bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma pTau isoform assessment across disease stages
Authors: Blennow Kaj 
Published: December 2021

AbstractBackgroundPhosphorylated tau (P‐tau) in CSF is an established AD biomarker that is seemingly specific for Alzheimer’s disease (AD). Several recent papers also show highly promising results for plasma P‐tau, with a clear increase in AD, also in the very early phases of the disease. Further, increased plasma P‐tau correlates with tau pathology assessed by PET, predicts cognitive decline, and specifically identifies AD‐type pathology at post‐mortem. Several different P‐tau species can be quantified in CSF and plasma, including P‐tau181 and P‐tau217, and recently also other species such as P‐tau231 and P‐tau235.MethodValidated immunoassays (Simoa and MS) with analytical sensitivity in the low pg/mL range has been developed for these P‐tau species are available. Further, mass spectrometry (MS) methods have been developed for absolute quantification of several of these P‐tau species simultaneously.ResultAlthough measured using different assays and in different cohorts, plasma P‐tau accurately predicts progression to AD dementia in individuals with memory complaints in models including APOE and cognition (AUCs: 0.91 for P‐tau217 and 0.90 for P‐tau181), and AD pathology at autopsy in samples taken 3 years before death (P‐tau217 AUC 0.89) and 8 years before death (P‐tau181 AUC 0.98). When measured in CSF using either Simoa assays or antibody‐free quantitative MS, P‐tau181, P‐tau217 and P‐tau231 correlate tightly (R‐values around 0.90). A first study found slightly higher performance of plasma P‐tau231 than P‐tau181 to identify early amyloid pathology and to differentiate AD across the entire Braak stage spectrum.ConclusionPlasma P‐tau is a novel very promising class of blood biomarkers for AD. Recent studies add knowledge to the characteristics of the different P‐tau biomarker species and analytical methods to measure them, and how these biomarkers and methods perform to identify early both amyloid and tau AD pathophysiology.
Prospective and retrospective memory complaints in early and late stages of amnestic mild cognitive impairment
Authors: Ryu Seon Young , Lee Sang Bong , Lee Taek Jun , Jung Yu Jin 
Published: December 2021

AbstractBackgroundMemory complaints are a frequent phenomenon in elderly people. These subjective memory complaints are a cardinal feature of amnestic mild cognitive impairment (aMCI) known as the first symptomatic stage of Alzheimer's disease. The objective of this study was to compare memory complaints and determine whether there were differences of types of memory complaints (i.e. prospective memory (PM) versus retrospective memory (RM) complaints) in early‐stage aMCI (EMCI) and late‐stage aMCI (LMCI).MethodOne‐hundred and twenty‐two aMCI subjects (mean age: 70.07 ± 8.54 years) were divided into EMCI (n = 72) and LMCI (n = 50) according to their Clinical Dementia Rating Sum of Boxes score. Memory complaints were assessed using the Prospective and Retrospective Memory Questionnaire (PRMQ) consisting of 16 items that describe everyday memory failure of both PM and RM. All participants underwent clinical assessment and completed detailed neuropsychological tests. Group comparisons of types of memory complaints were assessed between EMCI and LMCI subjects.ResultLMCI subjects showed more subjective memory complaints based on PRMQ total sores than EMCI subjects. For types of memory complaints, LMCI group showed more RM complaints by PRMQ‐RM scores than EMCI group, but there were no differences of PM complaints between two groups. The results for PRMQ total scores and PRMQ‐RM scores remained significant after adjusting for age, education, and depressive symptoms.ConclusionLMCI showed more RM complaints than EMCI among subjective memory complaints. There might be differences in types of memory complaints according to disease stage of clinical spectrum of MCI. Therefore, more consideration for types of memory complaints might be needed in the clinical correlation of individuals with MCI.
Pathological correlates of clinical heterogeneity in Alzheimer's disease
Authors: Grinberg Lea T. 
Published: December 2021

