bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMS for the characterization of different types of dementia disorders: A systematic review and meta‐analysis
Authors: Quintanilla‐Sanchez Carolina , Salcido‐Montenegro Alejandro , Antal Andrea , Nañez‐Terreros Homero 
Published: December 2021

AbstractBackgroundAt early stages, dementia disorders share similar clinical symptoms. For an appropriate classification, more practical and non‐invasive diagnostic methods are needed. Transcranial magnetic stimulation (TMS) assess non‐invasively the imbalance of cortical excitability and related neurotransmitters levels in the brain(1‐3). Characterizing the spectrum of dementia with TMS could enable a more accurate diagnosis and optimize interventions at earlier stages.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to dementia of different etiologies and TMS. It was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies comparing dementia disorders using TMS were included. Risk of bias was assessed using QUADAS. Meta‐analyses comparing diverse TMS parameters between AD to FTD, DLB and VAD as well as FTD to DLB were made.ResultOur search yielded 2702 results, with 227 articles reviewed in full text. Finally, 14 articles were included in the review(4,5,14–17,6–13) and 11 in the meta‐analysis(4–14). A total of 983 patients were analyzed: Alzheimer disease (AD) 50.25%, frontotemporal dementia (FTD) 28.89%, dementia with Lewy bodies (DLB) 10.57%, vascular dementia (VaD) 5.59% and other dementias 4.7%. In the comparison between AD to FTD, the mean difference of resting motor threshold (RMT) short‐latency afferent inhibition (SAI), short‐acting cortical inhibition (SICI), intracortical facilitation (ICF) and central motor conduction time (CMCT) were statistically significant (Fig 1‐2). No significant difference when comparing the AD group to DLB nor VaD. Finally, RMT and SAI were the only parameters that differed between patients diagnosed with FTD and DLB (Fig 3). The main concerns of risk of bias were the retrospective study design and differences in diagnosis method and TMS protocols.ConclusionThe meta‐analysis of observational studies showed that TMS measurements as biomarkers seem to be useful for differentiating FTD from AD and DLB in patients with mild‐stage dementia. Accurate classification may allow more appropriate interventions and slow disease progression. However, study design and protocols may limit our results. Hence, more homogenous, and prospective studies with bigger sample size are needed.
Item‐level analysis of clinical measures in patients with early symptomatic Alzheimer’s disease following treatment with high‐dose aducanumab in the phase 3 study EMERGE
Authors: Cohen Sharon , He Ping , Benea Mihaela Levitchi , Miller Ryan , Forrestal Fiona , Pang Menglan , Castrillo‐Viguera Carmen , Harrison John E , Jaeger Judy , Mummery Catherine J. , Porsteinsson Anton P. , Cummings Jeffrey L. , Tian Ying , Yang Lili , Haeberlein Samantha Budd 
Published: December 2021

AbstractBackgroundEMERGE (NCT02484547), 1 of 2 Phase 3 trials evaluating aducanumab in patients with early Alzheimer’s disease (AD), demonstrated a statistically significant drug‐placebo difference in the prespecified primary and secondary clinical endpoints. We examined in EMERGE participants the change from baseline item‐level scores in primary, secondary, and tertiary clinical endpoints that, in combination, comprised a set of cognitive, functional, and neuropsychiatric instruments that provide a comprehensive assessment of AD.MethodEMERGE (N=1643) included participants aged 50‐85 years who met clinical criteria for MCI due to AD or mild AD dementia, with confirmed amyloid pathology. Participants were randomized to receive high‐dose aducanumab, low‐dose aducanumab, or placebo. The primary endpoint was change from baseline in CDR‐SB score at Week 78. Secondary outcome measures included MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI scores. NPI‐10 score was a tertiary outcome. Item‐level analyses using mixed model for repeated measures (MMRM) were conducted on these clinical efficacy endpoints using the ITT population. This analysis is considered descriptive due to its deviation from the normality assumption and thus no multiplicity adjustment was considered.ResultThe aducanumab high‐dose group demonstrated a consistent drug‐placebo difference across 5 clinical efficacy endpoints, slowing clinical decline over 78 weeks. Treatment effects were observed across all 6 domains of the CDR. An aducanumab treatment effect was evident by slowing of decline on the ADAS‐Cog13 items sensitive to change in early symptomatic AD (e.g., orientation, word recall [immediate and delayed], word recognition, and number cancellation). Additionally, clinical benefit of aducanumab with respect to preserving daily function was observed across a broad range of items on the ADCS‐ADL‐MCI. Finally, aducanumab treatment was associated with an attenuation of behavioral and psychiatric symptoms associated with AD, as measured by NPI‐10, and an accompanying decrease in caregiver distress.ConclusionAducanumab treatment effects, observed across a broad array of outcome measures, are clinically relevant. Item‐level analyses demonstrated consistency across cognitive, function, and behavioral domains sensitive to impairments that are detectable even in the early stages of AD. Holistically, these measures reflect the perspectives of patients, caregivers, and clinicians, thereby supporting the importance and meaningfulness of an aducanumab treatment effect in early AD.
