bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secondary tauopathy in a genetic synucleinopathy, mitochondrial protein–associated neurodegeneration (MPAN)
Authors: Nguyen Vy , Garcia Daphne , Setthavongsack Naly , Shirley Kristen , Krajbich Victoria , Clark David , van der Weijden Marlous , Zhen Dolly , Wakeman Katrina , Jeong Suh Young , Freed Alison , Gregory Allison , Hogarth Penelope , Hayflick Susan , Woltjer Randall 
Published: December 2020

AbstractBackgroundTauopathy and α‐synucleinopathy often occur together in human brain diseases but most commonly in the context of β‐amyloidosis. Tauopathy induced by α‐synucleinopathy in the absence of β‐amyloid has been demonstrated in vitro and in cultured cells but compelling examples of this in human disease rarely occur, most commonly in familial Parkinson's disease due to mutations in the α‐synuclein gene. Mitochondrial protein‐associated neurodegeneration (MPAN) due to mutations in C19orf12 produces neurodegeneration with brain iron accumulation as well as widespread α‐synucleinopathy. We report here on the findings and significance of associated tauopathy in MPAN.MethodFour patients with genetically confirmed MPAN were referred for brain autopsy and a complete histologic and immunohistochemical evaluation was undertaken for lesions and proteinopathies of common neurodegenerative diseases as well as the specific reported lesions of MPAN.ResultAll patients had hallmark pathologic features of MPAN including atrophy, gliosis, and iron accumulation involving the globus pallidus as well as abundant α‐synucleinopathy manifest as Lewy bodies and neurites thoughout the brain. Tauopathy was present in each case with neurofibrillary tangles distributed in Braak stages I to V with pretangles and more widely distributed tau‐positive dystrophic neurites. The distribution and regional burden of tauopathy was less than that of α‐synucleinopathy in each case. β‐amyloid or TDP‐43 abnormalities were not identified in any case.ConclusionThe lesional burden and distribution in MPAN are consistent with a pathogenetic model in which dysmetabolism of α‐synuclein is sufficient, in the absence of other common neurodegenerative pathologies, to induce tauopathy. Study of rare familial diseases such as MPAN may enhance our understanding of the pathogenesis of more common idiopathic neurodegenerative diseases.
Subjective memory ability correlates with functional connectivity between the medial temporal lobe and posterior default mode network in cognitively normal older adults
Authors: Mah Linda , Murari Geetanjali , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Herrmann Nathan 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) increases the risk of developing Alzheimer's disease (AD) but the neural mechanisms underlying this association remain unclear. Multimodal neuroimaging studies suggest that large‐scale network disruptions occur before amyloid plaques appear in the brain, beginning with alterations in the posterior default mode network (DMN). Here we investigated the association between subjective report of memory ability and functional connectivity between the posterior DMN and medial temporal lobe structures. We hypothesized that self‐report of greater memory ability would be positively correlated with functional connectivity between the posterior DMN and the medial temporal lobe.MethodsParticipants were 46 older adults [27 females, mean age=71.2 (6.5)] free of psychiatric or neurological illnesses, and normal cognition based on neuropsychological assessment. Subjective memory was evaluated using the Memory Functioning Questionnaire (MFQ). Resting state functional magnetic resonance imaging was acquired using gradient‐echo EPI BOLD at 3T and processed using CONN toolbox. A seed‐based analysis using the posterior cingulate cortex, a key node within the posterior DMN (x=‐6, y=‐52, z=40), as the seed was conducted to measure functional connectivity between the PCC and the hippocampus and parahippocampal regions. Correlations between functional connectivity measures and subjective memory [MFQ Frequency of Forgeting (MFQ‐FF)] as well as objective memory (California Verbal Learning Test‐II delayed recall) were performed.ResultsMFQ‐FF scores were significantly correlated with functional connectivity between the PCC and left parahippocampal gyrus (r = .52, p < .001). MFQ‐FF scores were similarly correlated with functional connectivity between the PCC and hippocampus (r=.34, p=.02) but this finding was not statistically significantly after applying a Bonferroni correction. In contrast, CVLT delayed recall scores were not correlated with functional connectivity of the posterior DMN and the medial temporal lobe.ConclusionsDisruption of functional connectivity between the posterior DMN and the medial temporal lobe may mediate the association between SCD and AD risk.
