bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations in Alzheimer’s disease between intracranial vascular metrics from 4D‐flow MRI and β‐amyloid and tau PET
Authors: Rivera‐Rivera Leonardo A , Cody Karly Alex , Betthauser Tobey J , Cadman Robert V , Reher Thomas , Rowley Howard A. , Carlsson Cynthia M , Eisenmenger Laura , Johnson Sterling C. , Johnson Kevin M 
Published: December 2021

AbstractBackgroundCerebrovascular disease (CVD), has been linked with dementia stages of Alzheimer’s disease (AD); however, the question of whether CVD is associated with underlying AD pathophysiology remains unresolved. This work investigated the relationship between advanced MRI based cerebrovascular markers with AD biomarkers of β‐amyloid deposition and neurofibrillary tau tangles in subjects spanning the AD clinical spectrum.MethodSubjects: Study groups are summarized in figure 1. MRI: Whole brain 4D‐Flow data were acquired on a 3.0T system using a 32‐channel head coil. From 4D‐Flow images, intracranial blood flow, trans‐capillary pulse wave delay, and low frequency oscillations (LFOs) were estimated. Trans‐capillary pulse wave delay was defined as the cardiac pulse wave transit time from intracranial arteries‐to‐capillaries‐to‐veins and was measured from cardiac wave time‐to‐upstroke differences in arteries and veins. White matter hyperintensity (WMH) lesion volumes were segmented from T2‐FLAIR images using the Lesion Segmentation Toolbox in SPM12. PET: Four groups were established based on clinical diagnosis and biomarker positivity. Subjects were classified as cognitively normal (CN) or impaired (IM) (MCI or dementia) based on a clinical consensus review. Amyloid (A) (+/‐) was determined using a previously established global PiB DVR threshold >1.19 and tau (T) (+/‐) was determined using a previously established entorhinal cortex MK‐6240 SUVR threshold >1.27. Pairwise statistical differences were assessed using ANOVA followed by post‐hoc analysis (P<0.05 significance).ResultTrans‐capillary pulse wave delay was significantly longer in controls (A‐/T‐/CN) when compared with AD biomarker confirmed groups (fig 2 b) (P<0.001). Low frequency flow range and LFOs were significantly lower and diminished in A+T+ groups both cognitively normal and impaired (fig 3 P<0.001; fig 4 P=0.027, P=0.046, P=0.046). Linear regression analysis showed a weak correlation between trans‐capillary pulse wave delay and PiB and MK‐6240 (R2=0.12, R2=0.04), and between LFOs and PiB and MK‐6240 (R2=0.07, R2=0.03) (fig 5). No significant AT biomarker group differences were observed across other modalities such as traditional cardiovascular and cerebrovascular metrics, including WMH lesion volumes (fig 1).ConclusionAlthough more traditional measures of CVD were not related to biomarker groups, 4D‐Flow MRI based vascular markers suggest significant intracranial vascular stiffness and reduced autoregulation‐related vasomotion in AD biomarker positive subjects during preclinical AD.
