bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decline in cognitive trajectories in the neuropathological spectrum of Lewy Body disease
Authors: Choudhury Parichita , Zhang Nan , Boeve Brad F. , Tremblay Cécilia , Choi Alexander , Belden Christine , Mehta Shyamal , Driver‐Dunckley Erika , Shill Holly , Shprecher David , Serrano Geidy E , Beach Thomas G , Atri Alireza 
Published: December 2023

AbstractBackgroundPathological Lewy body disease (LBD) may commonly present clinically as Parkinson’s disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer’s disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE.Result287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p<0.001), fluency scores (declining 1.02 unit/year faster p<0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups.ConclusionIn autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups.
The SMOC1‐matrisomal proteomics network M42 controls brain homeostasis and modulates toxicity in fly Alzheimer’s Disease models
Authors: Li‐Kroeger David , Al‐Ramahi Ismael , Smith Nathaniel , Marella Aditi , Amoh Bismark K , Saladi Saathwik , Botas Juan , Seyfried Nicholas T , Levey Allan I. , Shulman Joshua M 
Published: December 2023

AbstractBackgroundRecent evidence indicates Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways collude to disrupt neuronal function, yet the molecular changes underlying AD remain poorly understood. To identify changes associated with AD, we previously performed mass‐spectrometry (MS) on post‐mortem brain tissue and identified protein co‐expression networks correlated to AD pathological and clinical traits. The network most strongly correlated with AD pathology (M42) is enriched in components of the matrisome and consists of 32 proteins including multiple signaling pathways, Aß, APOE, and SMOC1, a predicted driver of network behavior. SMOC1 is a key matrisomal protein with conserved roles in modulating TGF‐Beta and wnt signaling during development, yet its role in the adult brain remains unstudied.MethodsWe evaluate the M42 protein network using the powerful genetics of Drosophila melanogaster to determine its role in the brain and uncover links to specific triggers of AD: Amyloid‐Beta (Aβ) and tau. We use a high‐throughput robotic screening platform and video assisted software which enables quantitative assessments of neurological function to identify proteins that modify Aβ‐ or tau‐induced neurodegeneration. We use Mass‐Spectrometry to identify protein changes in the brains of flies harboring homozygous loss‐of‐function mutations in dSMOC1 and genetics, cell biology, and immunofluorescence to characterize dSMOC1 in the fly.ResultsWe identified 13 genes with robust evidence of interactions with either tau or Aβ toxicity including dSMOC1 and multiple signaling components. We focused on dSMOC1, finding that flies homozygous for null mutations (dSMOC1−/−) suffer severely decreased survival upon aging. In the fly brain, dSMOC1 is expressed primarily in glia while the protein is localized around most neuronal cell bodies, consistent with its matrisomal role. Finally, we determined protein changes in the brain of dSMOC1−/− flies and found that ECM/receptor interactions and many metabolic pathways including KREBs/TCA cycle, lipid metabolism, and Oxidative Phosphorylation were perturbed.ConclusionThe M42 protein co‐expression network contains multiple proteins with links to AD. We identified multiple conserved M42 member proteins interacting with specific AD triggers. Together, the genetics and proteomics data support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting survival.
Induced Epileptiform Activity is Increased in Ex Vivo Hippocampal Slices Derived from the AppNL‐F and AppNL‐G‐F Humanised Knock‐In Mouse Models of Alzheimer’s Disease at a Young Age
Authors: Kelly Tommy L , Turner Richard J , Chen Yuqing , Fuchsberger Tanja , Nagappan P G , Nishimaki T , Paulsen Ole 
Published: December 2023

