bluuebunny/crossref_metadata_2025_split huggingface dataset:
Posterior cortical atrophy syndrome: Asian study
Authors: Pai Ming‐Chyi , Likitjaroen Yuttachai , Lim Levinia , Ryoo Nayoung , Chiu Pai‐Yi , Hsu Jung‐Lung , Suzuki Kyoko , Chang Ya‐Ting , Kandiah Nagaendran , Kim SangYun 
Published: December 2020

AbstractBackgroundPosterior cortical atrophy (PCA) syndrome is a rare clinical syndrome occurred in the first several years of several progressive neurodegenerative diseases, of which the manifestations are mainly confined to the impairments in the functions of posterior cerebral cortices. The underlying pathomechanisms may include Alzheimer‘s disease, Lewy body disease, corticobasal degeneration and prion disease. A consensus of the diagnostic procedures for PCA syndrome has been published in 2017, based on cases from Western countries.MethodWe invited behavioral neurologists from five Asian countries to join the study and followed the suggestions of the paper published by Scott and Crutch (2019). Each research participant investigated their cases and submitted the results to chief principal investigator. Data were analyzed and compared with those of Western countries. Moreover, a workshop was held at Tainan, Taiwan in the winter of 2019 for all investigators to reach consensus on the results.ResultA total of 63 cases (26 male) from Taiwan, Thailand, Singapore, Korea and Japan were included. Their mean age was 64.48 (SD 8.26) years, onset age 59.7 (8.37) years, and education 10.76 (5.43) years. 94.9% of the findings of brain MRI and 86.8% of the brain SPECT supported a diagnosis of PCA syndrome. As compared with the results of Crutch et al (2017), the Asian data showed more often in space perception deficits, simultanagnosia, construction dyspraxia, oculomotor apraxia, dressing apraxia, optic ataxia, alexia, left/right disorientation, acalculia, agraphia, finger agnosia, limb rigidity, onset before 65, prominent early memory disturbance, and prominent early language disturbance, while less often in hallucination. The PCA‐plus cases (n=12), as defined by 2017 consensus, were older and more in favor of Lewy body disease. Meanwhile, PCA‐plus cases had more dressing apraxia and more alexia. PCA patients with Parkinsonism had more optic ataxia, dressing apraxia, left/right disorientation, acalculia, more relative spared memory impairment and less relative spared executive dysfunction.ConclusionThe public awareness of PCA syndrome is inadequate, which may delay its timely diagnosis. The differences in clinical features between Asian and Western countries need further investigation.
GMP‐1 and its analogues bind Cu2+ and Zn2+ and protect neurons against amyloid beta toxicity
Authors: Winblad Bengt , Pavlov Pavel F. , Kumar Rajnish 
Published: December 2020

AbstractBackgroundAlzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. Recently, we have shown that GMP‐1, a 2‐(methoxymethyl)pyrimido[1,2‐a] benzimidazol‐4‐ol protects mitochondrial function in drosophila and mice models of AD, improved memory and behavior indicating neuroprotective effect of GMP‐1 treatment. Here, we have found that GMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain.MethodUsing UV/Vis Spectroscopy we have determined specificity and stoichiometry of metal binding to GMP‐1. To investigate GMP‐1 impact on metal‐dependent enzymatic reactions we have used proteolysis assay with Zn2+‐dependent collagenase and Cu2+‐dependent cytochrome c oxidase assay. Time course thioflavin T fluorescence was used to assess the effect of GMP‐1 and its analogues on amyloid beta fibrillization in the presence of Cu2+. The effect of GMP‐1 and its analogues on ROS production and viability of differentiated SH‐SY5Y cells in the presence of amyloid beta and metals was evaluated using DCFDA and TUNEL assay, respectively.ResultGMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP‐1 does not inhibit metal‐dependent enzymatic reactions. Binding of Zn2+ and Cu2+ by the GMP‐1 is weaker than the 8‐hydroxyquinoline scaffold compound clioquinol (CQ) previously tested in AD clinical trials. However, GMP‐1 affects Cu2+‐dependent Ab fibrillization as well as oxidative damage and viability of SH‐SY5Y cells upon addition of Cu2+ and Ab.ConclusionOur data provide new insight on GMP‐1 as Zn2+ and Cu2+ specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.
Clinical study on intracranial venous system lesions and cognitive impairment
Authors: Qian Hairong 
Published: December 2020