Association of lower dementia risk with improved air quality in older women
Authors: Wang Xinhui , Younan Diana , Millstein Joshua , Petkus Andrew J , Garcia Erika , Beavers Daniel P , Espeland Mark A , Chui Helena C , Resnick Susan M , Gatz Margaret , Kaufman Joel D , Wellenius Gregory , Whitsel Eric A , Manson JoAnn E , Rapp Stephen R , Chen Jiu‐Chiuan 
Published: December 2021

AbstractBackgroundLate‐life ambient air pollution is a novel risk factor for brain aging. Air quality improvement has been associated with improved cardiopulmonary health and reduced mortality; however, whether it is associated with reduced dementia risk is unknown.MethodWe studied a geographically‐diverse cohort from the Women’s Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO). Participants included 2239 older women (aged 74‐92) without dementia at WHIMS‐ECHO enrollment in 2008‐12. Incident dementia cases, based on DSM‐IV criteria, were centrally‐adjudicated annually (2008‐18). Yearly mean concentrations of ambient PM2.5 (fine particulate matter) and NO2 at residential locations were estimated using validated regionalized universal kriging models. These annual estimates were then averaged over 3‐year periods at both immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS‐ECHO enrollment. Individual‐level improved air quality was defined as reduction from remote to recent exposures. We used Cox proportional hazard models to estimate the hazard ratios (HR) for dementia risk associated with air quality measures, adjusting for sociodemographic, lifestyle, and clinical characteristics. We incorporated inverse‐probability weighting to account for differential attrition during the follow up. Models were replicated using multiple imputation to include those with missing air pollution and covariate data as sensitivity analyses.ResultsWe identified 398 incident dementia cases during median 6.1 years of follow up (interquartile range [IQR]=5.2 years). PM2.5 and NO2 reduced significantly over the 10 years before WHIMS‐ECHO enrollment. Greater improvement in air quality was significantly associated with reduced dementia risks (HRPM2.5=0.80 per IQR=1.78µg/m3, 95% confidence interval [CI]=[0.71, 0.91]; HRNO2=0.80 per IQR=3.91ppb, 95%CI=[0.71, 0.90]), equivalent to the lower risk observed in women 2.4 years younger at baseline. There was some evidence that recent PM2.5 exposure was associated with higher dementia risk (HRPM2.5=1.16 per IQR=2.90µg/m3, 95%CI=[0.98, 1.38]), but the lower dementia risk associated with improved air quality remained after further adjusting for the recent exposure effects. The observed associations did not substantially differ by age, education, geographic region, APOE e4 genotypes, or cardiovascular risk factors. Similar results were found in the sensitivity analyses using multiple imputation.ConclusionsLong‐term air quality improvement in late‐life was associated with lower dementia risk in older women.
Inflammatory biomarkers are associated with cerebral large artery thickening and dilatation in older adults
Authors: Cambronero Francis E. , Liu Dandan , Bown Corey W. , Kresge Hailey A. , Pechman Kimberly R. , Khan Omair A. , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Donahue Manus J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L. 
Published: December 2021

AbstractBackgroundAge‐associated changes in intracranial large arteries, including hypertrophic and dilatative remodeling, contribute to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a novel neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Research suggests inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation visible on VWI MRI.MethodsVanderbilt Memory & Aging Project participants free of clinical stroke and dementia were studied (n=117, 74±7 years, 73% male). Systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples and neuroinflammatory biomarkers (sTREM2, YKL‐40) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using VWI MRI. Linear regressions related each inflammatory biomarker to intracranial artery lumen diameter and thickness in separate cross‐sectional models, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein ε4 status, and T1‐weighted intracranial volume.ResultsTNF‐α was related to right ICA thickness (b=0.01, p=0.03), left ICA thickness (b=0.01, p<0.05), and left ACA thickness (b=‐0.01, p=0.04); TNF‐α was unrelated to lumen diameters (p>0.51). IL‐6 was related to right ICA thickness (b=0.01, p=0.003) and was unrelated to lumen diameters (p>0.18). sTREM2 was related to left MCA lumen diameter (b=0.0001, p=0.03), right ACA lumen diameter (b=0.0001; p=0.001), and right ACA thickness (b=0.00003, p=0.03). YKL‐40 was unrelated to intracranial artery thickness (p>0.27) and lumen diameter (p>0.05).ConclusionsResults suggest TNF‐α, IL‐6, and sTREM2 are related to intracranial large artery thickening, and sTREM2 may further relate to large artery dilatation. Given the increased reliability of ICA and BA manual measurements on VWI MRI, these findings may be most robust. Proinflammatory cytokines and microglia‐mediated immune responses may be key pathophysiological mechanisms underlying age‐related arterial remodeling within the brain.
How often is EEG used as part of routine dementia evaluation in community practice?
