bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s disease heterogeneity explained by polygenic risk scores based on brain transcriptomic profiles
Authors: Chung Jaeyoon , Panitch Rebecca , Hu Junming , Zhu Congcong , Mez Jesse , Farrer Lindsay A. , Stein Thor D. , Crane Paul K. , Nho Kwangsik , Jun Gyungah R. 
Published: December 2021

AbstractBackgroundConsidering the complex etiology of Alzheimer’s disease (AD), classifying AD patients into clinically‐relevant subtypes is important for precision medicine. We proposed a novel way to decompose AD heterogeneity using AD polygenic risk scores (PRSs) from biologically coherent gene‐sets, which were developed based on coexpressed genes in AD brains.MethodWe conducted network analysis using RNA‐sequencing data from 64 autopsied AD brains in the Framingham Heart Study and Boston University Alzheimer’s Disease Research Center and validated preservation of modules in independent AD brain RNA‐Seq datasets from Religious Orders Study and Memory and Aging Project (n=363) and Mayo Clinic Study of Aging (n=82). Next we identified AD‐associated modules by enrichment analyses using a false discovery rate (FDR)<0.05 with gene‐sets informed by GWAS for neuritic plaque and neurofibrillary tangles. Based on the genes ascribed to each module, we computed and evaluated associations of module‐based PRS (mbPRS) for NP and NFT mbPRSs with i) domain‐specific neuropsychological performances, ii) cognitively‐defined subgroups including memory (n=196), executive functioning (n=16), language (n=52), visuospatial functioning (n=91), multiple domain (n=28), and no domain (n=289) (Mukherjee, 2018), and iii) cortical thickness across whole brains in the 672 AD patients of Alzheimer’s Disease Neuroimaging Initiative (ADNI).ResultAmong the 143 co‐expressed gene‐sets (modules) identified in the discovery, 14 modules were preserved in both validation datasets with significant enrichment FDR<0.05 for AD associated genes. PRSs from three modules were significantly associated with performance on a particular cognitive test (logical memory test, Boston Naming test, and Clock copy score) each representing a distinct cognitive domain (memory, language, and visuospatial functioning, respectively). Importantly, mbPRS was significantly associated cortical atrophy in module‐specific regions. Further analysis showed that PRS for each of these three modules significantly differentiated subgroups of AD patients by memory (P=0.02), language (P=0.01) and visuospatial (P=0.04) dysfunction, respectively.ConclusionOur findings indicate that an approach integrating genetics and transcriptomic data can differentiate subtle variations in neuropsychological performance among AD patients and clinically‐defined AD subgroups (especially, memory, language, and visuospatial domains), which can be utilized for genetically‐informed AD patient classification.
Herpes zoster diagnosis and treatment in relation to incident dementia
Authors: Weinmann Sheila , Rawlings Andreea , Koppolu Padma , Prado Yolanda K , Rosales A Gabriela , Schmidt Mark A 
Published: December 2021

AbstractBackgroundRecent evidence suggests that some infectious diseases, such as herpes zoster (HZ), are positively associated with cognitive impairment and dementia, while certain anti‐viral medications have been reportedly associated with lower risk. We sought to evaluate associations between HZ diagnosis and treatment with incident dementia in a large, retrospective matched cohort.MethodUsing ICD‐9 and ICD‐10 diagnosis codes in electronic medical records, we identified members of Kaiser Permanente Northwest who were age 50 and older between 2000‐2019 inclusive with a HZ diagnosis during this period. A comparison group without HZ diagnosis was individually matched 3:1 on age at HZ diagnosis date (index date), sex, and membership length prior to index date. We excluded subjects with dementia diagnosed before the index date. Follow‐up time started at the index date and ended on the date of dementia diagnosis (based on ICD‐9 and ICD‐10 codes), membership end date, death, or end of follow‐up, whichever came first. Medication for HZ was identified using the first anti‐viral pharmacy fill within 6 months before or after the index date. We used survival analysis to examine the associations between dementia and HZ diagnosis (yes/no, overall, by sex, age), HZ medication (yes/no), and HZ medication by tertiles of cumulative dose of medication dispensed. We adjusted models for demographic and clinical factors.Result109,830 persons (27,500 with HZ) were included. The mean age was 65.5 years, and 61.5% were female. Over a mean follow‐up of 6.3 years, 11,386 developed dementia. HZ diagnosis, overall or within subgroup, was not associated with higher risk of dementia (Figure). Among persons with HZ, receipt of anti‐viral medication (any vs. none) was not statistically associated with lower dementia risk. None of the hazard ratios for tertiles of cumulative anti‐viral dose was statistically significant, though the one for the highest tertile was suggestive.ConclusionIn our retrospective study of over 27,000 persons with HZ and matched comparison persons without HZ, we found no evidence for an association between HZ diagnosis and dementia. Anti‐viral medications prescribed around the time of the HZ diagnosis were not statistically associated with lower risk of dementia.
Defining physical activity: A comparison of actigraphy monitoring and self‐report measures
Authors: VandeBunte Anna M. , Djukic Nina , You Michelle , Fonseca Corrina , Kramer Joel H , Casaletto Kaitlin B 
Published: December 2021