CSF SNAP‐25 dynamics in healthy aging and across the spectrum of Alzheimer's disease
Authors: Lewis Alexandria , Darrow Jacqueline A. , Zhang Yifan , Ball Andrew J. , Mendes Muriel , Jeromin Andreas , Moghekar Abhay 
Published: December 2021

AbstractBackgroundThe turnover of synaptic proteins with aging and in different phases of AD is poorly understood. We measured CSF SNAP‐25, a protein localized to the presynaptic processes, using a novel SIMOA assay across 2 cohorts comparing cognitively normal young vs cognitively normal older adults as well as those with early and late MCI, in addition to those with dementia due to AD.MethodSubjects from the CSF Clinic were classified as cognitively normal or MCI based on NIA‐AA criteria in cohort 1. Subjects from the Johns Hopkins ADRC were classified clinically as cognitively normal, early MCI, late MCI and dementia in cohort 2. CSF SNAP‐25 was measured using a SIMOA assay on the Quanterix HD‐X. CSF AD biomarkers (abeta42, abeta40, total tau, ptau181) were measured using Fujirebio Lumipulse assays.ResultLevels of CSF SNAP‐25 were similar in cognitively normal young controls (YN) vs older controls (ON) in the first cohort with elevated levels in MCI (median [IQR] YN 66.0 [53.0,74.6], ON 57.7 [44.9,76.8], MCI 105.5 [97.3,124.1]; YN vs. ON p=0.44; ON vs. MCI p<0.001). In a validation cohort, CSF SNAP25 was similar in cognitively normal controls vs early MCI (median [IQR] ON 70.7 [60.3,86.8] EMCI 75.3 [60.3,92.6]; p=0.55). However, levels were elevated in late MCI and were higher than even in those with AD dementia (median [IQR] LMCI 150.5 [115.4,193.6] AD 97.8 [89.0,122.3]; LMCI vs. ON p<0.001; LMCI vs. AD p=0.014). CSF SNAP25 correlated better with CSF ptau181 across both cohorts (r=0.85, p <0.001) as compared to CSF amyloid ratio, abeta42/abeta40 (r=‐0.38, p <0.001). A CSF SNAP25 cut‐off of 121.85 pg/ml provided a sensitivity of 75% (95% CI: 51‐90%) and a specificity of 96% (95% CI: 81‐99%) in differentiating early and late MCI.ConclusionThe turnover of presynaptic SNAP25 as measured in CSF is relatively stable across the lifespan in healthy individuals. CSF SNAP25 levels correlate better with tau pathology rather than amyloid suggesting that increased SNAP25 turnover in CSF is not present the early preclinical phase of AD. Levels of CSF SNAP25 are elevated in the late MCI phase as compared to those in early MCI or dementia.