Authors: Pippenger Mark A 
Published: December 2021

AbstractBackgroundRecommendations for evaluation of patients with dementia have changed little in the last thirty years. The guideline for diagnosis of dementia published by the American Academy of Neurology (AAN) in 1984 recommended against routine use of EEG for evaluation of dementia, and in the updated guideline from 2001 EEG is not specifically mentioned. Some authors continue to argue for use of EEG in dementia research, though mostly this focuses on specialized EEG techniques like quantitative EEG. There are few reports, however, on the frequency of EEG use in community neurological evaluations for dementia.MethodAll new patient referrals to the Novant Health Memory Clinic in Charlotte, NC, for 2020 were reviewed. Information was tabulated for those patients who had been previously evaluated by a neurologist in the community, specifically to determine how often EEG was included as part of the routine evaluation. Results of the EEG as taken from the clinician’s report were tabulated, though there was no opportunity to examined the EEG tracing itself. The author made a judgement as to whether the results of the EEG affected the clinical diagnosis or provided useful information for management of the patient in each case, and these data were tabulated.ResultDuring the year of observation, there were a total of 845 new patient evaluations in the Memory Clinic. Of those, 274 patients met clinical criteria for “Probable” Alzheimer Disease, 237 met criteria for Mild Cognitive Impairment, and 207 for Subjective Cognitive Decline. Out of these patients, 89 had been previously evaluated by a community neurologist. In 63 of the evaluations, EEG was obtained as part of the routine evaluation. Of these, 16 were read as “normal,” and 47 were read as “abnormal” due to slowing of background rhythm. In 2 of the 47, the reader also reported finding “sharp waves” in temporal leads, and these 2 patients were treated by the reading neurologist with anticonvulsants, later discontinued in both cases. In no case did the EEG provide useful information for either diagnosis of management of dementia.ConclusionThese data support the AAN guideline’s recommendation against routine use of EEG for dementia evaluation.
Urine dicarboxylic acids are metabolic biomarkers of early Alzheimer’s disease
Authors: Harrington Michael G. , Maldonado Salvador , Sagare Abhay P. , Zlokovic Berislav V. , Chui Helena C. , Fonteh Alfred N. 
Published: December 2021

AbstractBackgroundWe previously identified urine dicarboxylic acids (DCA) of carbon length 4‐9 as candidate biomarkers of probable Alzheimer’s disease (AD) and energy dysregulation, and found their levels correlated with hippocampal volume. Our aim was to evaluate these initial findings in a second cohort.MethodStudy participants (> 65 years) were classified clinically as cognitively healthy (CH, n=188) or with probable AD (n=66) based on Uniform Data System‐3 of the National Alzheimer’s Coordinating Center criteria. Cerebrospinal fluid (CSF) amyloid ß42 (A) and phospho‐ tau (T) levels were measured by validated immunoassay. Urine was collected in a “spot” sample after a 12 h overnight fast; target DCAs were detected using gas chromatography coupled with negative ion chemical ionization mass spectrometry and each DCA was normalized to deuterated internal standards and to a percent of total fatty acids.ResultThe mean of short‐chain DCA’s (C4‐C5) were higher in CH (44.38% ±17.79) compared to AD individuals (34.79% ±12.39) (p=0.0002), while the long‐chain DCA’s (C7‐C9) were lower for CH (34.70% ±16.88) when compared to AD individuals (45.22% ±15.11) (p<0.0001). DCA levels in the subset of CH participants with A+/T+ were in a transition to the levels of the AD group and C4‐C5 and C7‐C9 differed from those with A‐/T‐ biomarkers (p=0.0001). Combining results into a ratio of short‐ to long‐chain DCAs distinguished the A‐/T‐ (2.330 ±2.144) from the A+/T+ group (1.178 ±0.946); p<0.0001. ROC curve of the DCA ratio between CH‐NAT and AD is 82%. Study participant clinical and DCA groups were not significantly correlated with the common confounders of age, sex, education or ApoE genotype.ConclusionOur data extends our initial finding that urine DCA measures have potential as biomarkers of AD pathology, including for cognitively healthy individuals who are positive for CSF AT biomarkers. We propose that measurement of urine DCAs provides a new approach to screen for metabolic fluctuations in early AD and to monitor the effect of novel therapies in clinical trials. While studies are needed, including with other populations, varied clinical classifications, simplified chemistry, this data supports DCA biomarkers for widespread screening since the necessary urine sample is available from everyone.