AbstractBackgroundPhysical activity (PA) helps preserve age‐related brain health. However, PA is a broad construct and its operationalization can vary. Actigraphy monitors are gold‐standard measures of PA, but not always feasible. The Community Healthy Activities Model Program for Seniors (CHAMPS) and Physical Activity Scale for the Elderly (PASE) are widely‐used self‐report questionnaires of PA for older adults, but are limited by scope and subjectivity. We aimed to examine the ecological validity of objective and subjective measures of PA and determine how self‐reported PA relates to distinct actigraphy metrics.Method104 functionally normal older adults completed 30‐day Fitbit monitoring (average daily steps and calories burned), and reported PA levels via PASE (total activity) and CHAMPS‐METs (metabolic expenditure calories burned). Participants also completed measures of vascular (hypertension diagnosis, resting heart rate), neurobehavioral (cognition, Perceived Stress Scale, Everyday Cognition Scale), and brain MRI (medial temporal lobe volume) outcomes. Spearman’s rank correlations and regression models evaluated the associations among PA measures and with outcomes of interest.ResultGreater Fitbit step count associated with higher PASE (r=0.30, p=0.005), but not CHAMPS‐MET scores (r=0.15, p=0.20). On the other hand, Fitbit calories burned related to higher CHAMPS‐METs (r=0.35, p=0.003), but not PASE scores (r=0.16, p=0.15). Only Fitbit measures demonstrated expected positive associations with cognitive outcomes, with slightly stronger associations shown with step count (r range=0.23‐0.26). All 3 PA measures demonstrated expected negative associations with perceived stress and cognitive complaints (r range=‐0.07‐0.26). Greater PA, as measured by Fitbit metrics or CHAMPS‐MET, was associated with less hypertension (Fitbit steps t=0.15; CHAMPS‐METs t=‐2.04) and lower resting heart rate (Fitbit calories burned r=‐0.26). PASE did not significantly associate with vascular health (HTN t=0.93; HR r=‐0.02, ps>0.05). Lastly, greater Fitbit step count (β=0.32, p<0.01) and calories burned (β=0.29, p<0.01), but not PASE or CHAMPS‐MET (β range=0.05‐0.15, ps>0.05), were associated with larger medial temporal lobe volumes.ConclusionObjective indicators of PA demonstrate greater overall ecological validity compared to self‐report. Our findings suggest PA is comprised of several constructs. Metrics capturing PA intensity via calories burned may not be interchangeable with metrics of overall movement. Careful understanding what PA metrics represent will facilitate better‐informed recommendations for healthy aging.
Non‐fluent/agrammatic variant of primary progressive aphasia with progressive supranuclear palsy
Authors: Castro‐Suarez Sheila , Osorio‐Marcatinco Victor , Guevara‐Silva Erik Alberto , Caparo‐Zamalloa Cesar , Meza‐Vega Maria 
Published: December 2021

