bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenesis of degenerative dementia: Emerging role for inflammation
Authors: Arshad Faheem , Alladi Suvarna , Varghese Feba Anna , Ramakrishnan Subasree , Nashi Saraswati , Mahadevan Anita 
Published: December 2020

AbstractBackgroundRecent evidence proposes a role for immune‐mediated mechanisms in pathogenesis of neurodegenerative dementias. Contribution of inflammatory processes to the progression of neurodegeneration has also been hypothesized. While deposition of various proteins is recognised as the pathological hallmark for the neurodegenerative dementias, Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), the role of inflammation secondary to immune dysregulation in neurodegeneration remains to be determined. In this study, we aimed to investigate the profile of autoantibodies in patients diagnosed to have neurodegenerative dementia and compare the association between the different subtypes.MethodWe performed immunological screening in a large cohort of neurodegenerative dementias. Diagnosis was based on standard criteria, on review of clinical, MR imaging and laboratory features. Dementia types comprised of Alzheimer’s disease (AD), Frontotemporal dementia (FTD), and Dementia with Lewy Bodies (DLB). The immunological screening consisted of antinuclear antibody (ANA) profile, paraneoplastic and autoimmune encephalitis profile.ResultOf 274 consecutive patients with degenerative dementia evaluated in the Cognitive Disorders Clinic (AD = 62, FTD = 202, DLB = 10), autoantibody profile was done in 174(63.5%). ANA profile was positive in 18.3%, paraneoplastic panel in 8.3% and autoimmune panel in 2.1% of patients. We observed a significantly higher frequency of immunopositivity in patients with FTD (34.4%) compared to AD(10.4%) and DLBD(14.2%). The range of antibodies detected included antibodies against anti‐Ro 52(SS‐A), anti‐La(SS‐B), PM‐Scl, centromere protein B(CENP‐B), dsDNA, histones and ribosomal P‐proteins in the ANA profile; anti‐Hu, anti‐Ri, anti‐Yo, anti‐CV‐2, PNMA2 (Ma2/Ta), Anti‐amphiphysin, Anti‐ SOX1, anti‐glial nuclear antibody(AGNA), anti‐Tr, Anti‐GAD65, anti‐Zic4, anti‐titin and anti‐recoverin in paraneoplastic and in the autoimmune profile autoantibodies present were N‐methyl‐D‐asparate(NMDA), alpha‐amino‐3‐hydroxy‐5 methyl‐4‐isoxazoleproprionic acid (AMPA), Leucine rich glioma‐inactivated protein‐1(LGI1), Contactin‐associated protein‐2(CASPR2), and GABAB receptor antibody. There were no significant systemic complaints in majority of patients, and no difference was observed in the mean age, gender and duration of illness between immune‐positive and immune‐negative patients.ConclusionOur findings further substantiate the emerging role for neuroinflammation secondary to immune dysregulation, in patients with classical neurodegenerative dementias. Establishing the profile of specific autoantibodies that occur in association with dementia subtypes, especially FTD, may aid in understanding mechanisms that underlie role of autoimmunity in neurodegenerative dementias, with therapeutic implications.
Pleiotropy analyses using TADs identify genomic regions affecting risk of AD and stroke
Authors: Greenfest‐Allen Emily , Stoeckert Christian J. , Wang Li‐San , Schellenberg Gerard D. , Naj Adam C. 
Published: December 2020

AbstractBackgroundAlthough stroke is an established risk factor for Alzheimer’s disease (AD), the role vascular factors play in driving AD remains uncertain. Here we leverage GWAS summary statistics to assess the genetic correlation (pleiotropy) between stroke and AD and introduce a novel fine‐mapping approach to pinpoint shared causal variants in the context of higher‐order genome organization.Method32 stroke‐risk associated variants identified by the MEGASTROKE consortium (Malik et al. Nat Genet 2018) were mapped to topologically associating domains (TADs) identified in H1‐hESCs (Dixon et al. Nature 2015). Coloc was used to compare GWAS summary statistics for stroke and AD (Kunkle et. al Nat Genet 2019) within the TADs containing each stroke variant. As genes located within the same TAD tend to be coregulated and contacts between enhancers and gene promoters are mainly restricted within TADs, predicted shared causal variants can be functionally linked to genes and their downstream interactants within the same domain. STRING pathway analysis was run on the resultant gene sets to tie putative target genes to processes affecting disease progression.ResultThe strongest evidence for shared genetic risk between AD and stroke is in the promoter region of CDK6 (posterior probability [PP] of common causal variants in the TAD>70%; Figure 1, Tables 1/2), which encodes a serine/threonine‐protein kinase involved in the negative regulation of cell cycle and the promotion of G1/S transition. Levels of CDK6 have been found to be higher in AD patients and affect pathways tied to neuronal cell death in stroke. Genetic correlations supporting pleiotropy due to distinct causal variants were found in TADs containing known interactants of CDK6, including FBXO31 (PPD = 19.1%) and CDKN2A/B (PPD = 66.6%; Table 2). CDKN2A/B is part of a known chromosome 9p21.3 susceptibility locus for both AD and vascular dementia.ConclusionWe identified several candidate loci affecting AD/stroke pleiotropy, most of which contain no documented variants with genome‐wide significance for AD risk. Pathway analysis of genes contained within TADs reveals a link between the shared risk between AD and stroke and the disruption of neuronal cell cycle at the onset of the G1/S phase.