Verbal fluency associated with tau accumulation and not amyloid deposition in the Alzheimer’s disease spectrum
Authors: Rahmouni Nesrine , Stevenson Alyssa , Stevenson Jenna , Tissot Cécile , Lussier Firoza Z , Bezgin Gleb , Therriault Joseph , Chamoun Mira , Kang Min Su , Pascoal Tharick A. , Gauthier Serge , Benedet Andréa Lessa , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundRecent studies have shown that pathological amyloid deposition and tau accumulation, hallmarks of the Alzheimer's disease, are closely related to cognitive deficits in older individuals. The present study evaluates the associations between the Alzheimer's disease hallmarks and verbal fluency and lexical speed access impairment.MethodThe study was conducted in a population of 262 individuals (162 cognitively unimpaired individuals (CU), 100 cognitively impaired individuals (CI; 61 MCI and 39 AD). The verbal Letter Fluency test was used to assess the vocabulary size and lexical speed access. Individuals underwent an MRI, a [18F]AZD4694 amyloid‐PET scan and a [18F]MK6240 tau‐PET scan. [18F]AZD4694 and [18F]MK6240 standardized uptake value ratio (SUVRs) were calculated between 40 to 70 min and 90 to 110 min post‐injection, respectively, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET markers [18F]AZD4694 and [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisonsResultNegative correlations were found between Letter Fluency scores and tau accumulation. The associated regions were medial frontal, superior temporal, medial occipital lobes and precuneus area. No associations were found between the Letter Fluency scoring and amyloid deposition.ConclusionOur results suggest that tau accumulation is associated with lower vocabulary size and lexical speed access, whereas amyloid deposition does not influence this neuropsychological field.
Accumulation of depressive symptoms over time in cognitively impaired individuals
Authors: Bhattacharya Gogol , Tosun Duygu 
Published: December 2021

AbstractBackgroundDepressive symptoms in elderly are common, but the persistence of depressive symptoms in older adults with and without cognitive impairment (CI) is less studied. Accumulation of depressive symptoms over time might be a sign of developing chronic depressive course and therefore increased risk for cognitive decline and dementia. The aim of the present study was to assess patterns of depressive symptom accumulation over time among older adults, and to explore the association between the course of depressive symptoms over time and demographic and clinical characteristics at baseline.MethodA data‐driven approach was used to cluster ADNI participants based of their longitudinal Geriatric Depression Scores (GDS‐15). We leveraged modern time‐series analysis techniques including the Dynamic Time Warping and Dynamic Barycenter Averaging as the clustering generation technique. ADNI participants were clustered to data‐driven groups presenting with unique time course of depressive symptom accumulation.ResultWe ran a search for the optimal number of clusters using the silhouette score as the indicator of a strong clustering. This resulted in the generation of 3 unique profiles with differing patient demographics. Specifically, 1st group presented with the lowest baseline depressive symptoms (GDS=0.44±0.61) and stayed stable over the course of ADNI study (GDS=1.03±1.25). P2nd group presented with slightly elevated depressive symptoms at baseline (GDS=1.78±1.10) and accumulated depressive symptoms (GDS=2.74±2.05). In contrast, 3rd group presented with significant depressive symptoms (GDS=3.80±1.42) and accumulated more symptoms over time (GDS=4.50±2.56). Although groups did not different in age at the baseline or prevalence of females, patients that have CI, indicated by both the clinical diagnosis and the patient's Clinical Dementia Rating, are more likely to have higher GDS scores and are at higher risk of developing depressive symptoms (i.e., baseline CI prevalence of 40% in Group 1 compared to 74% and 75% in Groups 2 and 3, respectively).ConclusionThe data shows that there are differences in the persistence of the depressive symptoms in elderly population with and without CI. Identifying individuals that are more susceptible to depressive symptom accumulation might significantly improved patient outcomes and higher quality of life.
Inflammation and innate immune system activation in neurodegeneration, Down syndrome, aging, and infection: Therapeutic target or partner?