AbstractBackgroundNon‐fluent/agrammatic variante of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder characterized by speech production impairment (1). The overlap of nfvPPA and progressive supranuclear palsy (PSP) and corticobasal syndrome cases have been reported (2). As nfvPPA progresses, a parkinsonian disorder often co‐occurs (3). There are different kinds of language impairment including articulatory deficits, agrammatism, reduced speech rate, and anomia (1). Here we present a Peruvian woman with nfvPPA with single‐photon emission computed tomography (SPECT) and parkinsonian syndrome.MethodWe describe a 73‐year‐old woman with progressive speech production impairment and parkinsonian syndrome. She completed standard neurological, neuropsychological, and speech‐language evaluations, as well as brain MRI and SPECT scan.ResultThe patient is a right‐handed woman with 16 years of education. No family history of dementia, parkinsonism or motor neuron disease was reported. At age 71, she presented progressive difficulty in speaking, anomia and verbal hesitancy; but she can understand conversations, send and read text messages. She also had depressive symptoms. MRI showed mild left frontal and perisylvian > right atrophy (fig 1).By age 73, she developed a prominent reduction in spontaneous speech, mild difficulties in reading and writing, occasional paraphasia, less empathy, dietary change, moria and, mild parkinsonism (she expresses less emotion, tremor, slowly walk and falls). Her episodic memory starts to decline thereafter.On examination, she had mild‐moderate telegraphic speech, imitation behavior, mild facial masking, bradykinesia and mild postural instability but no abnormal extraocular movement. Speech‐language assessment showed non‐fluent aphasia and apraxia of speech. Impaired comprehension of syntactically complex sentences. Naming was mildly impaired. Syntactic errors were present. Executive function was also impaired, but visuoperceptual skills were preserved.Serological analyses were unrevealing. Brain SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion (fig 2).ConclusionWe report a Peruvian case of an elderly woman presenting with a 3‐year history of nfvPPA features and PSP. Her SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion. Consider early evaluating motor function in nfvPPA patients in light of the possibility of CBS or PSP overlap.
A Canadian cohort with the IVS10+14 MAPT mutation
Authors: Maxwell Selena P , Cash Meghan K , Rockwood Kenneth , Fisk John D , Darvesh Sultan 
Published: December 2021

AbstractBackgroundThe IVS10+14 microtubule‐associated protein tau gene (MAPT) mutation causes dysregulated protein splicing of MAPT, resulting in abnormal 4‐repeat isoform tau accumulation and associated with neurodegeneration. Three families expressing the IVS10+14 MAPT mutation have been reported who express the IVS10+14 MAPT mutation displaying a high degree of interfamilial heterogeneity in their clinical presentation. Herein, we describe the clinical and neuropathological presentation of a new Canadian cohort with this mutation.MethodClinical and neuropathological records, including neuropsychological and cognitive assessments, and stained neuropathological sections, were obtained for three family members with the IVS10+14 MAPT mutation. The records were reviewed and compared to previously reported families with this mutation.ResultThe Canadian cohort displayed many of the symptoms previously described in cases with the IVS10+14 MAPT mutation, including prominent motor, cognitive, behavioural, and behavioural symptoms. Additionally, consistent with the interfamilial heterogeneity described in literature, our cohort exhibited profound sensory and sleep abnormalities. Neuropathological information was available for two cases, in which one had widespread cortical and subcortical tau deposition and atrophy, while neuropathological changes in the other case was milder with the exception substantia nigral atrophy.ConclusionOur cohort demonstrate that while the IVS10+14 MAPT mutation often results in motor, cognitive and behavioural clinical features, sensory and sleep abnormalities are also manifestations of the mutation. Clinicopathological correlations were able to explain symptom presence and severity for two of the three examined cases. This underlines the need to explore alternate mechanisms and metrics of brain dysfunction in tauopathy in addition to tau burden and neuronal loss. Reference: Maxwell SP, Cash MK, Rockwood K, Fisk JD, Darvesh S. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.
Intra‐individual variability in processed EEG (bispectral index monitor) under general anesthesia predicts postoperative cognitive change after total knee arthroplasty
Authors: Dion Catherine , Tanner Jared J. , Hernaiz Carlos , Parvataneni Hari K. , Price Catherine C. 
Published: December 2021