Elevated plasma neurofilament light (NfL) is associated with incident Alzheimer’s disease and accelerated cognitive decline in adults with Down syndrome
Authors: Dang Lam‐Ha T. , Krinsky‐McHale Sharon J. , O'Bryant Sid , Pang Deborah , Zigman Warren B , Silverman Wayne , Schupf Nicole , Lee Joseph H. 
Published: December 2020

AbstractBackgroundThe value of plasma neurofilament light (NfL), a marker of neurodegeneration, in Alzheimer’s Disease (AD) has been reported in the general population. However, evidence for NfL as a predictive marker of neurodegeneration in adults with Down Syndrome (DS) is limited. The small number of longitudinal studies have short follow‐up periods. Thus, the value of NfL as a prognostic indicator of AD is still unknown. To date, no study has examined whether levels of NfL predict the trajectories of cognitive decline in adults with DS. In this study, we will examine the association of NfL with incident AD and trajectories of cognitive decline.MethodWe studied 271 adults with DS who were dementia‐free at the baseline and were assessed at 14‐ to 18‐month intervals for up to 5‐cycles. Baseline plasma NfL was measured using the Simoa platform. Neuropsychological tests assessing various cognitive domains were administered at each follow‐up visit and AD status was determined by consensus diagnosis. Cox proportional hazards models were used to assess the association between baseline NfL and incident AD. Linear mixed modeling was used to evaluate the relations between NfL and changes in neuropsychological measures over time. Estimates were adjusted for age at blood collection, sex, presence of APOE ε4 allele, and level of premorbid intellectual functioning.ResultOver the follow‐up period, 54 (21%) individuals developed AD with the mean follow‐up of 4.7 years. Elevated plasma NfL levels were significantly associated with incident dementia (p < 0.001); the risk of AD increases by 34% per 10 pg/mL increase in NfL. Participants who were in the highest quartile of NfL (41‐120 pg/mL) were 8 times (95% CI: 2.5‐25.3) more likely to develop AD, compared to those in the lowest quartile. Moreover, elevated NfL levels were significantly associated with faster declines in various neuropsychological domains (i.e., mental status, episodic memory, visuospatial organization), but not verbal fluency and construction.ConclusionElevated baseline plasma NfL is a prognostic marker of accelerated cognitive decline and subsequent incident dementia in adults with DS. Our findings suggest that NfL may have utility for use in routine disease monitoring and clinical trial screening.
