietal region, and temporal region, and were normalized to the respective regional volumes. Cognition was assessed with the Cognitive Abilities Screening Instrument, the Digit Symbol Coding, and the Digit Span test. APOE‐ε4 isoforms were estimated from single nucleotide polymorphisms (rs429358,rs7412). The relationships of normalized regional ePVS volumes with demographic and vascular risk factors, neuroimaging indices, cognition, and APOE genotype were explored using generalized linear models.ResultBasal ganglia was the anatomic region with the largest ePVS burden (median[IQR] = 1.9[1.4] % of total regional volume), followed by the frontoparietal region (0.6[0.5]), temporal region (0.4[0.4]), and thalamus (0.3[0.3]) – Figure 1,Table 1. Basal ganglia ePVS volume was positively associated with age, systolic blood pressure (SBP), use of antihypertensives, white matter hyperintensity volume (WMHV), and microbleeds (MBs), and negatively associated with white matter fractional anisotropy (FA) and Black race (Tables 1,2). Thalamic ePVS volume was positively associated with age, use of antihypertensives, WMHV, and MBs, and negatively associated with FA. Frontoparietal ePVS volume was positively associated with SBP, and negatively associated with age. Temporal region ePVS volume was negatively associated with age, Chinese and Hispanic ethnicity. No significant associations were observed between regional ePVS volumes and cognition or APOE genotype.ConclusionIncreased ePVS burden in the basal ganglia and thalamus was associated with hypertension and imaging biomarkers of vascular brain damage in a multi‐ethnic population of older adults, likely reflecting underlying SVD. Compared to other racial/ethnic groups, White race was associated with higher ePVS burden in the basal ganglia and temporal regions.
Path integration deficits predict phosphorylated tau accumulation in the entorhinal cortex: Assessment of Braak stage I,II using 3D Virtual reality goggles
Authors: Takashima Akihiko , Koike Riki , Soeda Yoshiyuki , Fujioka Yusuke , Ishigaki Shinsuke , Watanabe Hirohisa 
Published: December 2023

AbstractBackgroundWe aimed to develop behavioral tasks that can identify early signs of Alzheimer’s disease (AD) in order to facilitate the development of preventative and therapeutic interventions.MethodTo do this, we created a 3D virtual reality task that is sensitive to the activity of grid cells in the entorhinal cortex, a region that is affected early on in AD. We tested path integration in a spatial navigation task in 177 volunteers between the ages of 20 and 89 who did not have a self‐diagnosed AD.ResultOur results showed that the percentage of subjects showing impaired path integration correlated with the percentage of subjects showing neurofibrillary tangles in the entorhinal cortex, as seen in previously published autopsy data. To further confirm this relationship, we also tested a tauopathy mouse model and found that mice with accumulation of phosphorylated tau in the entorhinal cortex had impaired path integration without impairments in spatial cognition or novel object recognition.ConclusionThese findings suggest that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex and may allow for early identification of individuals at risk for developing AD.