AbstractBackgroundAtypical variants of Alzheimer's Disease (AD) manifest predominantly with non‐memory complaints, including visuospatial (posterior cortical atrophy), language (logopenic variant of primary progressive aphasia), motor (cortico‐basal syndrome), executive or cognitive‐behavioral patterns. Compared to typical (amnestic) AD, these atypical profiles are characterized by faster cognitive decline rates, syndrome‐specific atrophy patterns, younger age at onset, and tend to be less associated with apolipoprotein E (APOE) ɛ4 allele genotype.Despite clinical differences, both typical AD and atypical AD variants feature deposits of amyloid plaques and neurofibrillary tangles and can be staged using the same neuropathological guidelines. Although it is clear that AD atypical phenotypes presented different atrophy and hypometabolism patterns among themselves and compared to typical AD, it is unclear what is the neuropathological subtract underlying an atypical AD presentation. Our work, supported by the literature, suggests that the regional pattern of plaque accumulation in advanced disease is not distinctive in each of the clinical variants of AD. Conversely, cumulative evidence from neuropathology and neuroimaging studies suggests that variations in the regional tau burden are closely related to the expression of AD's clinical variants.MethodThis presentation will review published and unpublished evidence from human neuropathological studies addressing the neurobiological substrates atypical AD variantsResultIt will include a discussion on similarities and differences in plaque and tangle burden, neuropathological comorbidities. We will also present unpublished results from a systematic study with over 140 AD cases (35% atypical) showing that comorbid pathologies do not play an essential role in determining atypical ADConclusionFinally, it will discuss the role of distinct mechanisms of selective neuronal vulnerability in concern with atypical AD.
Survey outcomes on neuropsychological testing in posterior cortical atrophy
Authors: Pelak Victoria S. , Holden Samantha K. , Crutch Sebastian J. , Yong Keir X.X. 
Published: December 2021

AbstractBackgroundPosterior cortical atrophy (PCA) is a clinico‐radiological syndrome mostly commonly underpinned by Alzheimer’s disease (AD) pathology and has been referred to as the most common atypical AD clinical phenotype. PCA consensus classification criteria emphasize core clinical and cognitive features comprising visual and other posterior features in contrast to relatively spared episodic memory, language, executive functions and behavior (Crutch et al., Alzheimers Dement., 2017). However, posterior features are less commonly evaluated in standard neuropsychological batteries compared to other domains, possibly contributing towards common diagnostic delays, and memory and executive function tests that have visual or numerical demands are particularly challenging in the evaluation of relatively spared functions. Standardization of the neuropsychological assessment of PCA is vital for multi‐center research collaborations, the development of outcome measures for future clinical trials, and better characterization of the extent of overlap with related neurodegenerative syndromes. Experts were surveyed regarding their practice preferences in the assessment of the PCA syndrome.MethodThe membership of the ISTAART Atypical Alzheimer’s Disease Professional Interest Area was invited to participate in a survey examining preferences for measures employed in the assessment of the visual and core cognitive features of PCA, as defined by the 2017 PCA consensus criteria.ResultAtypical AD PIA members included those with backgrounds in neurology, neuropsychology, psychiatry, geriatric medicine and clinical research (respondents N=55). Most commonly assessed features were space perception deficits, simultanagnosia and constructional apraxia, followed by dominant parietal features and alexia. Object perception deficits and early visual functions were less frequently assessed. A subset of respondents included preferred tests to evaluate global functioning and relatively spared features, including example measures less susceptible to visual dysfunction.ConclusionVariations in assessing PCA features are considered with implications for characterizing the extent of AD phenotypic heterogeneity, including proposed ventral and caudal PCA presentations. Results will inform future work to develop consensus recommendations for a short clinical PCA battery and an extended, formal PCA battery, in order to promote capacity for multi‐center studies and advance the development of appropriate outcome measures in trials enrolling patients with PCA and/or prominent posterior dysfunction.
The synaptic marker neurogranin as a disease state biomarker in Alzheimer’s disease: A systematic review and meta‐analysis
Authors: Wang Zhibin , Yang Jianwei , Zhu Wei , Tang Yi , Jia Jianping 
Published: December 2021