Prevalent skin cancer and conservative faith may be linked with cognitive impairment in Ashkenazi Jewish exceptionally long‐lived individuals
Authors: Rivkin Elina , Weinstein Galit , Barzilai Nir , Atzmon Gil 
Published: December 2020

AbstractBackgroundExceptional long‐lived individuals (ELLI) are known for their improved health status and independence regardless of life‐style and health behaviors. Yet, little is known about their cognitive function correlates. The aim of the present study was to assess the correlation between social, clinical, behavioral and personality factors and cognitive impairment in a sample of Ashkenazi Jews (AJ) ELLIs.MethodThe study sample included 401 AJ participants, aged 95 years or older, of the Longevity Genes Project at Einstein, who were residents of the northeastern United States and lived independently in the community. Socio‐demographic, medical history data and life‐style factors were collected via mailed questionnaires, telephone calls, or in‐person visits. Personality was assessed through the Personality Outlook Profile Scale. In the event that participants had difficulty responding to questions in a reliable manner, their children or legal guardian assisted them. Cognitive status was assessed using the Mini Mental State Exam (MMSE) with a score of 24 or lower considered as cognitive impairment. Cross‐sectional associations of medical, social, life‐style and personality characteristics with odds for cognitive impairment were assessed using logistic regression models while adjusting for potential confounders.ResultOf the total sample (mean age=97.72.8 years, 84% women), 178 (44%) were cognitively impaired. Following adjustment for age, sex and education, prevalent skin cancer (OR, 95% CI: 0.40, 0.22‐0.74) as well as being conservative religious (OR, 95% CI: 0.18, 0.03‐0.97) and attending temple in Holidays only (OR, 95% CI=0.25, 0.07‐0.88) and weekly (OR, 95% CI: 0.25, 0.06‐0.97) at age ∼70 years were associated with lower odds for cognitive impairment.ConclusionCognitive impairment correlates in ELLI may differ from those in the general population. Future studies are warranted to explore the role of religious involvement in brain aging. Furthermore, the strong link between a history of skin cancer and cognition in the oldest‐old should be examined.
Assessing the relationship between cognitive dysfunction and brain atrophy in Alzheimer's disease
Authors: Edison Paul , Femminella Grazia Daniela , Nowell Joseph , Raza Sanara , Livingston Nicholas R , Blunt Eleanor G , Carver Stefan , Holmes Clive , Ritchie Craig W , Lawrence Robert M , McFarlane Brady , Tadros George , Ridha Basil H , Bannister Carol , Walker Zuzana , Archer Hilary , Coulthard Elizabeth , Underwood Ben , Prasanna Aparna , Koranteng Paul , Karim Salman , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Macharouthu Ajayverma , Donaldson Andrew , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Harrison John E , Brooks David J , Passmore Anthony Peter , Ballard Clive 
Published: December 2020

AbstractBackgroundBrain atrophy can be reliably measured through volumetric analysis of structural MRI and is a valid biomarker of neurodegeneration in Alzheimer’s disease (AD) pathology1. The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog12) is a neuropsychological test designed to assess the level of cognitive dysfunction in AD within cognitive domains such as memory2. This study aimed to assess the relationship between brain atrophy and ADAS‐Cog12 score in patients with AD.Methods172 patients with mild‐to‐moderate Alzheimer’s disease (Age range 51‐58, Mean=71, SD=+/‐8) underwent a T1‐weighted MPRAGE MRI scan and neuropsychological testing using the ADAS‐Cog12. Volumetric MRI measures extracted using Freesurfer for the hippocampus, medial temporal lobe, temporal lobe and total grey matter were individually correlated with each patient’s ADAS‐Cog12 score using Pearson’s correlation coefficient following removal of outliers in each data set (+/‐ 2SD from the mean).ResultsIncreasing ADAS‐Cog12 score was significantly correlated with decreasing volume of the hippocampus (r=‐0.280, p<0.001), medial temporal lobe (r=‐0.246, p=0.001), temporal lobe (r=‐0.300, p<0.001) and total grey matter (r=‐0.236, p=0.002).ConclusionsThis study demonstrated that the ADAS‐Cog12 correlated with AD‐related regional brain atrophy, suggesting that ADAS‐Cog could be used as an outcome measure in AD trials and reflects underlying neuronal damage along with cognitive function.
Olfaction, the ‘Olfactory Stress Test’ and correlates in a sample of elders
Authors: Bukajumbe Emmanuel , Attia John , McEvoy Mark , Jones Alison L , Schofield Peter W. 