Rhythmic Musical Intervention Improves Short‐term Memory Function in Healthy Elderly: A Prospective Pilot Study of a Group‐based African Drum Training
Authors: Hao Ziyu , Chan Aaron TC , Tran Joshua YS , Cheung Ruby SM , Lam Amy SM , Leung Philip SK , Tsoi Kelvin KF 
Published: December 2023

AbstractBackgroundMemory complaints are the early symptoms of cognitive impairment, and it usually brings anxiety about cognitive deterioration among the elderly population. Musical interventions were demonstrated to relieve dementia symptoms1. This study is to investigate the potential benefits of African drum intervention on cognitive functions.MethodParticipants were recruited in July 2022 through social media advertisement. Classes were organized in a drumming activity center in downtown, Kowloon. Participants joined 8 sessions of African drum training which covered rhythmic clapping and drumming, power control, and overall performance with songs. The inclusion criteria were participants (1) aged over 50 years old and (2) able to use a smartphone. Participants who could not understand Chinese or had been diagnosed with active psychosis or dementia were excluded. Cognitive function was screened by an online platform, ScreenMat2, for short‐term and long‐term memory, orientation, calculation, visual function, and followed up with the Hong Kong version of the Montreal Cognitive Assessment (HK‐MoCA). Anxiety and depression levels were assessed by State‐Trait Anxiety Inventory (STAI) and Geriatric Depression Scale (GDS). All assessments were performed before and after the drumming classes (Figure 1). The outcomes were evaluated using Wilcoxon Signed Rank Test with 0.05 as the significance level.ResultTwenty‐four participants joined this study with an attendance rate of 83%. The overall cognitive function of the participants was good with an average score of 27 for HK‐MoCA. After 8 sessions of African drum intervention, the cognitive function did not show significant improvement (p = 0.108), but the response time of answering the digital cognitive questions was significantly faster than that before the intervention (‐39.9 seconds, p = 0.03) (Table 1). The response time for the short‐term memory function was the most significantly reduced better after the African drum training (‐13.5 seconds, p = 0.005) The STAI and GDS scores also significantly decreased (p<0.001).ConclusionRhythmic Musical Intervention, such as the African drum, can improve the response time of cognitive tests and also relieve anxiety and depression levels.1. Tsoi et al. J Am Med Dir Assoc. 2018;19(7), 568‐576. https://doi.org/10.1016/j.jamda.2017.12.0092. Lam et al. In Proceedings of the 51st HICSS. 2018. doi:10.24251/HICSS.2018.353
Socioeconomic position, modifiable dementia risk and cognitive decline: results of 12‐year Maastricht Aging Study
Authors: Heger Irene , van Boxtel Martin P.J. , Deckers Kay , Bosma Hans , Verhey Frans R.J. , Köhler Sebastian 
Published: December 2023

AbstractBackgroundEvidence of modifiable risk factors for cognitive decline and dementia is accumulating, showing the potential of dementia risk reduction via lifestyle modification and cardiovascular risk management. People with low socioeconomic status (SES) have increased dementia risk and on average worse health. This study investigated whether the association between a modifiable dementia risk score and rate of cognitive decline differs across SES strata.MethodData were used from Maastricht Aging Study (MAAS), a prospective cohort study with a 12‐year follow‐up. Participants aged ≥40 years with complete dementia risk profiles were included (n = 1223). The validated ’LIfestyle for BRAin health’ (LIBRA) index was used to assess the modifiable dementia risk fraction. Cognitive performance was serially assessed at baseline, 6 and 12 years and measured in the domains of information processing speed, executive functioning and verbal memory function. A SES compound score was calculated from equivalent income and educational level and divided into tertiles (low, middle, high). Linear mixed models were used to study the association between LIBRA, SES and their interaction on the rate of cognitive decline.ResultParticipants in the lowest SES tertile displayed more decline in information processing speed (vs. middle SES: X2 = 7.08, p = 0.029; vs. high SES: X2 = 9.49, p = 0.009) and verbal memory (vs. middle SES: X2 = 9.28, p<0.001; vs. high SES: X2 = 16.68, p<0.001) compared to their middle‐ and high‐SES counterparts. Higher (unhealthier) LIBRA scores were also associated with more decline in information processing speed (X2 = 12.66, p = 0.002) and verbal memory (X2 = 4.63, p = 0.032). No consistent effect modification by SES on the association between LIBRA and cognition was found.ConclusionThis study shows that lower SES and higher modifiable dementia risk predict faster decline in information processing speed and verbal memory function over 12 years. Results suggest that lifestyle is an important determinant of cognitive decline across SES groups. Yet, people with low SES had a more unfavourable modifiable risk score suggesting more potential for lifestyle‐based interventions. LIBRA could be useful as a participant selection tool or as a surrogate outcome measure in lifestyle intervention trials, and can inform people about individual risk behaviours as part of public health initiatives.