Inclusive support: Addressing the needs of black family caregivers of persons with dementia
Authors: Robinson‐Lane Sheria G , Zhang Xingyu (Mark) 
Published: December 2020

AbstractBackgroundFamily caregivers of Black older adults with Alzheimer’s disease and/or related dementias (ADRD) have an increased risk, compared to White family caregivers, for developing ADRD themselves and premature death. An effective minority family caregiver support intervention may be designed, or current program appropriately modified, by understanding the relationships between family caregiver support needs, health challenges, and predominantly used coping strengths.MethodA cross‐sectional sample of Black family caregivers living in southeastern Michigan (n=56) completed a survey comprised of a demographic tool, and multiple assessment measures including, the Promise Global Health Scale, the Personal Resource questionnaire, the Revised Scale for Caregiving Self‐Efficacy, and the Coping and Adaptation Processing Scale. Descriptive statistics and Spearman correlation coefficients were used to identify the prevalence of population health concerns and the relationships between particular health outcomes and caregiving strengths.ResultMore than 90% of the sample were educated Black women over the age 50 caring for parents (36%), grandparents (5%), Spouses (20%), children (14%), and other relatives (18%). The most common care recipient diagnoses included dementia non‐specified (52%), Alzheimer’s disease (20%), and vascular dementia (13%). The average body mass index for the caregivers was 31.7 indicating a high prevalence of obesity. Related caregiver health concerns included hypertension (70%) and diabetes (22%). Adaptive coping by caregivers was significantly associated with positive physical health (p = 0.000), mental health (p=0.001), perceived social support (p=0.001) and self‐efficacy for controlling upsetting thoughts (p=0.014). The predominant coping strategies used by the sample were spiritual coping, information gathering, and drawing upon past experiences.ConclusionFamily caregiver support programs that are designed to target Black adults may be enhanced through an increased focus on health promotion—particularly weight and disease management. Programs should also consider supporting caregivers in developing effective coping strategies in alignment with their preferred ways of coping, including an increased focus on spirituality, optimizing information sourcing, and utilizing effective past strategies.
Stages of tau aggregation associated with amyloidosis reflected in non‐negative matrix factorization components
Authors: Srinivasan Dhivya , Truelove‐Hill Monica , Erus Guray , Sotiras Aristeidis , Doshi Jimit , Wolk David A. , Davatzikos Christos , Nasrallah Ilya M. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundTau aggregation, when accompanied by amyloid deposition, is a key neuropathological signature of Alzheimer’s disease (AD). The regional distribution of tau may be a more sensitive marker of AD pathology than total tau level, however the spread of disease is unlikely to conform to common atlas‐based regions of interest. As such, methods for evaluating tau’s regional distribution could be useful for predicting AD staging or disease progression. In this analysis, we derive regional patterns of tau aggregation in AD using nonnegative matrix factorization (NNMF), a data‐driven method of identifying areas of the brain that consistently covary across individuals.MethodWe used data from 269 ‐amyloid (A) positive subjects with 18F‐flortaucipir‐PET data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and the AVID study (138 females, mean age = 73.09; 110 healthy controls, 118 MCI, and 41 AD). PET data were registered to Standard Montreal Neurological Institute (MNI152) 182x218x182 grid with 1mm resolution. SUVR maps were computed with a cerebellar gray matter reference and NNMF was used to estimate common patterns of tau aggregation. Once these patterns were identified, mean SUVR for each component computed for each participant. We performed Gaussian mixture modeling for each component to determine optimal tau positivity cutpoint, and subjects were classified as positive or negative for each component. Components were ordered by frequency of appearance in subjects in order to determine staging.Result12 regional patterns of tau binding were identified (Figure 1). The patterns most commonly expressed among subjects reflected regions of the temporal lobe (Figure 2a). This was particularly noted in those with AD (Figure 2b). These components were followed by a component including the lingual gyrus, and then by components involving frontal lobes, precuneus, and parietal lobes.ConclusionNNMF‐derived tau PET components provide a data‐driven method for identifying common patterns of tau aggregation, producing stages that are consistent with previous research on tau pathology in AD. These components may provide a more sensitive method for identifying disease progression in AD.