AbstractBackgroundHyperexcitability of neurons in the hippocampus and entorhinal cortex has been demonstrated in Alzheimer’s disease.MethodWe performed multi‐electrode array (MEA) recordings of hippocampal slices from young wild‐type mice, and the AppNL‐F and AppNL‐G‐F knock‐in (App‐KI) mouse models of Alzheimer’s disease amyloidopathy. To investigate the potential for amyloid pathology to drive early hyperexcitability, epileptiform activity was induced in these slices by treatment with aCSF supplemented with high K+ concentrations. A novel automated analysis pipeline was designed to detect epileptiform activity.ResultSubsequent analysis demonstrated an increased frequency of induced epileptiform activity in the hippocampus of App‐KI mice from as early as 4‐5 weeks old — the earliest that hyperexcitability has been observed in these mouse models to date. At this age, amyloid deposition has not yet begun, thus suggesting soluble amyloid oligomers are the driving factor behind increased epileptiform activity. In 12‐13 week‐old AppNL‐ F mice, where amyloid plaque deposition is still yet to occur, increased induced epileptiform activity was maintained, however, slices derived from AppNL‐G‐F mice, which have plaques at this age, had comparable levels of epileptiform activity to WT.ConclusionThese findings suggest that inducible hyperexcitability occurs at an early age in App‐KI mouse models of Alzheimer’s disease amyloidopathy, driven by soluble amyloid oligomers. The paradigm employed — and the robust, comparable metrics which it outputs — are analogous to electroencephalogram recordings and could potentially be used as a clinical biomarker to diagnose Alzheimer’s disease at a pre‐symptomatic, treatment‐sensitive stage.
Lewy body co‐pathology contributes to frontal lobe atrophy in Alzheimer’s disease and primary age‐related tauopathy
Authors: Almeida Francisco , Oliveira Tiago Gil , Jesus Tiago , Coelho Ana , Quintas‐Neves Miguel , Gauthreaux Kathryn , Mock Charles , Kukull Walter A. , Crary John F. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous proteinopathy. Co‐pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age‐related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid‐beta plaques, LB co‐pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.MethodsWe selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante‐mortem volumetric MRI from the National Alzheimer’s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p‐value < 0.05 after false discovery rate correction for multiple comparisons.ResultsWe found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.ConclusionsAltogether, these results suggest that LB co‐pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha‐synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART‐ and AD‐continuums.
Clearance of intracellular lipids by lipophagy impaired in APOE ε4 human astrocytes
Authors: Rosa Juao‐Guilherme S , Qian Lu , Tuck Tony , Scrivo Aurora , Cuervo Ana Maria , TCW Julia 
Published: December 2023

AbstractBackgroundApolipoprotein E (APOE) ɛ4 is the strongest known genetic risk factor for Alzheimer’s disease. APOE ɛ4 has been found to impair lipid metabolism in human glia causing accumulation of intracellular lipid droplets. We hypothesized that this phenotype in human APOE ɛ4/ɛ4 astrocytes was due to defective clearance via lipophagy.MethodGlobal transcriptomic analyses were performed on astrocytes derived from isogenic and population model human induced pluripotent stem cells (iPSCs). Fluorescent reporters, immunocytochemistry, and western blotting were used to quantify lipid droplets and autophagic machinery in iPSC‐based models.ResultGlobal transcriptomic analyses reveal that APOE ε4 drives autophagy dysregulation in astrocytes from human iPSCs. High‐content imaging of fluorescent autophagy reporters and immunocytochemistry revealed accumulation of lipid droplets and autophagy machinery in APOE ɛ4/ɛ4 astrocytes which was ameliorated by induction of autophagy.ConclusionHuman iPSC‐derived APOE ɛ4/ɛ4 astrocytes exhibit impaired lipophagy.
The unappreciated roles of oligodendrocytes in the etiology of Alzheimer’s disease
Authors: Herrup Karl 
Published: December 2023