Vascular risk factors and fMRI activation in a prodromal dementia population
Authors: Kallevag Oystein 
Published: December 2023

AbstractBackgroundVascular risk factors (VRF) are associated with an increased risk of developing dementia (1). Functional magnetic resonance imaging (fMRI) demonstrates the ability to detect early changes in neuronal activation before cognitive changes are clinically measurable (2). We investigate whether the number of VRF in cognitively healthy persons with a minimum of two VRF present was associated with a change in neuronal activation in the brain measured with task‐based fMRI.Methods56 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR), elderly persons completed an fMRI examination with task‐based fMRI and N‐Back paradigm to access Working Memory (WM). Vascular risk factors included in the study were stable coronary artery disease or cerebrovascular disease according to MRI criteria, hypercholesterolemia, hypertension, diabetes mellitus and overweight (3).We analyzed the fMRI data at a single time point using the FMRIB Software Library (FSL v6.0; Analysis Group, Oxford, UK).ResultsThe mean age was 68.4 (± 5.4) years. The number of VRF present were VRF2 (n = 21), VRF3 (n = 25) and VRF4 (n = 10). The median MMSE were: VRF2: 29 (IQR 29 ‐ 30), VRF3: 30 (IQR 28.8 ‐ 30) and VRF4: 29.5 (IQR 28.3 ‐ 30). A low number of VRF (VRF2) revealed higher neuronal activation than the groups with a higher number of VRF (VRF3 and VRF4). The regional activated clusters in the VRF2 group showed activation in the superior parietal lobule, visual cortex, premotor cortex, Broca’s area and anterior intra‐parietal sulcus.ConclusionOur results show that a lower neuronal activation measured with fMRI is associated with a higher number of VRF. We suggest further studies to assess whether altered neuronal activation measured by fMRI in cognitively healthy elderly persons with VRFs can be associated with a higher risk of developing cognitive decline and dementia.1. O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698‐706.2. Chen J, Glover G. Functional Magnetic Resonance Imaging Methods. Neuropsychology Review. 2015;25(3):289‐313.3. Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.
DNA methylation clustered by predicted chromatin state reveals distinct association patterns with neuropathologic and biochemical measures in the AD brain
Authors: Oatman Stephanie R , Quicksall Zachary , Reddy Joseph S. , Carrasquillo Minerva M. , Wang Xue , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Malphrus Kimberly G. , Heckman Michael G. , Martens Yuka A , Zhao Na , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Bu Guojun , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilufer 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms, the identification of which may reveal important biological insights into AD pathophysiology. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm clusters from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, and CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from neuropathologically‐confirmed AD cases available through the Mayo Clinic brain bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Neuropathology was scored by an experienced neuropathologist. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged. Averaged CpGm clusters were tested for their association with each endophenotype through multi‐variable linear regression. The influence of CpGm clusters on expression levels of nearby genes was also investigated through multi‐variable regression.ResultsOur innovative binning method demonstrated expected and biologically relevant CpGm patterns. We identified multiple epigenome‐wide significant CpGm clusters unique to each AD‐related endophenotype and brain region. Comparisons between the TCX and CER further revealed brain region‐specific enrichment of distinct CpGm clusters. Significant CpGm clusters were further characterized by their influence on gene expression.ConclusionsAlthough all neuropathologic and biochemical endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. By discovering brain region‐specific DNAm changes that contribute to each neuropathologic or biochemical outcome, we can identify core components of complex mechanisms that individually and jointly contribute to AD.