Microglial sex dimorphism poses greater vulnerability to Alzheimer’s disease in females: A cross‐species study
Authors: Kang Min Su , Ottoy Julie , Aliaga Arturo Aliaga , Mathotaarachchi Sulantha , Savard Mélissa , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Thomas Emilie , Benedet Andréa Lessa , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro , Terada Tatsuhiro 
Published: December 2020

AbstractBackgroundUnderstanding sex dimorphism in neurodevelopment and neurodegeneration is imperative for therapeutic strategy, clinical trial enrichment, and personalized medicine. However, the cellular underpinning of sex dimorphism in Alzheimer’s disease (AD) pathophysiology is still poorly understood. Here, we aimed to investigate the effect of sex on microglial activation and its effect on cognition using the major targets of AD clinical trials – amyloid ([18F]AZD4694), tau ([18F]MK6240), and neuroinflammation ([11C]PBR28) – through a multimodal PET study in humans and rats.MethodA total of 108 participants (70 CN, 25 MCI, and 13 AD; 36 M, 72 F) with a high‐affinity binder for TSPO from the TRIAD cohort underwent 3 PET scans and MMSE for cognitive assessment. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. Furthermore, 29 rats (8 WT, 21 Tg; 13 M, 16 F) underwent a 60‐min dynamic [18F]AZD4694 and [11C]PBR28 PET scans. All PET images were normalized to the average template. [18F]AZD4694 and [11C]PBR28 BPND were quantified based on SRTM method using Pons and midbrain as a reference region, respectively. The sex effect on neuroinflammation is evaluated based on a linear regression model in humans and rats. Consequently, sex dimorphism induced neuroinflammation effect on cognition was assessed using MMSE. All the models were corrected for age, APOE, education, amyloid and tau status.ResultIn this study, females showed greater [11C]PBR28 binding in basal temporal regions in humans and parietotemporal cortex, hippocampus, and basal forebrain in rats. Consequently, greater neuroinflammation in females showed negative effects on MMSE but not in males, p = 0.033.ConclusionThis study demonstrated the greater microglia activation in females compared to males. Considering the difference in the microglia reaction to amyloidosis in rodents compared to humans, the increased microglial activation effect on cognition was only assessed in humans. Here, microglial sex dimorphism showed deleterious effects on cognition only in females. This study highlights the difference in microglial reactivity leading to greater vulnerability to cognitive decline in females. As such, it is imperative to explore a sex‐specific therapeutic strategy for AD clinical trial.
Neuroimaging and neuropsychological findings in MAPT N279K mutation phenoconverters
Authors: Forsberg Leah K. , Fields Julie A. , Brushaber Danielle , Chen Qin , Kantarci Kejal , Senjem Matthew L. , Jack Clifford R. , Gavrilova Ralitza H. , Graff‐Radford Jonathan , Graff‐Radford Neill R. , Jones David T. , Knopman David S. , Kremers Walter K. , Petersen Ronald C. , Savica Rodolfo , Syrjanen Jeremy , Rademakers Rosa , Wszolek Zbigniew , Boeve Bradley F. 