AbstractBackgroundDementias such as Alzheimer’s disease are characterized as neurodegenerative diseases. While researchers accept that the etiology of dementia involves multiple cell types, the use of “neuro” as a prefix to “degeneration” biases our mechanistic thinking towards the nerve cell. The cell type that has been most marginalized by this bias is the oligodendrocyte and its myelin ensheathment of the larger axons of the brain. As early as the 1960’s the involvement of myelin pathology had been recognized in the Alzheimer’s disease (AD) brain. Later, with advances in imaging technology, a strong argument was advanced for the mechanistic involvement of myelin, a cholesterol rich membrane, in the etiology of dementia.MethodFixed frozen human prefrontal cortex (BA9), hippocampus, and cerebellum were received from both the University of Pittsburgh ADRC and the NIH‐sponsored NeuroBioBank. Mouse brain from wild type and AD models (R1.40 and APP/PS1) were also obtained. Cryostat sections were immunostained for APP and various myelin‐related peptides.ResultThis myelin hypothesis will be reviewed and put in the AD context by summarizing recent results on the impact of APOE, a cholesterol carrier and a major risk factor gene for sporadic AD, on the cells of the oligodendrocyte lineage. Observations on the presence of APP and its processing secretases in oligodendrocytes will deepen the connection to the etiology of ADConclusionBoth past and present data support the assignment of an important role for oligodendrocytes in the initiation and progression of Alzheimer’s disease. Broadening our current “neurocentric” view will speed progress towards meaningful therapeutic approaches.
Association of plasma biomarkers with imaging markers of brain atrophy and white matter disease across three neurodegenerative diseases and cerebrovascular disease
Authors: Sanchez Erlan , Coughlan Gillian T , Wilkinson Tim , Baril Andree‐Ann , Binns Malcolm , Bartha Robert , Symons Sean , Hegele Robert , Black Sandra E. , Lang Anthony E , Tartaglia Carmela , Finger Elizabeth , Freedman Morris , Swartz Richard H. , Kvartsberg Hlin , Zetterberg Henrik , Munoz Douglas , Masellis Mario 
Published: December 2023

AbstractBackgroundIt is necessary to better understand the value of plasma biomarkers in reflecting ongoing neurodegenerative processes before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of disease progression in trials. Herein, we investigate their association with imaging markers of brain atrophy and white matter disease across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted using the semi‐automated SABRE pipeline on 3T structural MRI sequences harmonized across sites. Fractions of supratentorial total intracranial volume were used when appropriate. Linear regression models controlling for age and sex were used to test the association between plasma biomarkers and MRI variables in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with extensive grey matter atrophy, ventricular expansion and, excluding p‐tau181, with increased white matter hyperintensities. In FTD, increased Aβ42/40 ratio was associated with frontal grey matter atrophy, and higher levels of NfL were associated with ventricular expansion. In PD, higher levels of NfL were associated with frontal, temporal and hippocampal grey matter atrophy. In CVD, higher levels of GFAP and NfL were associated with temporal and subcortical grey matter atrophy and ventricular expansion. Higher levels of GFAP were also associated with enlarged perivascular spaces, while higher levels of NfL were associated with increased lacunes. Finally, still in CVD, higher levels of GFAP and p‐tau181 were associated with increased stroke volumes.ConclusionExcluding Aβ42/40, plasma biomarkers appear to reflect various levels of brain atrophy in all neurodegenerative diseases studied, but reflect markers of white matter disease only in AD/MCI and CVD.
Preliminary neurocognitive finding from a multi‐site study investing long‐term neurological impact of COVID‐19 using ultra‐high field 7 Tesla MRI‐based neuroimaging
Authors: Tannous Jonika D , Vahidy Farhaan S , Patira Riddhi , Luckey Alison M. , Gonzales Mitzi M. , Hosseini Akram A. , Girard Timothy D. , Ibrahim Tamer , Jacobs Heidi I.L. , Roman Gustavo C , Masdeu Joseph C. , Karmonik Christof , Li Karl , Garbarino Valentina R. , Goss Monica , Nair Rejani R , Patel Vibhuti N , Snyder Heather M , de Erausquin Gabriel A. , Ganguli Mary , Seshadri Sudha , Snitz Beth E. 
Published: December 2023