AbstractBackgroundPrevious research shows 1) clock drawing performance slows for older adults after total knee arthroplasty (TKA; Hizel et al., 2018), and 2) brain‐behavioral associations with intra‐individual variability on an EEG‐derived index during TKA (Hernaiz et al., 2019). The current study expanded upon these findings by examining how preoperative cognition and intraoperative responses to anesthesia may predict postoperative clock drawing performance. We hypothesized greater intraoperative intra‐individual BIS variability would explain a significant portion of variance in four primary latency measures to command and copy condition at 3‐weeks following surgery.MethodThe final prospectively recruited IRB consented participant sample included 54 non‐demented patients age 60+ receiving TKA under general anesthesia. Consistent with Hernaiz et al., (2019), derived 2‐channel EEG variability was studied from tourniquet inflation to tourniquet release, thereby establishing a consistent period of examination. Intra‐individual variability was calculated as the squared deviation from the mean BIS value over the duration of measurement. Clock drawing to command and copy was recorded with digital pen technology and scored with semiautomatic rater‐guided software (Souillard‐Mandar et al., 2016). Outcome latency variables of interest: 1) total completion time in seconds (TCT), 2) time prior to setting the first hand in seconds (pre‐first hand latency; PFHL), 3) seconds after drawing the clock face to next pen stroke (post‐clock face latency; PCFL).ResultAt 3‐weeks, participants took, on average, six seconds longer to complete the drawing compared to baseline performance, and two seconds longer to set the first clock hand. Correcting for baseline performance, separate hierarchical regressions showed intra‐individual EEG‐derived variability explained an additional 4.3% of variance in postoperative command TCT (F(2,51)=28.301, p<.038, R2=.536, ∆R2=.043), such that those with greater intraoperative BIS variability took longer to complete the drawing to command.ConclusionIn non‐demented older adults undergoing TKA, higher intra‐individual BIS variability significantly contributed to total clock drawing time during the command condition. Command total completion time is sensitive to numerous cognitive domains including processing speed, language, working memory, and declarative memory (Dion et al., 2020). Fluctuations during general anesthesia as recorded on an EEG‐derived index may help explain postoperative slowing during clock drawing at 3‐weeks post‐surgery.
INVOKE‐2: A phase 2 randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early Alzheimer’s disease
Authors: Paul Robert , Jackson Sam , Ward Michael , Joshi Aashka , Castro Abraham , Yeh Felix L , Liao Yijie , Morrison Glenn 
Published: December 2021

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain predominantly by microglia. Mutations in TREM2 cause an increased risk of developing Alzheimer’s Disease (AD). E.g., the R47H coding variant confers similar risk for AD as does one copy of APOE4. AL002 is a humanized monoclonal IgG1 antibody (mAb) that activates the TREM2 signaling pathway to increase the ability of microglia to clear pathology and protect neurons. AL002 is believed to be the first anti‐TREM2 mAb in clinical development for the treatment of AD. AL002 was generally well tolerated in a Phase 1 study (INVOKE) and has demonstrated proof of target engagement and proof of mechanism. These results have supported progressing AL002 to the INVOKE‐2 Phase 2 study of AL002 in patients with early AD.MethodINVOKE‐2 is a randomized, double‐blind, dose‐ranging, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early AD (NCT04592874). This is a global study that will enroll approximately 265 participants in North America, Australia, New Zealand, Europe, and South America. Participants will be randomized to receive one of 3 doses of AL002 or placebo, administered via IV infusion every 4 weeks, for up to 96 weeks. The objectives of this Phase 2 study are to assess the efficacy and safety of AL002.ResultAll participants must have a diagnosis of early AD with evidence of cerebral amyloidosis and a clinical severity consistent with Stage 2 to early Stage 4 (2018 Research Framework), including a CDR‐GS of 0.5 or 1, MMSE from 22 to 30, and RBANS DMI of 85 or lower. Efficacy will be assessed with clinical outcome assessments (including CDR‐SB and ADAS‐Cog13), and fluid and imaging biomarkers. Safety will be assessed through monitoring of AEs, suicidality assessments, changes in laboratory and vital signs, ECG and MRI. PK in serum and CSF will be assessed.ConclusionINVOKE‐2 is designed to investigate the efficacy and safety of AL002, representing a novel, first‐in‐class neuro‐immunological approach for treating AD. Enrollment is ongoing.
The Addenbrooke’s Cognitive Examination–Revised in the differential diagnosis between Alzheimer's disease and behavioral variant frontotemporal dementia: A new model
Authors: Carvalho Viviane Amaral , Lima‐Silva Thais Bento , Mariano Luciano Inácio , de Souza Leonardo Cruz , Guimarães Henrique Cerqueira , Bahia Valeria S , Nitrini Ricardo , Barbosa Maira Tonidandel , Yassuda Monica Sanches , Caramelli Paulo 
Published: December 2021