AbstractBackgroundSynaptic degeneration is the pathologic foundation of cognitive decline in the Alzheimer’s disease (AD) continuum. We aimed to determine whether cerebrospinal fluid (CSF) synaptic marker neurogranin (Ng) is a disease state or a disease stage biomarker in the AD continuum.MethodStudies comparing CSF Ng levels among AD, mild cognitive impairment (MCI) and healthy participants were included. Studies were eligible if the correlation between CSF Ng levels and Mini‐Mental Status Examination (MMSE) scores was investigated.ResultTwenty‐one studies met our inclusion criteria (n = 4515). The magnitude of effect sizes was more apparent in AD (standardized mean difference [SMD] = 1.72; 95% confidence interval [CI] = 1.23–2.22), than in MCI (SMD = 0.82; 95% CI = 0.29–1.34) compared to control populations. These results suggest that CSF Ng can discriminate AD and MCI from control populations, implying that synaptic degeneration worsens as patients progress from MCI to AD. However, there was a very weak correlation between CSF Ng levels and MMSE scores (r = ‐0.15; 95% CI = ‐0.21–‐0.08) among the whole populations, suggesting that an increment of CSF Ng is best considered a biological evidence of disease state in the AD continuum.ConclusionOur study provides evidence that the synaptic marker CSF Ng can be used as a disease state biomarker for the AD continuum. Because synaptic degeneration is a distinct pathologic event from amyloid deposition and neurofibrillary tangle formation, CSF Ng may provide an important supplementation to the AT(N) biomarker system to reveal the sequence of neuropathology.
The incidence of young onset dementia: A systematic review and meta‐analysis
Authors: Hendriks Stevie , Peetoom Kirsten , Bakker Christian , Koopmans Raymond , van der Flier Wiesje M , Papma Janne M , Verhey Frans RJ , de Vugt Marjolein , Koehler Sebastian 
Published: December 2021

AbstractBackgroundYoung‐onset dementia (YOD) denotes persons who have an onset of the disease before the age of 65. Information on the epidemiology of YOD, especially the incidence, is scarce. Insight into the incidence can contribute to further research on the etiology, mechanism and risk factors of YOD. Therefore, we aimed to conduct a systematic review and meta‐analysis collecting all published data on the incidence of YOD worldwide.MethodThis systematic review and meta‐analysis was conducted using the PRSIMA guidelines. A thorough literature search was performed in PubMed, Embase, CINAHL and PsychINFO. Eligible studies were prospective or retrospective population‐based studies reporting on the incidence of dementia under the age of 65. No restrictions on language were applied, and studies published between 1990 and March 2020 were screened. Random‐effect meta‐analyses were used to pool 5‐year incidence rates together. Incidence rates were age‐standardized for the World Standard Population whenever possible. Subgroup analyses and meta‐regression were used to identify factors influencing heterogeneity between studies. The study is registered with PROSPERO, number CRD42019119288.Result50 articles were included in the systematic review, of which 42 were included in the meta‐analysis. Studies were mostly conducted in Europe, with few studies from North America, Asia and Oceania. Age‐standardized incidence rates of YOD increased from 0.15/100,000 in the age group 30‐34 years, to 4.83/100,000 in the age group 60‐64 years, resulting in an overall incidence rate of 11/100,000 in the total age group 30‐64. This corresponds to 360,000 new cases globally per year. Heterogeneity between studies was high. Subgroup analyses showed incidence rates between males and females were similar. Meta‐analyses of different dementia subtypes showed incidence was highest for Alzheimer’s disease, followed by vascular dementia and frontotemporal dementia. Meta‐regression showed geographic location of the studies significantly influenced heterogeneity.ConclusionThis review showed current age‐standardized incidence rates of YOD are estimated to be 11/100,000 person‐years. However, there are still knowledge gaps to address in future research, such as differences in incidence by ethnicity and subtypes of dementia.
Lower nutritional indicators associated with higher mortality in patients with MCI and dementia—the Amsterdam Ageing Cohort study
Authors: Verhaar Barbara JH , Van de Schraaf Sara AJ , Meester Hanneke FM Rhodius‐ , Trappenburg Marijke C , Peters Mike JL , Muller Majon 
Published: December 2021