AbstractBackgroundVascular cognitive impairment and Alzheimer's disease are the two major causes of cognitive impairment. Previous studies have focused on the relationship between arterial‐derived diseases and/or small cerebrovascular disease and cognitive impairment, but the cognitive impairment caused by intracranial venous system lesions has received less attention. Intracranial venous system lesions include venous sinus thrombosis, deep vein thrombosis, cortical venous thrombosis, chronic subdural hematoma, dural arteriovenous fistula, venous collagen disease, etc. The pathogenesis and clinical characteristics of cognitive impairment caused by different lesions are different.Method48 cases of intracranial venous lesions including venous sinus thrombosis, deep vein thrombosis, cortical venous thrombosis and dural arteriovenous fistula admitted to the department of neurology of the sixth medical center of PLA general hospital were retrospectively analyzed.Result24 cases of venous thrombosis related lesions were male and 14 were female, aged 18‐80 years, including 20 cases of venous sinus thrombosis, 8 cases of deep venous thrombosis, 10 cases of cortical venous thrombosis, with 8 cases of acute cognitive impairment. There were 10 cases of dural arteriovenous fistula, with 6 cases of cognitive impairment. The main clinical manifestations of cognitive impairment were decreased execution speed, forgetfulness, dysarthria, mental changes, urinary incontinence and gait abnormalities. The patients with subcortical white matter, thalamus and other white matter areas involved have more obvious cognitive impairment, while those with mild cortical involvement have relatively less cognitive impairment. The incidence of cognitive impairment of older people was higher than that of younger people, and the incidence was higher in those with significant white matter damage.ConclusionCognitive impairment caused by intracranial venous system lesions are tightly linked with cerebral white matter lesions in addition to lesions of key parts of brain damage, which may be related to increased intracranial pressure and other factors caused by venous reflux obstacle. Cognitive impairment with venous system lesion deserves more clinical attention and may provide more insights into the causes of dementia.
The IMI‐EU H2020 project MOPEAD: Outcome of different screening methods to identify MCI/early AD
Authors: Winblad Bengt , Jessen Frank , Kramberger Milica G. , Visser Pieter Jelle , Rodrigo Adrián , Jamilis Laura , Rodriguez‐Gomez Octavio , Sannemann Lena , Zwan Marissa D. , Bon Jaka , Johansson Gunilla , Nelvig Anders , Haglund Anders , Jelic Vesna , Campo Laura , Wimo Anders , Boada Mercè , Consortium MOPEAD 
Published: December 2020

AbstractBackgroundThe MOPEAD project (Rodríguez‐Gómez O et al, Alzheimers Dement 2019) aims to explore different ways to stimulate early diagnosis of Alzheimer Disease (AD). Four innovative pre‐screening strategies are pursued to identify individuals at high risk for mild cognitive impairment (MCI) or early AD. We aimed to validate positive results from these pre‐screening strategies by performing a full clinical evaluation of the patients at specialized memory clinics.MethodIndividuals with a positive pre‐screening result were referred to one of the five participating memory clinics in Ljubljana (Slovenia), Barcelona (Spain), Stockholm (Sweden), Amsterdam (Netherlands), and Cologne (Germany). A harmonized clinical evaluation including physical, neurological, neuropsychological and functionality assessment was performed in these centers as well as MRI neuroimaging and optional cerebral spinal fluid sampling. Based on the result of this evaluation, we estimated the positive predictive value (PPV) of the different pre‐screening strategies, as the proportion of patients with MCI or AD among all referred individuals.ResultA total of 402 individuals with a positive pre‐screening result were evaluated: 91 from a web‐based pre‐screening tool, 161 from an open house initiative, 94 patients from a primary care‐based pre‐screening, and 56 patients identified at diabetes clinics. The number confirmed cases of MCI/AD and PPV were 49(53.8%), 82(50.9%), 58(61.7%), and 47(83.9%) respectively. Within pre‐screening strategy, the results varied greatly between participating countries. Thus, PPV for the web‐based tool was 0% in Germany, and over 70% in Spain and Sweden. Similarly, PPV for the open house initiative was 3% in the Netherlands, but over 95% in Spain. Germany and the Netherlands showed the lowest PPVs (20% and 17% respectively) for the primary care‐based strategy, whereas the all remaining countries had PPVs well over 70%. Country‐specific PPVs estimates in the diabetes clinic strategy were not very reliable due to the small number of patients evaluated.ConclusionWe were able to confirm more than half of patients with a positive result in all four pre‐screening strategies being evaluated. However, our results suggest that despite the harmonization efforts, PPVs of these innovative pre‐screening strategies are highly dependent on the study site.
Small vessel disease neuroimaging markers contribute robustly and independently to longitudinal cognitive decline in older adults
Authors: Bown Corey W. , Khan Omair A. , Liu Dandan , Cambronero Francis E. , Moore Elizabeth E. , Jindal Ria , Pechman Kimberly R. , Schrag Matthew , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2020