AbstractBackgroundGlobally, over six hundred million cases of SARS‐CoV‐2 have been confirmed. As the number of individuals in recovery rises, examining long‐term neurological effects, including cognitive impairment and cerebral microstructural and microvascular changes, has become paramount., We present preliminary cognitive findings from an ongoing multi‐site study investigating the long‐term neurological impacts of COVID‐19 using 7 Tesla MRI‐based neuroimaging.MethodsAcross 3 US and 1 UK sites, we identified adult (> = 18) COVID‐19 survivors (CS) and healthy controls (HC) without significant pre‐existing medical, neurological, or psychiatric illness. Using the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS‐3) battery and Norms Calculator, 12 cognitive scores were adjusted for age, sex, and education and classified as either unimpaired or mild (<9th percentile), moderate (<2nd percentile), or severely impaired (<1st percentile). The observed frequency of impairment across the two groups is reported along with proportional differences (PD) and confidence intervals (CI). Illness severity and time since infection were evaluated as potential associates of cognitive impairment.ResultsOver a period of 11 months, we enrolled 108 participants. At the time of reporting, 80 (46.3% female; mean age: 60.3 ± 8.6; 61 CS, 19 HC) had completed cognitive assessments. Of the participants for whom we ascertained time since symptom onset and illness severity (n = 51 and 43, respectively), 31.4% had their index COVID‐19 infection within the past year, and 60.5% had a severe to critical infection (Table 1). Table 2 reports observed frequency of impairment for each metric. Aggregating all 12 cognitive metrics, we found 45 (73.8%) of CS had at least one impairment [vs HC: 10 (52.6%)]. A significantly greater proportion of CS had at least one moderate to severe or severe impairment (Figure 1). CS also had significantly higher frequencies of presenting with two or more mild to severe impairments [PD 0.33 (0.13, 0.54)]. Illness severity and time since infection were not significantly associated with cognitive impairment.ConclusionOur preliminary results are consistent with potentially sustained COVID‐associated cognitive impairment in a subset of participants. Enrollment in the multi‐site cohort is ongoing, and updated results will be presented along with ultra‐high field MRI‐based neuroimaging correlates.
Plasma tau phosphorylation at T217 predicts amyloid deposition in dominantly inherited and late onset Alzheimer disease participants without clinical symptoms
Authors: Barthélemy Nicolas R. , Li Yan , Janelidze Shorena , He Yingxin , Xiong Chengjie , Stomrud Erik , Fagan Anne M. , Karch Celeste M. , Benzinger Tammie L.S. , McDade Eric , Hansson Oskar , Gordon Brian A. , Bateman Randall J. 
Published: December 2023

AbstractBackgroundProgressive amyloid plaque accumulation in the brain precedes the emergence of clinical symptoms in Alzheimer disease (AD). This asymptomatic phase, referred to as preclinical AD, induces significant modification of tau phosphorylation in the cerebrospinal fluid (CSF). CSF tau phosphorylation occupancy at Threonine 217 (T217) becomes abnormal more than 20 years before cognitive decline in dominantly inherited AD (DIAD). CSF hyperphosphorylation at T217 also associates with amyloid pathology in late‐onset AD (LOAD) individuals with preclinical AD. In this study, we examined the performance of plasma T217 phosphorylation to detect amyloid plaques deposition measured by amyloid‐PET in asymptomatic participants with DIAD or late‐onset AD (LOAD).MethodWe measured plasma T217 phosphorylation using tau immunoprecipitation and high‐resolution mass spectrometry. Phosphorylation abundance at T217 was expressed as p‐tau217 ratio defined using the level of T217 phosphorylated tau peptide normalized to total tau level. The DIAD cohort included 355 samples from 176 CDR0 and 51 CDR>0 participants in the DIAN Observational study with 62% mutation carriers, all collected in relation to the estimated years to symptom onset (EYO). The LOAD cohort included 321 cross‐sectional samples from BioFINDER‐2 study. Amyloid positivity was determined using cross sectional amyloid‐PET scan available for each participant.ResultWe observed abnormal plasma p‐tau217 ratio in DIAD mutation carriers more than 15 years before EYO (Figure 1). Plasma p‐tau217 ratio accurately predicted amyloid PET positivity for individuals across multiple preclinical stages (Table 1, AUC respectively 0.89 and 0.98 for EYO brackets ‐20 to ‐10 and ‐10 to 0). The plasma test had similar performance in distinguishing amyloid status in the DIAD and the LOAD cohorts (AUC respectively 0.96 and 0.97, Table 1). In LOAD, plasma p‐tau217 ratio identified amyloid positivity independently of the cognitive status (AUC respectively 0.96 and 0.97 for asymptomatic and symptomatic).ConclusionOur results support the use of plasma p‐tau217 ratio to screen cognitively normal populations at risk of developing AD dementia. This blood‐based biomarker can support the recruitment of asymptomatic participants for prevention trials and help identifying patients who might benefit from early care using future AD drugs more than a decade before the detection of cognitive symptoms.