AbstractBackgroundOur objective was to investigate associations between indicators of nutritional status, including weight and body composition, and survival across cognitive diagnosis groups within a geriatric population.MethodFrom the ongoing Amsterdam Ageing cohort study, 719 patients were included, comprising 111 with subjective cognitive decline (SCD; 76±7 years, 54.1% female, MMSE 28[27‐29]), 213 with mild cognitive impairment (MCI; 79±6 years, 44.6% female, MMSE 26[24‐27]) and 395 with dementia (81±7 years, 53.9% female, MMSE 22[18‐24]). Indicators of nutritional status were measured and dichotomized, including body mass index (BMI), fat percentage (Fat%), skeletal muscle mass index (SMI) and Mini Nutritional Assessment Short‐Form (MNA‐SF) scores. Survival data were requested from the municipality population registry on January 22nd 2020. Associations between indicators of nutritional status and survival among different cognitive diagnosis groups were analyzed using Kaplan Meier analyses, and cox regression models adjusted for age, sex and number of prescribed drugs.ResultThe overall mortality was 15.8% during a median follow‐up duration of 610 [256‐964] days, with a significant difference between the cognitive diagnosis groups (p<0.0001). Kaplan Meier survival curves stratified for BMI and MNA are presented in Figure 1 and 2. Low BMI (<20 kg/m2) was associated with higher mortality risk in patients with dementia in the adjusted cox regression model (HR 3.1, 95%‐CI 1.7‐5.9). In patients with MCI, the association with BMI was not significant (HR 3.0, 0.6‐14.4). Low MNA‐SF scores (<12) were associated with higher mortality in both patients with MCI (HR 3.55, 1.23‐10.18) and patients with dementia (HR 2.1, 1.3‐3.5). However, there were no significant associations with Fat% and SMI. In patients with SCD, there were no significant associations between the indicators of nutritional status and mortality.ConclusionLower indicators of nutritional status were associated with higher mortality in patients with MCI and dementia, warranting increased focus on nutritional status in patients with cognitive decline. We plan to repeat these analyses after a longer follow‐up in this ongoing cohort study. Dietary intervention studies aimed at preventing weight loss could shed light on causality in the association between nutritional status and progression of disease.
Theta phase‐gamma amplitude coupling during working memory and its relationships with demographic, clinical, genetic, neurochemical, and neurostructural measures in older adults at risk for dementia
Authors: Patterson Rachel A. , Brooks Heather J. , Mirjalili Mina , Rashidi‐Ranjbar Neda , Zomorrodi Reza , Blumberger Daniel M. , Kumar Sanjeev , Fischer Corinne E. , Flint Alastair , Graff‐Guerrero Ariel , Herrmann Nathan , Kennedy James L. , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Voineskos Aristotle N. , Rajji Tarek K. 
Published: December 2021

AbstractBackgroundTheta phase‐gamma amplitude coupling (TGC) is a neurophysiological mechanism that underlies working memory (WM)1. WM is also associated with demographic, clinical, genetic and neuroimaging measures. However, the relative contributions of TGC and these measures to WM, and the relationship between TGC and these measures, remains unclear. We examined the relative contributions of TGC and these measures to WM performance in a group of participants at‐risk for Alzheimer’s dementia.MethodOlder participants (age=71.2±6.0, N = 206) with Mild Cognitive Impairment (MCI), Major Depressive Disorder (MDD), or MCI+MDD completed clinical assessment, N‐back WM task with EEG to measure TGC, genetic testing, PET with [11C]‐Pittsburgh Compound B ([11C]‐PIB PET) and brain 3T MRI. Linear regressions were used to assess the relationships among 2‐back WM performance; demographic and clinical variables; TGC; ApoE4 carrier status; total beta‐amyloid SUVR ([11C]‐PIB PET); and regional cortical thickness, subcortical volumes, and white matter fractional anisotropy (MRI).Result2‐back WM performance was associated with age and TGC after controlling for all other measures (Age: β=‐0.253; p=0.039, TGC: β=0.300; p=0.005). TGC was not associated with any other measures after correction for multiple comparisons.ConclusionTGC predicts WM performance in contrast to demographic, clinical, genetic, and PET and MRI imaging measures. Our findings underline the strong association between WM and TGC, a dynamic time‐based neurophysiological measure that is capturing a functional process which may not be captured by these static measures. Future studies could explore other dynamic measures with other imaging modalities and their relationships with TGC or other neurophysiological measures.1. Rajji, T.K., et al., Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. Cerebral Cortex, 2017. 27(2): p. 1482‐1490.
Superiority of the Dépistage Cognitif de Québec (DCQ) over the Montreal Cognitive Assessment in differentiating dementia with Lewy bodies from Alzheimer's disease
Authors: Poulin Elizabeth , Sarao Pamela , D'Amours Marie‐Frédérique , Laforce Robert 
Published: December 2021