AbstractBackgroundThe increase in life expectancy implies the emergence of chronic‐degenerative and disabling conditions, such as cognitive impairment and dementia. Among the frequent disorders in clinical practice, the differential diagnosis between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) may be challenging, which justifies the improvement in cognitive tools to be used in clinical practice.MethodThe Addenbrooke’s Cognitive Examination‐Revised (ACE‐R) was administered to 102 patients diagnosed with mild dementia due to probable AD and 37 with mild probable bvFTD from two Brazilian research centers (Table 1). All individuals were submitted to the Mattis Dementia Rating Scale (DRS) and the ACE‐R. The performance of the patients was compared and analyzed. ROC curve analyses were conducted to assess the ACE‐R accuracy in the diagnosis of AD and bvFTD. Multivariate logistic regression analysis was used to develop a new model to refine the diagnostic accuracy of the ACE‐R.ResultMean total scores in the ACE‐R were 70.2 (standard deviation ‐ SD = 10.8) in patients with AD and 72.2 (SD = 11.1) in bvFTD. The VLOM ratio showed an area under the curve (AUC) of 0.816, with 87% sensitivity (Sens.) and 71% specificity (Spec.), 73% positive predictive value (PPV) and 86% negative predictive value (NPV) for the differential diagnosis between AD and bvFTD. The logistic regression method with cross‐validation showed that the relationship between Attention and Orientation, Fluency, Language and Age, as independent variables, shared the importance to the diagnostic differentiation between bvFTD and AD (p <0.05; Table 2). The proposed logarithm was superior in discriminating bvFTD and AD than the VLOM ratio, with AUC of 0.865 (Figure 1) with 78% Sens., 85% Spec., 65% PPV and 91% NPV (Table 3).ConclusionThe ACE‐R achieved very good diagnostic power to discriminate AD and bvFTD in the present sample. Furthermore, the final ROC curves showed the superiority of the model proposed in relation to the analysis of the subscales individually. Further analysis in larger samples, with biomarkers or pathological confirmation, are necessary to confirm these findings.
Ten‐minute cognitive screening tool for mild cognitive impairment and prediction of pathological ß‐amyloid
Authors: Butler P. Monroe , Osik Jason , Schwartz Joel , Irzhevsky Victoria , Hansson Oskar , Brown Roland , Gao Feng , Moss Mark 
Published: December 2021

AbstractBackgroundEarly detection of cognitive decline is critical to improve outcomes for Alzheimer’s disease (AD) and other dementias. Screening for dementia risk during prodromal stages such as mild cognitive impairment (MCI) typically occurs through brief, bedside cognitive measures. While these tests readily detect dementia, the relative sensitivity/specificity for identifying MCI is variable and the ability to predict underlying AD is poor. Herein, we compare traditional cognitive screening tools with a novel ten‐minute battery to test predictive performance to discriminate MCI from normal cognition, and MCI with vs. without ß‐amyloid burden. The ten‐minute battery consisted of the Digit‐Symbol Substitution Test, Trail Making Tests A and B, and a delayed recall task.MethodClinical data were assessed from healthy aging and MCI patients from: (i) the AD Neuroimaging Initiative Study (ADNI), (ii) the Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably Study (BioFINDER), and (iii) the screening phase of aducanumab’s Phase 2 EVOLVE study (NCT03639987) before the trial was prematurely terminated. Datasets were used to build and validate the performance of a statistical model derived from outcome measurements extracted from the ten‐minute battery to predict imaging or fluid biomarker‐based readouts of pathological ß‐amyloid load. Feature selection and model performance evaluations were achieved in two independent ways: stepwise model building and coefficient penalization. Neuropsychological variables were z‐scored against normative data. Additional predictors included age and APOE genotype. Model performance were compared with a standardized screening tool (MMSE) to assess relative ability to differentiate MCI from normal cognition, and MCI with vs. without ß‐amyloid burden based on imaging/fluid biomarkers.ResultThe findings showed greater sensitivity and specificity achieved with the ten‐minute battery relative to the standard cognitive screening tools for MCI detection (AUC‐ROC 0.98 vs. 0.78) and Aß prediction (AUC‐ROC 0.81 vs. 0.58), respectively. Of striking interest, removing APOE as a predictor markedly reduced accuracy in the traditional, but not in the novel ten‐minute battery.ConclusionThese preliminary data suggest that the novel combination of neuropsychological tests performed in ten‐minutes may serve as a compact, more sensitive and specific screening tool to identify patients with MCI with Aß burden compared to traditional screening batteries.