Authors: Potter Huntington , Boyd Timothy D. , Ahmed Md. Mahiuddin , Kendall Lon V. , Sillau Stefan H , Coughlan Christina M , Clarke Penny , Stonedahl Sarah , Chial Heidi J 
Published: December 2021

AbstractBackgroundCharacteristic features/biomarkers of innate immune system activation and inflammation are associated with neurodegenerative diseases (e.g., Alzheimer’s disease [AD], Parkinson’s disease [PD]), Down syndrome [DS], normal aging, and many infectious diseases. Evidence also suggests that peripheral inflammation interacts with and mirrors inflammation in the central nervous system (CNS) and can yield useful biomarkers of the disease or disorder and potentially of the efficacy of therapies. These findings have led to the additional conclusion that developing methods to dampen inflammation would be an effective therapeutic approach. However, recent findings indicate that innate immune system activation, including inflammation, may, instead, be beneficial.MethodWe used the proinflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) to modulate the innate immune system and determine the effects on biomarker, clinical, and/or behavioral outcomes in mouse models of AD, DS, aging, and viral infection and in a clinical trial in AD.ResultRecent published and unpublished results from our laboratory and others show that treatment with GM‐CSF increases inflammatory biomarkers and also effectively reduces cognitive decline, brain pathology, and disease‐associated peripheral blood biomarkers in mouse models of AD, PD, DS, and normal aging. Interestingly, GM‐CSF treatment also reduces viral titer and mortality in mouse models of West Nile Virus and SARS‐CoV‐2 infection. Our retrospective study of patients with cognitive deficits due to chemotherapy‐induced CNS inflammation showed that recombinant human GM‐CSF (sargramostim) treatment was associated with improved cognition. A sargramostim clinical trial in PD also showed promising results. Finally, our recently‐completed clinical trial in AD showed that sargramostim treatment increased inflammatory cytokines and improved toward normal both a measure of cognition (MMSE) and blood biomarkers of amyloid (A) and Tau (T) deposition and neurodegeneration (N). Sargramostim clinical trials in COVID‐19 are underway.ConclusionTogether, these results indicate that targeted enhancement of the innate immune system and of inflammatory cytokines, specifically in response to GM‐CSF, can effectively treat many disorders that exhibit characteristic inflammation and innate immune system activation. Thus, the long‐held belief that inflammation and innate immune system activation only play a negative role in neurodegenerative diseases, DS, viral infections, and normal aging should be reassessed.
Effects of gamma sensory stimulation on cognitive function in Alzheimer’s disease patients
Authors: Cimenser Aylin , Konisky Alexandra , Shukla Mohinish , Mrozak Holly , Cohen Jacob , Kolin Katharine , Martin Karen , Boasso Alyssa , Hempel Evan , Malchano Zach , Hajos Mihaly 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) patients exhibit distorted excitatory‐inhibitory balance of neuronal activity, leading to accelerated worsening of functional and cognitive abilities. Improving abnormal neuronal synchrony by long‐term non‐invasive, gamma sensory stimulation at 40 Hz in transgenic mice carrying pathological AD human genes has been shown to beneficially affect neural activity and improve learning and memory. In the present translational clinical trial, the effects of gamma sensory stimulation on cognition and global function were evaluated in AD patients using an at‐home therapy device (Cognito Therapeutics, Cambridge, MA).MethodThe phase I/II randomized, controlled, single‐blinded multi‐center clinical trial (Overture study; NCT03556280) evaluated safety, adherence rates and efficacy of gamma sensory stimulation therapy in patients with mild to moderate Alzheimer’s disease (MMSE 14‐26, inclusive). The 6‐month trial included treatment and sham groups receiving daily, one‐hour sensory stimulation but only participants in the treatment group were exposed to 40Hz auditory and visual stimulations. During the trial, cognitive functions were measured by Alzheimer's Disease Assessment Scale (ADAS‐Cog), Mini‐Mental State Examination (MMSE), and Clinical Dementia Rating Sum of Boxes (CDR‐SB). In order to align assessment data in time to study events (therapy start and end) and account for variable study visit intervals at start and end of therapy period, cognitive measures were calculated on a per‐patient basis by a model of AD‐related cognitive decline derived from a large‐scale dataset. Finally, adjusted cognitive scores were compared between the two groups.ResultThe trial has been completed by 33 and 19 patients in the treatment and sham groups, respectively. Daily therapy of gamma sensory stimulation was well tolerated, confirming safety and high adherence. The three independent cognitive tests demonstrated a diminished cognitive decline in the treatment group compared to the sham group. Final analysis results from MMSE, ADAS‐Cog, CDR‐SB and Integrated Alzheimer's Disease Rating Scale (iADRS) will be presented at the meeting.ConclusionThe present findings, together with the established safety profile, functional benefit, and improvement in sleep justify further evaluation of gamma sensory stimulation in AD patients.