AbstractBackgroundRecent criteria for dementia with Lewy bodies (DLB) are available but early diagnosis remains a challenge since few cases display all core clinical features. Discriminating Alzheimer’s disease (AD) from DLB is also complex given the overlap in cognitive dysfunctions between the two conditions. We aimed to study their differential neurocognitive profile using the Dépistage Cognitif de Québec (DCQ), a newly developed screening tool for atypical dementias. Moreover, we explored whether the DCQ was superior to the Montreal Cognitive Assessment (MoCA) in identifying DLB.MethodsWe compared the performance of 15 patients with DLB to 72 patients with the amnestic variant of AD on the five indexes of the DCQ (Memory, Visuospatial, Executive, Language and Behavioral) as well as the MoCA test, administered in random order. Participants were recruited prospectively in a tertiary memory clinic and diagnosed according to current clinical criteria for AD and DLB.ResultsThere were no significant differences between the groups in age (AD: 72.97; DCL: 72.13) or level of education (AD: 12.88; DCL: 12.40). Mean Total MoCA score was similar across conditions (19.01 vs 20.00, p = .54) whereas the Total DCQ score revealed a significant difference between AD and DLB (66.39 vs 72.60, p < .05) (Fig. 2). Further analyses showed superior Area Under the Curve for the DCQ (69.23%; moderately strong) over the MoCA (55.26%; weak) in discriminating DCL from AD (Fig. 1). Bivariate analyses on the DCQ and MOCA indexes were performed using Wilcoxon‐Mann‐Whitney tests. When compared to AD, DLB participants performed worse on the Visuospatial Index (5.04 vs 4.10, p < .05) (Fig. 4), particularly the visuospatial construction task (1.33 vs 0.67 p < .05) while AD participants were significantly more affected on the Memory Index (recall and recognition) (16.13 vs 24.73, p < .0001) (Fig. 3). The remaining DCQ indexes (Executive, Language and Behavioral) were similar between groups.ConclusionsOur data suggests that the DCQ may be a superior tool than the MoCA in distinguishing AD from DLB. The DCQ allowed better characterization of the neurocognitive profile between AD and DLB, where DLB preferentially affects visuospatial skills while AD targets memory abilities.
Quantitative measurement of CSF Aβ1‐38, Aβ1‐40, Aβ1‐42, and Aβ1‐43 by high sensitivity liquid chromatography mass spectrometry
Authors: Kawarabayashi Takeshi , Nakamura Takumi , Takatama Masamitsu , Shoji Mikio 
Published: December 2021

AbstractBackgroundHigh sensitivity liquid chromatography mass spectrometry (LC‐MS/MS) was recently introduced to measure amyloid‐ß (Aß) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. We validated the Aß1‐38, Aß1‐40, Aß1‐42, and Aß1‐43 assay by LC‐MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application.MethodCSF samples from 120 subjects [8 Alzheimer's disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer's disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC‐MS/MS system. Aß1‐40 and Aß1‐42 levels were validated using ELISA.ResultCSF levels in CU were 666±249 pmol/L in Aß1‐38, 2199±725 pmol/L in Aß1‐40, 153.7±79.7 pmol/L in Aß1‐42, and 9.78±4.58 pmol/L in Aß1‐43. The ratio of the amounts of Aß1‐38, Aß1‐40, Aß1‐42, and Aß1‐43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aß species. Both Aß1‐40 and Aß1‐42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aß1‐38 or Aß1‐40 levels between AD and CU. Aß1‐42 and Aß1‐43 levels were significantly lower, whereas the Aß1‐38/1‐42, Aß1‐38/1‐43, and Aß1‐40/Aβ1‐43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aß species were adequate for clinical usage.ConclusionA quantitative LC‐MS/MS assay of CSF Aß species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.