bluuebunny/crossref_metadata_2025_split huggingface dataset:
White Matter Degeneration Pathways Associated with Tau Deposition in Alzheimer’s Disease
Authors: Tian Jianqiao , Reid Robert I. , Przybelski Scott A. , Raghavan Sheelakumari , Gebre Robel K , Graff‐Radford Jonathan , Lowe Val J. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi 
Published: December 2022

AbstractBackgroundThe dynamics of white matter (WM) changes are understudied in Alzheimer’s disease (AD). Leveraging tau deposition measured from Tau‐PET, our goal was to study the association between tau and white matter health using NODDI from multi‐shell diffusion MRI (dMRI). Specifically, we focused on the Neurite Density Index (NDI) from NODDI, which in WM captures the signal from axons.MethodWe identified 251 participants (126 cognitively normal, 58 MCI, 67 dementia) from the Mayo ADRC and Mayo Clinic Study of Aging with Aβ‐PET, Tau‐PET, and multi‐shell dMRI who were Aβ‐positive (mean age of 77 years and 55% male). We limited to Aβ‐positive participants because Aβ deposition accelerates tau deposition. For Tau‐PET, we estimated SUVRs from three regions corresponding to Braak I/II, III/IV, and V/VI (Figure 1.a). To understand the associations between Tau‐PET SUVRs at three Braak regions and NDIs at 30 candidate WM tracts, we implemented three analyses methods ‐ Pearson correlation, linear regression, and multilayer perceptron machine learning regression.ResultHigher tau burden in all three Braak regions was associated with lower neurite density in 10 significant WM tracts (Table 1). Interestingly, uncinate fasciculus (UNC) was found significantly associated with all three Braak regions. All three analysis methods consistently showed differential involvement of WM pathways for Braak staging such as ‐ Cingulum adjoining Hippocampus (CGH) for Braak I/II regions, Medial Temporal WM (MTWM) for Braak III/IV regions, and Inferior Occipital WM (IOWM) for Braak V/VI regions (Figure 1.b). The linear regression and machine learning regression models also suggested that WM measurements reflected 18‐35% of variance due to tau depositionConclusionWe found that CGH and UNC WM were the most impacted ROIs associated with Braak I/II regions as expected. UNC, directly connecting anterior temporal lobes to the orbitofrontal cortex, was a key WM tract identified as important for all Braak I‐VI regions and warrants further investigation in the study of AD progression. This study highlights the significant impact tau deposition may have on WM. This work also demonstrates the feasibility of using NODDI as an informative supplementary imaging modality for monitoring AD progression.
One‐year Longitudinal Stability of Plasma Biomarkers Associated with Dementia in Normal Controls
Authors: Liu H.C. , Chen Hsin‐Hsien , Wang Pei‐Ning , Yang Shieh‐Yueh 
Published: December 2022

AbstractBackgroundRegular examinations to assess dementia play a role in its prevention and early diagnosis. Plasma biomarker assays are possibly the most appropriate for routine assessments or monitoring severity of dementia in the clinic. To accomplish this task, the natural changes in biomarker levels over time should be determined first. With this information, the abnormal changes in plasma biomarker levels in longitudinal clinical visits could be determined. However, such studies are very rare.MethodIn this study, 27 subjects with normal cognition were enrolled for a 1‐year longitudinal study. Two of the 27 subjects returned for a follow‐up visit 71 days and 195 days after the first visit. Fourteen subjects returned 112–139 days after the first visit. Four subjects returned 132 and 405 days after the first visit. Five subjects returned 190 days after the first visit. Four participants returned 299 and 344‐405 days after the first visit. Plasma biomarkers of total tau protein (T‐Tau), amyloid β 1‐42 (Aβ1‐42), α‐synuclein and TAR DNA‐binding protein (TDP‐43) were assayed using immunomagnetic reduction (IMR).ResultThe occurrence percentages in the set of recovery rates were 0.8–1.2 and nearly higher than 85% for T‐Tau, Aβ1‐42 and Aβ1‐42xT‐Tau but were 74.1% for α‐synuclein and 77.8% for TDP‐43. Plasma T‐Tau and Aβ1‐42 showed a high degree of longitudinal stability, whereas plasma α‐synuclein showed poor stability over time.ConclusionAlthough there was a certain variation range for the plasma biomarker concentrations compared to baseline in the return visits, the concentration measurements of each biomarker for every normal subject at each visit were below the cutoff values to discriminate Alzheimer’s disease, Parkinson’s disease or frontotemporal dementia from normal controls. These results imply that the risk of misdiagnosis of dementia due to longitudinal instability using plasma biomarkers is low.
Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease
Authors: Gordon Brian A. , Wisch Julie K. , Hobbs Diana A. , McKay Nicole S. , Schultz Stephanie A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , Ances Beau M , Morris John C. , Schindler Suzanne E. , Fagan Anne M. , Benzinger Tammie L.S. 
Published: December 2022

AbstractBackgroundAlzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.MethodsData from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).ResultsGaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR >0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).ConclusionsNeuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.
Asian American and Pacific Islanders’ Attitudes on Alzheimer’s Disease and Related Dementias
Authors: Tan Zaldy S , Kremen Sarah , Garg Nimish , Joo Jin Hui , Sicotte Nancy 
Published: December 2022

AbstractBackgroundAsian American and Pacific Islanders (AAPI) are the fastest growing minority population in the United States. While 14% of older AAPIs have been reported to experience memory loss and confusion, the prevalence and incidence of Alzheimer’s disease and related dementias (ADRD) in the AAPI population are not well understood. Moreover, little is known about AAPI attitudes on memory loss and confidence in managing ADRD.MethodWe administered an 8‐item survey on attitudes and beliefs regarding memory loss and ADRD to attendees of a virtual conference on brain health. Responses were on a 5‐point Likert scale with range of 1 = strongly disagree to 5 = strongly agree. We analyzed responses (agree/strongly agree vs. disagree/strongly disagree) of AAPI participants and non‐AAPI attendees using chi‐square test.ResultFifty‐four participants completed the survey, with majority of respondents aged 65 years or older (56%) and women (72%). AAPI participants (N = 37) self‐identified to be Chinese, Filipino, Indian, Japanese, Korean, Vietnamese, Native Hawaiian or other Pacific Islander. Non‐AAPI respondents (N = 14) self‐identified to be White, Black or African American, American Indian or Alaska Native. We found that compared to non‐AAPI, AAPI individuals were less confident in navigating the healthcare system for persons with ADRD (p = 0.049). AAPI respondents were also less confident in finding community resources for ADRD, though this did not reach statistical significance (p = 0.073). We found no significant differences between AAPI and non‐AAPI participants’ attitudes and beliefs on the normality of memory loss with age, understanding of ADRD as a medical condition, or interest in participating in and understanding of clinical trials for ADRD.ConclusionAsian Americans and Pacific Islanders (AAPI) have less confidence in navigating the complex healthcare system for patients with Alzheimer’s disease and related dementias (ADRD). More research is needed to better characterize the differences in prevalence, presentation, challenges, and outcomes of ADRD in the AAPI population.
Evidence of Plasma Biomarkers Indicating High Risk of Dementia in Cognitively Normal Subjects with a History of Stroke, a Family History of Alzheimer’s Disease, Diabetes Mellitus, End‐stage Renal Disease and Obstructive Sleep Apnea
Authors: Pai Ming‐Chyi , Yang Shieh‐Yueh 
Published: December 2022

AbstractBackgroundSubjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration.MethodIn this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1‐42 and total tau protein (T‐Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end‐stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty‐seven healthy controls (HCs) were enrolled.ResultThe measured concentrations of plasma Aβ1‐42 were 14.26±1.42, 15.43±1.76, 15.52±1.60, 19.74±2.92, 16.52±0.59, 15.97±0.54 and 20.06±3.09 pg/ml in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T‐Tau were 15.13±3.62, 19.29±8.01, 17.93±6.26, 19.74±2.92, 21.54±2.72, 20.17±2.77 and 41.24±14.64 pg/ml. The plasma levels of Aβ1‐42 and T‐Tau in the PS, ADFH, diabetes, ESRD and OSA groups were relatively high compared to HC group but were lower than AD group.ConclusionThis evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers.
Effect of Concurrent Use of Memantine on The Efficacy of Masupirdine (SUVN‐502): A Post‐hoc Analysis of a Phase‐2 Randomized Placebo‐Controlled Study
Authors: Goyal Vinod Kumar , Pandey Santosh Kumar , Benade Vijay , Shinde Anil K , Rasheed Mohammed Abdul , Badange Rajesh Kumar , Palacharla Veera Raghava Chowdary , Ravulu Jyothsna , Jetta Satish , Subramanian Ramkumar , Nirogi Ramakrishna 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder manifested by progressive deterioration in cognition, memory and activities of daily living. The commonly used treatments in the management of cognitive and memory deficits associated with AD are either minimally effective, provide temporary relief or limited to use in a highly selected population. Selective blockade of serotonin‐6 (5‐HT6) receptors, which are exclusively localized in the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5‐HT6 receptor antagonist with pro‐cognitive properties in animal models of cognition.MethodThe efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio, using permuted blocked randomization. The study consisted of a 2 to 4‐week screening period, a 26‐week double blind treatment period, and a 4‐week washout period. The primary efficacy outcome was the 11‐item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐Cog 11). In post‐hoc analyses, patients were subdivided based on the use of memantine dosage form and memantine plasma concentrations to assess the impact of memantine on the efficacy of masupirdine.ResultIn this exploratory post‐hoc analysis, less worsening of cognition (ADAS‐Cog 11 scores) was observed with masupirdine treatment as compared to placebo in subjects whose trough memantine plasma concentrations were ≤100 ng/mL.ConclusionThese exploratory and thought provoking observations merit better understanding and further possible investigations of masupirdine effects and its role as a potential future drug in the AD pharmaceutical armamentarium.
Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States
Authors: Campbell Kyle A , Fu Mingzhou , MacDonald Elizabeth , Zawistowski Matthew , Ware Erin B , Bakulski Kelly M 
Published: December 2022

AbstractBackgroundPrior research is mixed concerning the association between alcohol consumption, a modifiable factor, and dementia. Genetic causal inference approaches may help elucidate the relationship between alcohol consumption and dementia.MethodWe performed a two‐sample Mendelian randomization study using harmonized, genome‐wide significant (p‐value<10−8), and independent (r2<.001) single nucleotide polymorphisms’ (SNPs) summary statistics from the largest publicly available meta‐analyses of genome‐wide association studies of weekly alcohol consumption (Liu et al., 2019, n = 941,280) and late onset Alzheimer’s disease (Kunkle et al., 2019, n = 21,982 cases, 41,944 controls). Next, in the 2012 wave of the United States Health and Retirement Study (HRS), we employed individual polygenic scores of alcohol consumption via one‐sample Mendelian randomization. Polygenic scores were calculated and standardized within genetic ancestry across 1,399,824 SNPs overlapping Liu et al. without HRS and 23andMe samples (n = 522,159). G‐estimation provided odds ratios (ORs) of the relationship between a standard deviation increase in genetic risk of alcohol consumption and dementia and cognitive impairment without dementia compared to normal cognition in models stratified by genetic ancestry.ResultOf 99 SNPs associated with weekly alcoholic drink consumption and 71 SNPs associated with late onset Alzheimer’s disease, 59 overlapping and harmonized SNPs met instrument selection criteria. We did not observe evidence of a relationship between alcohol consumption and late‐onset Alzheimer’s disease using the inverse variance weighted two‐sample Mendelian randomization estimator (OR = 1.15, 95% confidence interval (CI):[0.78, 1.72]), nor with complementary estimators. In HRS, Mendelian randomization revealed no relationship between cumulative genetic alcohol consumption risk and cognitive impairment without dementia (African ancestry sample (n = 2,402, OR = 0.86, 95% CI:[0.47, 1.58]); European ancestry sample (n = 9,576, OR = 0.96, 95% CI:[0.86, 1.07])) and dementia in the African ancestry sample (n = 1,908, OR = 0.50, 95% CI:[0.13, 2.00]). Alcohol consumption genetic risk was inversely associated with dementia in the European ancestry sample (n = 8,518, OR = 0.77, 95% CI:[0.62, 0.95]).ConclusionOur results largely suggest there is no causal relationship between alcohol consumption and dementia. The protective association observed between alcohol consumption and dementia among those of European ancestry in an aging American cohort may be due to genetic pleiotropy and/or selection bias in our empirical sample within the Health and Retirement Study.
The relationship between everyday functioning and cerebral tau burden in cognitively normal older adults
Authors: Dubbelman Mark A. , Sanchez Justin S , Schultz Aaron P. , Rentz Dorene M. , Amariglio Rebecca E. , Sikkes Sietske A.M. , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A ,   A4 Study team
Published: December 2022