Published: December 2020

AbstractBackgroundPreviously, we investigated the potential of an atropine challenge procedure (‘the Olfactory Stress Test’ (OST)) to detect early AD. Olfaction was tested with 20 items of the University of Pennsylvania Smell Identification test (UPSIT)) before, and with the remaining 20 items after, a unilateral intranasal spray of atropine. In that small study of individuals with normal cognition, cognitive impairment and probable AD, the change in olfaction after atropine (the ‘atropine effect’ (AE)) was significantly correlated with cognition, hippocampal volume and ApoE‐ε4 allele status. In the present study, we administered the OST to a larger sample of mainly cognitively normal elders.Method295 community‐dwelling elders (mean age of 72.63, SD=5.81 years) underwent olfactory testing as described above. Participants were administered the Audio Recorded Cognitive Screen (ARCS)), the Hyposmia Rating Scale (HRS), were genotyped for APOE, and a subsample underwent brain MRI. Linear regression analyses were undertaken seeking associations of olfactory measures, or the HRS, with cognition, hippocampal volume and APOE genotype.ResultMean post atropine UPSIT scores were lower than pre‐atropine UPSIT scores (‘preup’) (Student’s paired t‐test = 9.155, p<0.001). After controlling for sociodemographic and health factors, preup and AE were associated with ARCS (β=1.225 (0.621 – 1.889, p<0.001) and β = ‐0.598 (‐8.731 – ‐0.172, p=0.095)), respectively. Compared to preup scores ≥15, scores <15 were associated with a mean ARCS less by 6.509 (β = ‐6.509 (‐10.805 – ‐2.212, p=0.003)). Using a dichotomised AE, AE≥0 was associated with mean ARCS score less than AE<0 by 4.452 (β = ‐4.452 (‐8.731 – ‐0.172, p=0.042)). Preup (but not AE or HRS) was associated with hippocampal volume. HRS was negatively associated with ARCS (β = ‐0.672 (‐1.238 – ‐0.106, p=0.020)). None of the predictors were associated with APOE genotype.ConclusionThis study confirms previously reported associations of conventional olfaction tests with cognition. By contrast with our previous study, olfactory score change after atropine was more weakly, and negatively, associated with cognition. The current study failed to replicate our previous findings.
Effects of levetiracetam treatment on cognitive and noncognitive impairments in a mouse model of tauopathy
Authors: Joly‐Amado Aurélie , Novoa Michelle , Alvarez Luis , Chan Deanna , Paek Hyeonji , Willman Jonathan , Willman Matthew , Nash Kevin 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of diagnosis. Abnormal tau hyperphosphorylation and its accumulation into neurofibrillary tangles are linked to neurodegeneration in Alzheimer’s disease and similar tauopathies. Aberrant motor behaviors such as pacing/wandering are common in AD. Some AD cases have metabolic changes resulting in weight loss in spite of increased food consumption. Tg4510 mice are characterized by tau deposition in the brain together with cognitive and non‐cognitive impairments that resemble those seen in patients. Leviteracetam is an FDA approved drug that has shown cognitive improvements in mice models of amyloid deposition. The aim of this study was to test the effects of a Leviteracetam diet on cognitive and non‐cognitive impairments in a mouse model of tauopathy, the Tg4510 mice.MethodThree‐month old Tg4510 transgenic and non‐transgenic littermate mice were equally randomly assigned to treated (food containing 240mg/kg Levetiracetam) or placebo (normal diet) groups (n=10, 5F & 5M). All mice were single housed, and food intake and mice body weight were recorded once a week for 3 months. During the last 2 weeks before tissue collection the following behavioral tests were performed: open field, Y‐maze, marble burying, RAWM with reversal, rotarod, novel object recognition (NOR) and fear conditioning. On the last day, the brain was dissected, blood sample was collected, and muscle mass, white fat, and brown fat were weighed.ResultTreatment with Leviteracetam did not improve cognition or activity in Tg4510 during RAWM, open field, and fear conditioning tests. Although Leviteracetam improved performance during rotarod and reduced body weight in non‐transgenic littermates, such effects were not seen in Tg4510 mice.ConclusionThere were no significant improvements in cognitive and non‐cognitive deficits in Tg4510 mice treated with Levetiracetam. Interestingly, Leviteracetam diet resulted in a decrease in body weight together with improvement in rotarod in non‐transgenic littermates when compared to chow diet, whereas no effects were observed in Tg4510 mice treated with leviteracetam. Biochemical and histochemical analysis will be performed in brain tissue to know if treatment with Levetiracetam had an effect on tau pathology.