Physical activity and amyloid beta in middle‐aged and older adults: A systematic review and meta‐analysis
Authors: Rodriguez‐Ayllon Maria , Arroyo‐Avila Cristina , Alvarez‐Ortega Miriam , Molina‐Garcia Pablo , Solis‐Urra Patricio , Molina‐Hidalgo Cristina , Erickson Kirk I , Esteban‐Cornejo Irene 
Published: December 2021

AbstractBackgroundAlzheimer’s disease is the main cause of dementia in the world. Particularly, amyloid beta (Aβ) plaques are the primary hallmarks of this disease. Previous research has shown that higher levels of physical activity might be associated with lower levels of Aβ accumulation. However, a synthesis of evidence is needed to confirm or refute this hypothesis. The aim of the present study is to determine the overall effect of physical activity on Aβ by conducting a systematic review and meta‐analysis of available randomized clinical trials and interventions, and to systematically synthesize observational evidence on the association between physical activity and Aβ in middle‐aged and older adults.MethodA systematic search of 5 electronic databases (PubMed, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials and SportDiscuss) was performed from inception to 1st of April 2020. Studies were eligible if they included physical activity and Aβ data (i.e., any Aβ isoform measured by Positron Emission Tomography ‐PET‐, blood samples or lumbar puncture) in adults aged 45 years or older. Meta‐analyses were performed to examine the effect of physical activity on Aβ in randomized controlled trials (RCTs) and non‐RCTs (i.e., quasi‐experimental studies).ResultA total of 26 articles were included in this systematic review: 6 RCTs, 2 non‐RCTs, 4 prospective longitudinal studies, and 14 cross‐sectional studies. Of the 8 intervention studies, 5 were included in the meta‐analysis. In brief, the overall effect of physical activity on Aβ in middle aged and older adults was not significant (pooled SMD= ‐0.12; 95% CI ‐0.40 to 0.016; I2=3%). Additionally, 19 observational associations were synthesized in this systematic review. Overall, there was an unclear association between physical activity and Aβ at any of its isoforms (11 of 19 studies, 58%)].ConclusionDue to the small number of intervention studies included in the meta‐analysis (5 intervention studies) and the controversial findings provided by the observational studies, more studies are needed to understand the role of physical activity on Aβ in middle‐aged and older adults.
A patient who gradually progressed to corticobasal syndrome after traumatic brain injury
Authors: Chung Eunjoo 
Published: December 2021

AbstractBackgroundTraumatic brain injury (TBI) occurs when an external force injury the brain, and leads adult disabilities and death. A recent retrospective investigation found that TBI history was associated with a 1.6 higher risk for FTD diagnosis. Traumatic white matter injury has been already accepted as a critical contributor to post‐TBI neurological dysfunction. Now, we report changes of neurological features and serial followed up brain magnetic resonance images (MRI) in a patient with TBI.MethodA 48‐year‐old man visited the dementia clinic because of cognitive impairment. A month ago, an electric pole, which had been repairing by the patient, was broken and then it crashed to his head. Brain CT on the 7th day after the accident and brain MRI after one month were performed. First neuropsychological assessment was analyzed one year later since the accident occurred. B‐CT and B‐MRI were also performed in 4 years later.ResultBrain CT on the 7th day after the accident and brain MRI after one month, showed multifocal old infarctions, extensive rarefactions involving both periventricular and subcortical white matter, and moderate to severe diffuse brain atrophy. One year later since the accident occurred, he showed personality changes and the aggravated cognitive impairments. According to his wife, before he was injured, he easily memorized several phone numbers well. First neuropsychological assessment showed memory impairments (verbal and visual) and frontal executive dysfunctions. Fluency was decreased and naming difficulty was observed. He showed poor personal hygiene and delusion. Weight loss and dysphagia appeared since 4th year after the accident. He could not use his right arm and hand at will, and his parkinsonism seemed to be progressed. Brain CT and MRI still showed confluent cerebral white matter lesions and diffuse cerebral atrophy. He muttered only meaningless words and showed delusions.ConclusionHe showed changes in cognitive impairments, abnormal behavior and personality changes, parkinsonism, and aphasia in order after TBI. Brain MRI revealed an extensive white matter leukoaraiosis and brain atrophy. We thought that extensive white matter leukoaraiosis is associated with delayed various and complex complications after TBI.