Published: December 2020

AbstractBackgroundCharacterization of the changes that occur throughout the transition from asymptomatic to symptomatic for those with familial frontotemporal dementia is essential for planning future disease‐modifying trials.MethodWe identified four related microtubule associated protein tau (MAPT) N279K mutation carriers who have phenoconverted from the asymptomatic to the symptomatic state. Key features were as follows: Case 1 (female) initial exam age 36, onset age 44, current age 49; Case 2 (male) initial exam age 39, onset age 43, current age 48; Case 3 (female) initial exam age 41, onset age 47, current age 53; Case 4 (male) initial exam age 36, onset age 37, current age 46. MRI and neuropsychological data were analyzed.ResultStructural MRI was analyzed using Tensor Based Morphometry Symmetric Diffeomorphic Image Normalization (TBM‐SyN) methodology to quantify lobar volumes, which was then analyzed using a Mixed Effects Model to determine the annual change in lobar volumes. The phenoconverters had a greater estimated annual rate of cortical atrophy in temporal (p <0.001), frontal (p <0.01) and parietal (p <0.05) lobes compared to non‐carriers, with the rate of annual change in symptomatic individuals double that of asymptomatic individuals. Annual change in the parietal and occipital lobes was also analyzed and found to be similar to healthy controls of a similar age. Raw scores on neuropsychological measures were converted to z‐scores for analysis. Category fluency, letter fluency, and Trails A and B were all impaired (z‐score <‐1.5) following phenoconversion, but performance on these and other measures was variable across these four in the late asymptomatic state.ConclusionFor each of the four phenoconverters, structural MRI changes preceded symptom onset, whereas neuropsychological performance was more variable and occurred in closer proximity to the time of phenoconversion. Decrements in verbal fluency and cognitive flexibility were observed earlier than other cognitive domains. These findings suggest that changes in frontal and temporal volume on MRI precede symptom onset, with regional brain volumes most consistently tracking the evolution from the asymptomatic to symptomatic state in N279K MAPT mutation carriers. Supported by: AG063911, AG045390, NS092089, AG016976, AG016574, AG062677.
Amygdala tau in preclinical Alzheimer’s disease
Authors: Abiose Olamide , Deters Kacie D , Young Christina , Mormino Elizabeth C 
Published: December 2020

AbstractBackgroundPost‐mortem and neuroimaging studies have established the amygdala as one of the earliest sites of tau deposition and neurofibrillary tangles. We investigated the cognitive and anatomical consequences of amygdala tau levels in healthy, older adults.MethodWe examined 226 cognitively unimpaired ADNI participants who underwent AV‐1451 PET imaging (Aß‐ = 145, Aß+ = 81). We identified cognitive (memory, executive functioning) and MMSE scores — as well as neuroanatomical measures — closest in proximity to participants’ respective AV‐1451 PET scans (average time differences = 1.87 months, 2.04 months, and 11.05 months respectively). We used a series of linear regression models to explore the cross‐sectional relationships between amygdala and entorhinal tau/volume and cognition, as well as that between tau and volume. In a smaller set of 177 individuals, we also examined the extent to which neuropsychiatric symptoms (average time from AV‐1451 PET scan = 2.71 years) predicted amygdala tau and volume measures. All models controlled for age, sex, education level, and amyloid status. Models with volumetric measures also controlled for intracranial volume.ResultAmyloid‐beta positive participants had higher tau levels in both the amygdala and entorhinal cortex (p < 0.001); they also had smaller amygdala volumes than Aß‐ participants (p < 0.05). Within the Aß+ groups, elevated amygdala tau (only) was associated with lower amygdala volumes (ß=‐445.198, p=0.01). Both amygdala (ß=‐2.908, p=0.02) and entorhinal tau (ß=‐3.347, p=0.02) were significant predictors of MMSE scores, but only in Aß+ participants. Amygdala volume was a significant predictor of memory among Aß+ participants (ß=0.001, p=0.01), and there was a trend towards significance between amygdala volume and executive function (ß=0.001, p=0.07). There were no other significant effects on memory or executive functioning measures. Additionally, we found trend‐level inverse relationships between NPI anxiety and amygdala tau (ß= ‐0.073, p=0.1), as well as NPI anxiety and amygdala volume (ß= ‐104.975, p=0.06).ConclusionEarly amygdala tau is associated with reduced volume as well as worse overall global cognition in individuals thought to be in the preclinical stage of AD (Aß+ normal controls). Anxiety may possibly have a relationship with amygdala tau and volume (suggestively associated with less tau and less volume).