AbstractBackgroundAlzheimer’s disease is characterized by accumulation of amyloid and tau in the brain. While amyloid is hypothesized to accumulate earlier, tau has been shown to be more strongly related to clinical outcomes. Higher‐order cognitive functioning in daily life is a clinically meaningful outcome that has been shown to decline, even in early disease stages. We aimed to understand the cross‐sectional relationship between regional cerebral tau accumulation and everyday functioning in cognitively normal older adults.MethodWe used data from the A4 and LEARN Studies and included participants who underwent tau positron emission tomography (PET) scans using 18F‐flortaucipir (n = 447, age 71.9±4.9 years, 57.5% female). Everyday functioning was reported by both participant and study partner using the Alzheimer’s Disease Cooperative Study Activities of Daily Living‐Prevention Instrument (ADCS ADL‐PI). We dichotomized ADCS ADL‐PI total scores as ≤44 vs 45 (the maximum score). Additionally, based on previous analyses, we focused on four items and dichotomized scores as no difficulty vs. some/a lot of difficulty. We performed logistic regressions adjusting for age, sex and education.ResultParticipants (median 45, range 33–45) and study partners (median 45, range 23–45) reported high levels of everyday functioning. Neither entorhinal nor inferior temporal tau was associated with overall self‐ or study partner‐reported everyday functioning (Table; Figure1). Greater entorhinal tau was associated with study partner‐reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008). Greater inferior temporal tau was associated with self‐reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018). Greater entorhinal and inferior temporal tau were associated with study partner‐reported difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007 and OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005, respectively). Tau was not associated with difficulties remembering current events (Table; Figure2).ConclusionOur results suggest a weak cross‐sectional relationship between everyday functioning and tau in cognitively normal older adults. These findings are likely driven by the restricted variability in scores on the ADCS ADL‐PI, which could improve with longitudinal data. Moreover, future work should incorporate a measurement of everyday functioning that has a wider range of performance in this population even at baseline.
Neuropsychiatric Symptoms and Neuropathological diagnoses of Alzheimer’s Disease and Related Dementias
Authors: Devanand Davangere P. , Lee Seonjoo , Huey Edward D , Goldberg Terry E. 
Published: December 2022

AbstractBackgroundThe associations of Alzheimer’s disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) is not well‐established.MethodThis retrospective cohort study used 1,808 brains from 39 sites in the National Alzheimer’s Coordinating Center (NACC) V.10 collection for participants with the Neuropsychiatric Interview‐Questionnaire (NPI‐Q) administered annually and without consideration of clinical diagnosis. Brain autopsy diagnoses of AD, Lewy Body Disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), cerebrovascular disease (CVD), hippocampal sclerosis, and “no known pathology” were examined. NPI‐Q domain score if present at any timepoint was the primary outcome and average NPI‐Q domain score during follow‐up was secondary. The associations of ADRD diagnoses with twelve NPI‐Q symptom domains were examined in regression analyses, correcting for multiple comparisons.ResultThe study sample of 1,808 adults had a mean [SD] age 80.0 [11.0] years and 54.6% were male. Apathy was the most prevalent NPS, reaching 80% in hippocampal sclerosis. CVD showed few NPS associations. FTLD was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared to AD. Hippocampal sclerosis was associated with increased apathy (OR 2.60, 95%CI 1.86‐3.66, pfdr<.05) and disinhibition (OR 2.15, 95% CI 1.63‐2.84, pfdr<.05). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was associated consistently with increased NPS, e.g., LBD showed increase in hallucinations from brainstem (β=0.23, 95% CI 0.07‐0.76, p<.05) to limbic (β=1.69, 95% CI 1.27‐2.27, p<.01) to neocortical (β=4.49, 95% CI 3.27‐6.16, p<.001) pathology. Hallucinations were more common in participants with AD+LBD (168/534=31.5%) compared to AD without LBD (152/704=21.6%) and LBD without AD (23/119=19.6%).ConclusionVisual hallucinations may characterize LBD with AD more than LBD without AD. NPS criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported. In hippocampal sclerosis, the novel findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was related to NPS severity, indicating that NPS reflect underlying ADRD pathology and highlight the importance of diagnosing and treating NPS.