POINTER‐zzz: Study Design and Baseline Characteristics from the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Sleep Ancillary
Authors: Hayden Kathleen M. , Scales Margaret , Howard Marjorie , Desai Pankaja , Leng Xiaoyan , Lim Andrew , Molina‐Henry Doris P. , Redline Susan , Snyder Heather M , Stone Katie L , Woolard Nancy , Espeland Mark A. , Baker Laura D 
Published: December 2023

AbstractBackgroundSleep disordered breathing (SDB) leads to nocturnal hypoxemia and sleep disruption, which are linked to adverse health conditions, particularly in older adults at risk for dementia. Few prospective studies of SDB examine cognitive decline among those at increased risk for cognitive impairment and dementia. POINTER‐zzz, a sleep ancillary study of U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), allows us to examine the role of lifestyle intervention on sleep quality, and potential moderating effects of sleep on cognition to the intervention in medically and cognitively vulnerable older adults.MethodU.S. POINTER was designed to investigate the effects of two 2‐year lifestyle interventions on cognitive trajectories in 2,000 older, cognitively normal adults (aged 60‐79 yrs) at increased risk for cognitive decline and dementia due to physical inactivity, poor diet and cardiovascular disease. POINTER‐zzz enrolled a subset of parent trial participants and administered in‐home sleep assessments using WatchPAT (1 night) and ActiGraph (6 nights) devices. We summarize participants’ baseline characteristics including apnea hypopnea index (AHI), sleep duration and sleep efficiency.ResultTo date, 688 POINTER‐zzz participants enrolled and completed baseline WatchPAT and/or Actigraph assessments. Participant ages averaged 68.6 years old (standard deviation, 5.13); 21% of participants self‐identified as Black/African American, 4% Hispanic/Latino, and 66% White. More than half (68%) were female, and 69% had a Bachelor’s degree or higher. Overall, 87% of participants had at least mild sleep apnea (AHI>5). Severe sleep apnea (AHI≥30) was observed in 14% of participants overall, and 21% of those aged ≥75 yrs. Severe sleep apnea was more prevalent among males (19%) than females (11%). Overall, nightly sleep duration for the cohort averaged 6.6 hours, with 83% sleep efficiency, and an average of 79.3 minutes awake after sleep onset.ConclusionPOINTER‐zzz participants have sleep characteristics that align with expectations for a cohort that is broadly representative of a diverse older adult population in the US. POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep disturbances that are linked to cognitive decline and AD in a well‐characterized, diverse cohort of at‐risk older adults.
Apathy, cognition and beta amyloid in African Americans in the AA‐FAIM cohort
Authors: Fischer Barbara L. , Van Hulle Carol A. , Wyman Mary F. , Norton Derek L. , Carter Fabu P. , Salazar Hector , Bouges Shenikqua , Gooding Diane C. , Umucu Emre , Chin Nathaniel A. , Kirmess Kristopher M. , Meyer Matthew R. , Gleason Carey E. , Zuelsdorff Megan 
Published: December 2023

AbstractBackgroundThe prodrome of cognitive declines and/or dementia may include late‐life neuropsychiatric symptoms such as apathy. In primarily non‐Hispanic White samples, apathy associates with both cognition and amyloid deposition in cognitively intact patients and those with Alzheimer’s disease (AD). However, little is known about these relationships in African Americans, who are both disproportionately affected by AD and under‐represented in AD research. Apathy could reflect higher levels of proteinopathy or occur co‐morbidly, exacerbating its deleterious effects. We examined associations between apathy and cognition and their potential moderation by plasma beta amyloid in cognitively healthy African American participants.MethodStudy participants enrolled in African Americans Fighting Alzheimer’s In Mid‐Life(AA‐FAIM, a linked study to the WRAP and Wisconsin ADRC) were included in the analytic sample (N = 166; Table 1) if they had ≥1 cognitive visits, plasma amyloid biomarker data, and apathy ratings by study partners using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) or the Apathy Evaluation Scale (AES). Cognitive outcomes included performance on measures of processing speed, mental flexibility and immediate and delayed memory. We used linear mixed models to examine association of baseline apathy with cognitive performance measures at multiple time points, and the moderation of apathy‐cognition relationships by plasma Aβ42/40 ratio (C2N, USA). Apathy‐cognitive outcome pairings were selected based on significant findings from a proof‐of‐concept linear mixed effects analysis of the full Wisconsin ADRC sample.ResultResults are shown in Table 2. Among AA‐FAIM participants, NPI‐Q apathy was associated with RAVLT immediate (estimate = ‐7.7, p = .001) and delayed recall (estimate = ‐3.2, p = .001). However, AES was unrelated to Trails A or B performance. There were no associations between plasma amyloid or the Aβ42/40*apathy interaction term with any cognitive outcomes.ConclusionPartner‐rated apathy, but not plasma Aβ42/40, was related to cognition in our African American participants, an important finding given limited data available on this population. It will be critical to address apathy and its antecedents to improve the cognitive and affective health of African American older adults. Future research needs to expand cohorts to African American and other diverse populations to investigate disease mechanisms in Alzheimer’s disease and related dementias more inclusively.