The relation between accelerometer‐derived physical activity and brain structure: Findings from the Rhineland Study
Authors: Fox Fabienne A.U. , Reuter Martin , Breteler Monique M.B. , Aziz N. Ahmad 
Published: December 2020

AbstractBackgroundPhysical activity is associated with a reduced risk of dementia. Although physical activity induces potent neuroprotective effects in animals, human studies assessing its effects on brain structure are sparse and inconclusive. The discrepancies in human studies may have been due to application of subjective physical activity measures, low spatial‐resolution imaging or small sample sizes. Therefore, we aimed to assess whether objectively quantified physical activity levels are associated with detailed measures of brain structure in a large cohort study.MethodOur analyses were based on data of the first 4,000 participants (56.6% female, mean age: 55.2 years (range 30 – 95 years)) of the Rhineland Study, a population‐based prospective cohort study in Bonn, Germany. Free‐living physical activity over seven days was continuously measured using the ActivPAL™ accelerometer. Average daily physical activity measures included metabolic equivalent (MET)‐hours, total step count, as well as minutes spent stepping or performing light and moderate‐to‐vigorous physical activities. Grey matter (GM), white matter (WM) and total brain volume (TBV) estimates were obtained from 3T MRI scans using FreeSurfer. Multivariable regression models were used to examine the association between physical activity and brain structure, with physical activity levels as independent and brain structure measures as dependent variables, while adjusting for age, sex, intracranial volume, education and smoking status.ResultDaily MET‐hours were associated with all volumetric measures of brain structure (effect estimates [in cm3/hour] for TBV: ß=2.36, 95% CI: 1.05 – 3.67; GM: ß=0.82, 95% CI: 0.15 – 1.50; WM: ß=0.97, 95% CI: 0.08 – 1.85). Importantly, we found a significant interaction between the effects of MET‐hours and age on TBV: in participants below median age the effect of MET‐hours on TBV was 0.28 cm3/hour (95% CI: ‐1.40 – 1.97), while in those above median age the effect was 2.01 cm3/hour (95% CI: 0.08–3.94). Overall, we obtained comparable findings for other physical activity measures as well (data not shown).ConclusionPhysical activity was consistently associated with grey matter, white matter and total brain volumes in a large cohort of individuals from the general population. These findings suggest that promoting physical activity could be critical in the prevention of age‐associated brain atrophy.
Predicting the time to tau onset in Down syndrome using amyloid chronicity
Authors: Zammit Matthew D , Laymon Charles M , Koscik Rebecca L. , Tudorascu Dana L , Betthauser Tobey J , Ellison Paul , Cohen Ann , Minhas Davneet S , Zaman Shahid , Ances Beau M , Mathis Chester , Johnson Sterling C. , Klunk William E , Handen Benjamin L , Christian Bradley T 
Published: December 2020

AbstractBackgroundAdults with Down syndrome (DS) are predisposed to Alzheimer’s disease (AD) with the majority developing clinical dementia by their 60s. This study aims to estimate the time to tau onset in DS using the metric of Aβ chronicity (estimated duration of Aβ(+)) as a predictor.MethodN=140 adults with DS (age=39.3±8.4 years) were evaluated for Aβ and tau using [C‐11]PiB and [F‐18]AV‐1451 PET, respectively. 50‐70 minute PiB SUVr and 80‐100 minute AV‐1451 SUVr images were created (cerebellar gray matter reference region). Longitudinal PiB scans were conducted for n=68 (3.0±0.7 scans; 2.4±0.6 years apart). The Amyloid Load (AβL), calculated from PiB SUVr images, indicates global Aβ burden. Group‐based trajectory modeling (GBTM) was applied across longitudinal AβL data to identify Aβ accumulation groups. The trajectories with the lowest BIC were solved to determine the estimated age of Aβ(+) onset (AβL cutoff: 20.0% (Zammit, DADM 2020)) and Aβ chronicity was calculated as chronological age minus estimated Aβ(+) age (Koscik and Betthauser, DADM 2020). Regional AV‐1451 SUVr values were extracted based on ROIs encompassing the Braak staging of NFT pathology. Preliminary thresholds for elevated tau (tau(+)) were determined for each Braak composite region using k‐means clustering with resampling. Linear regression models were performed between Aβ chronicity and AV‐1451 SUVr. The functional form of the regression fit was solved to estimate average Aβ(+) chronicity at tau(+) in each Braak region.ResultGBTM identified two Aβ accumulator groups in our DS cohort with estimated ages of Aβ(+) onset of 32 and 49 years (Figure 1). Of the early accumulators, only n=2 carried the APOE E4 allele. Aβ chronicity and AV‐1451 SUVr displayed a linear relationship for Braak regions 1‐2, and a quadratic relationship for Braak regions 3‐6 (Figure 2). The pattern of tau deposition in DS followed the conventional Braak NFT staging observed in late‐onset AD. Estimated Aβ(+) chronicity at tau(+) onset increased as tau pathology progressed through each Braak stage (Table 1).ConclusionThese preliminary findings reveal insight on the time course of tau deposition relative to Aβ in DS. Longitudinal AV‐1451 scans are currently underway to further refine the model and characterize tau progression in this population.