Cognitive outcomes of anti‐amyloid‐β monoclonal antibodies in patients with Alzheimer's disease: A systematic review and meta‐analysis of randomized controlled trials
Authors: Fernandez Paulo Eduardo Lahoz , Silva Guilherme Diogo 
Published: December 2021

AbstractBackgroundFor the last 20 years, the amyloid‐beta (Aβ) cascade hypothesis has been dominant in the research of disease‐modifying therapeutics, with spent of financial and clinical resources in potential drugs targeting Aβ peptide production or clearance. (1) In this context, monoclonal antibodies targeting beta‐amyloid (Aβ‐mAbs) are being tested to reduce the amyloid burden in patients with Alzheimer’s Disease (AD). (2) However, the cognitive impact of Aβ‐mAbs remains controversial. (3) We aim to evaluate the conflicting results of previous studies using a meta‐analysis.MethodWe searched PubMed, Embase, and Cochrane databases, following until April 2021, using the search terms: ''Alzheimer's disease'' OR ''dementia'' cross‐referenced with ''monoclonal antibodies'', considering the synonyms. Eligible articles were randomized clinical trials with Aβ‐mAbs that reported cognitive outcomes. The cognitive function was assessed by Alzheimer’s Disease Assessment Scale (ADAS‐cog) and Mini‐Mental State‐Exam (MMSE). We performed a meta‐analysis comparing mAbs and placebo, considering a minimal significant clinical change of 3 points in ADAS‐Cog and 2 points in MMSE.ResultWe found 12 eligible studies in 443 identified records, involving 6736 patients, mean age 71.4 ± 2. We found a small benefit in cognitive outcomes in patients treated with Aβ‐mAbs: ADAS‐Cog: mean difference (MD) = ‐ 0.65; 95% CI (‐1.05 to ‐ 0.26); I² = 12%; (p = 0.001) and MMSE: MD = 0.40; 95% CI (0.18 to 0.63); I² = 10%; (p = 0.0004). The Funnel plot and Egger’s test did not show publication bias. MD was below the minimal clinically relevant change in both scales.ConclusionAβ‐mAbs may have a positive cognitive benefit in AD patients. However, the impact magnitude is small, not reaching minimal clinically relevant change for these scales. References: (1) Panza F, Lozupone M, Seripa D, Imbimbo BP. Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot? Ann Neurol. 2019 Mar;85(3):303–15. (2) Liu J, Yang B, Ke J, Li W, Suen W‐C. Antibody‐Based Drugs and Approaches Against Amyloid‐β Species for Alzheimer’s Disease Immunotherapy. Drugs Aging. 2016 Oct;33(10):685–97. (3) Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid‐β‐targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019 Feb;15(2):73–88.
Exosomal levels of soluble amyloid precursor fragments in aging and dementia
Authors: Martins Tânia Soares , Rosa Ilka Martins , da Cruz e Silva Odete , Henriques Ana Gabriela 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) neuropathological alterations begin around 15 years before clinical symptoms´ manifestation, highlighting the need to identify new molecular signatures that can assist in early and differential diagnosis. Alzheimer´s amyloid precursor protein (APP) can be cleaved to produce soluble fragments (sAPP), either by amyloidogenic (sAPPβ) or non‐amyloidogenic processing (sAPPα). The biomarker potential of both sAPP forms have been explored in CSF, plasma and plasma neuronal‐ and astrocyte‐derived exosomes, but some controversy arises regarding sAPP changes in AD.MethodThe levels of sAPPα and sAPPβ were measured by ELISA in serum and serum‐derived exosomes of Controls and individuals with dementia (Clinical Dementia Rating ≥1 and positively scored for Mini‐Mental State Examination) from a primary care‐based cohort (pcb‐cohort). ANOVA was used to assess sAPP differences in demographic and clinical data; Mann‐Whitney t‐test for sAPP median comparisons; and Spearman correlation coefficients to assess sAPP levels correlations in dementia. Statistical analyses were performed using SPSS v27 or Graphpad 7.00.ResultA tendency for lower sAPPα or sAPPβ levels and higher sAPPα/β ratios could be observed for serum and serum‐derived exosomes in the CDR≥1/MMSE+ and the AD subgroups when compared with Controls (CDR=0), although without statistical significance. Positive correlations were observed between sAPPα and sAPPβ levels, in exosomes but not in serum, for the CDR≥1/MMSE+ (r=0.63;p≤0.0001) and AD subgroups (r=0.79;p≤0.05). In addition, exosomal sAPPβ level significantly differ with age (p≤0.05), when individuals were separated in two groups (cut‐off stablished based on the age median), but only for the CDR=0 group (p≤0.05).ConclusionBlood‐derived exosomes recently emerged as peripheral sources of biomarkers for AD, reflecting disease stages. Exosomal sAPP forms did not exhibit a significant diagnostic relevance in discriminating AD or dementia. Interestingly, a significant difference was reported for sAPPβ in Controls with age. Since aging is the strongest risk factor for dementia, future studies should also address the advancing aging effect, when monitoring biomarkers for AD and/or other dementia‐related conditions. To this end research was funded by the Alzheimer’s Association 2019‐AARG‐644347 grant and supported by iBiMED UIDB/04501/2020,FCT,COMPETE program,QREN,European Union; T.S.M. is supported by an FCT individual PhD grant SFRH/BD/145979/2019.