Comparison of deep learning methods for brain age prediction
Authors: Lam Pradeep , Zhu Alyssa , Salminen Lauren , Thomopoulos Sophia I , Bright Joanna , Jahanshad Neda , Thompson Paul M 
Published: December 2020

AbstractBackgroundBrainAge ‐ an estimate of a person’s age predicted from their structural MRI ‐ is a biomarker used to quantify age‐related neurodegeneration. The deviation of BrainAge from chronological age (Predicted Age Difference ‐ PAD) is of interest for prognostic research. Here we evaluated the accuracy of several deep learning methods (convolutional neural networks; CNNs) in predicting brain age.MethodAll experiments were conducted with a subset of 10,801 neurologically healthy participants from the UK Biobank. Of these, 9,301 were scanned at a single site; an additional 1,500 were from auxiliary sites with the same calibration standards. Participants’ age range was 48.9‐76.6 years. The primary site data had a mean age of 62.4 (SD, 7.5; 47% women/53% men). The auxiliary site scanned subjects with a mean age of 63.9 (SD, 7.3; 55% women/45% men). From the 9,301 single‐site scans, 7,153 were used to train the models; the rest were split into validation and testing sets. All auxiliary site data was used for out‐of‐site testing. Each model was trained using a different divergence penalty. In addition, a single model was evaluated on 25,756 participants from the UK Biobank dataset. K‐fold Cross‐Validation was used to prevent overlap between train, validation, and test sets. For each training instance, 12,365 subjects were used for the training set; the rest were split evenly between validation and test sets. For this experiment, subjects were not filtered out based on neurological health.ResultAll models performed well on both the in‐site and out‐of‐site test sets with an average mean absolute error (MAE) of 2.98 and 2.94 years, respectively. The model evaluated on 25,756 subjects received a MAE of 2.85 (R 0.845) with a residual correlation of 0.432 between PAD and true age.ConclusionGood accuracy achieved by all models suggests the value of BrainAge as a holistic biomarker of brain aging.
Endophenotype driven polygenic risk scores for Alzheimer’s disease
Authors: Chasioti Danai , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Yan Jingwen , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundPrecision medicine is designed to resolve heterogeneity in complex diseases such as Alzheimer’s (AD) to deliver timely and tailored treatment. Using ADNI data, we developed profiling based on genetically driven endophenotype‐specific polygenic risk scores (PRS) and assessed participant clustering on these profiles.MethodWe used ADNI genetic, clinical and biomarker data for PRS development. We performed cross‐sectional and longitudinal analysis in order to identify individual profiles at the baseline and to track disease progression. We derived four ADRD endophenotype components including Amyloid (A), Tau (T), Neurodegeneration (N) and Vascular (V), by applying PCA on 10 phenotypic variables. Bootstrapping was used for SNP selection and weight re‐estimation. APOE SNPs (rs429358, rs7412) and nearby genes were excluded. We performed K‐means clustering on the 4 derived A/T/N/V PRSs and cluster assignment was computed for 839 individuals of the validation set (excluding AD at the baseline). Baseline levels of cognition and biomarkers were estimated using linear regression adjusting for age, sex, education and (ICV when necessary) (Table 1, Figure 2). Longitudinal trajectories were estimated using linear mixed models (LMM) (Table 2, Figure 3). The performance of the LMM was assessed using marginal R2 (Table 3).ResultCluster assignment placed 306 individuals in Cluster1 and 533 in Cluster2. Both were balanced in terms of APOE e4 status, and demographics. Cluster1 showed elevated genetic risk (Figure 1) that was manifest at baseline by higher levels of amyloid (PET, CSF) and reduced temporal lobe thickness and memory (Table 1, Figure 2). Longitudinally, significant effect differences among the clusters were observed in angular gyrus, temporal lobe, white mater hyperintensity (WMHI), and clinical/cognitive measures (ADNI_EF and FAQ) (Table 2, Figure 3). Among APOE e4 non‐carriers, Cluster1 had significantly worse scores compared to Cluster2 (ADNI_EF and WMHI).ConclusionUsing clusters derived from endophenotype specific genetic information we were able to identify distinct progression profiles with predictive value beyond APOE alone. Endophenotype‐based PRS may be useful for therapeutic enrichment and targeting strategies in development of personalized therapeutics. Validation in independent samples is a critical next step.