Bioinformatic analysis of senile plaques and neurofibrillary tangles proteomes
Authors: Ferreira Maria José , Martins Tânia Soares , da Cruz e Silva Odete , Vitorino Rui , Henriques Ana Gabriela 
Published: December 2021

AbstractBackgroundSenile plaques (SPs) and neurofibrillary tangles (NFTs) are the main histopathological hallmarks of Alzheimer’s disease (AD). Although these two deposits have main components, like amyloid fibrils in SPs and hyperphosphorylated tau protein in NFTs, the molecular composition underlying these lesions has not been completely unraveled. Hence, this work aims to characterize the SPs and NFTs proteomes’ by applying a bioinformatic analysis, to identify new possible biomarkers candidates for AD.MethodAn extensive literature research was carried out on Pubmed, using keywords that allowed the recovery of information regarding SPs and NFTs proteomes in AD brains. The data obtained was loaded and analysed on Cytoscape v3.8.2. For the Gene Ontology (GO) analysis, the plugins ClueGO v2.5.8 + CluePedia v1.5.8 were employed.ResultMore than 800 proteins were identified for SPs and more than 600 for the NFTs. GO analyses allowed the characterization of both proteomes at the biological process, molecular function, and cellular component levels. The top biological processes for SPs were related to cell development, secretion, and exocytosis, while for NFTs these were related to protein localization, vesicle‐mediated transport in synapse, and response to oxidative stress. Overlap of both proteomes revealed more than 300 proteins that represent interesting targets for AD. GO analyses revealed that these proteins are involved in biological processes like vesicle‐mediated transport in synapse and apoptotic signaling pathway. Additional experiments using antibody‐based methodologies need to be carried out to validate the potential of these candidates for AD.ConclusionThis study allowed the identification of several proteins, present in both SPs and NFTs, that can not only assist in unraveling pathways common to both histopathological hallmarks but also constitute possible biomarker candidates for AD diagnosis and/or therapeutics. To this end research was funded by a grant from the Alzheimer’s Association (2019‐AARG‐644347) and supported by iBiMED UIDB/04501/2020, FCT, COMPETE program, QREN, European Union. T.S.M. is supported by the FCT through the individual PhD grant (SFRH/BD/145979/2019). RV’s Fellowship Grant (IF/00286/2015).
The role of physical health on the relationship between subjective memory complaints, anxiety, and depression in older adults during the COVID‐19 pandemic
Authors: Sheffler Julia L , Taylor Diamond , Saliga Hollyn 
Published: December 2021

AbstractBackgroundResearch demonstrates that subjective memory complaints (SMCs) are associated with anxiety and depression; however, few studies have longitudinally examined the relationship between SMCs and new onset of anxiety and depression symptoms in older adults. In the context of the COVID‐19 pandemic, it is also important to consider how existing health conditions may impact these associations. We examined (1) if SMCs predict new onset of anxiety and depression symptoms during the COVID‐19 pandemic in older adults and (2) if physical health problems exacerbate this association.MethodWe performed hierarchical linear regression analyses to evaluate associations between SMCs and depression and anxiety symptoms during the COVID‐19 pandemic, controlling for age, sex, education, income, baseline anxiety and depression, and cognition. Next, we assessed the interaction between SMCs and health conditions on anxiety and depression symptoms.ResultSMCs (β= 0.021, p= .017) and health (β=.165, p<0.001) were directly associated with increased anxiety symptoms; however, the interaction effect was not significant (β=0.002, p=0.697). SMCs (β=0.006, p=0.493) and health (β=0.075, p=0.069) were not directly associated with increased depression symptoms; however, the interaction was significant (β=0.017, p<0.001).ConclusionSMCs and health problems exert independent effects on the development of anxiety symptoms; whereas the effect of SMCs on the development of depression symptoms depends on the presence of health problems. These findings highlight the role health plays in the development of depression and anxiety symptoms in older adults during societal stressors such as the COVID‐19 pandemic.