AbstractBackgroundCerebral small vessel disease (SVD) is visible on brain magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs), perivascular spaces (PVS), cerebral microbleeds (CMBs), and lacunes. This study expands our prior cross‐sectional work and examines how these four markers contribute to longitudinal cognitive trajectory to assess whether these markers represent common versus unique pathways of injury.MethodsVanderbilt Memory and Aging Project participants free of baseline clinical stroke and dementia (n=327, 73±7 years, 41% female) completed multimodal 3T brain MRI to quantify WMHs, PVS, CMBs, and lacunes at baseline and neuropsychological assessment at multiple time points (baseline, 18‐month, 3‐year, 5‐year). Linear mixed‐effects regression models related each baseline SVD marker to longitudinal neuropsychological trajectory through interaction with follow‐up time, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein E‐e4 status, and intracranial volume.ResultsMean follow‐up time was 3.9±1.1 years. Increases in each SVD marker related to faster episodic memory decline (p‐values≤0.04). Increased lacunes (p=0.04), WMHs (p≤0.008), and CMBs (p≤0.001) related to information processing speed decline. Increased WMHs (p=0.02) and CMBs (p=0.03) related to executive function decline. Increased WMHs related to language decline (p=0.02). Increased CMBs related to visuospatial decline (p=0.03). In combined models simultaneously considering multiple statistically significant SVD markers in relation to cognitive outcomes, WMHs independently predicted faster information processing speed (p=0.03), executive function (p=0.05), and episodic memory decline (p=0.02) beyond all other SVD biomarkers. CMBs independently predicted information processing speed decline beyond lacunes and WMHs (p‐values≤0.04). PVS independently predicted episodic memory decline beyond lacunes and CMBs (p=0.03).ConclusionsIncreased SVD, including PVS, CMBs, lacunes, and especially WMHs, was associated with faster longitudinal cognitive decline. In competitive models, WMHs consistently predicted faster decline in multiple domains despite inclusion of other significant SVD predictors. In a subset of models, CMBs and PVS independently predicted faster longitudinal cognitive decline yet lacunes did not. Thus, WMHs, CMBs, and PVS may each reflect a unique pathway of injury whereas lacunes may not. Funding: F31‐AG066358, T32‐AG058524, Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373.
Abnormal brain structure mediates the association between ApoE4 and slow gait among patients with pathological cognitive impairment: Results from the Ontario Neurodegenerative Research Initiative
Authors: Sakurai Ryota , Faria‐Pieruccini Frederico , Dilliott Allison Ann , Hegele Robert , Tartaglia Carmela , McLaughlin Paula , Binns Malcolm , Blue Korbin , Cornish Ben , Sunderland Kelly M , Beaton Derek , Haddad Seyyed M.H. , Tan Brian , Swartz Richard H. , Kwan Donna , Masellis Mario , Ramirez Joel , Roberts Angela C , Black Sandra E. , Symons Sean , Strother Stephen C , Borrie Michael , Pasternak Stephen H. , Freedman Morris , Bartha Robert , Lang Anthony , Munoz Douglas , McIlroy Bill , Montero‐Odasso Manuel 
Published: December 2020

AbstractBackgroundPresence of at least one copy of the polymorphic apolipoprotein E ε4 allele (ApoE4) increases the risk of impairments of gait performance, particularly in elderly individuals with cognitive impairment or at risk of dementia; however, its underlying neural mechanism are unclear. This study examined the association among ApoE4, gait performance, and brain structural changes among elderly individuals with cognitive impairment.MethodOverall, 269 older adults with Alzheimer’s disease, cerebrovascular disease with and without cognitive impairment, and mild cognitive impairment were included from the Ontario Neurodegenerative Disease Research Initiative, who were either ApoE4 carriers (n=98) or non‐ApoE4 (n=171) carriers. Gait speed was measured using an electronic walkway; speed <1 m/s was defined as slow gait. Participants were stratified into four groups according to the presence of at least one copy of ApoE4 and slow gait. Region of interest volumes were derived by automated segmentation using a 3.0T magnetic resonance imaging system.ResultAmong ApoE4 carriers, 65 (24.2%) participants had slow gait. ApoE4 carriers with slow gait showed significantly higher burden of white matter hyperintensities compared with ApoE4 carriers without slow gait. Moreover, they had significantly lower hippocampal volume and greater total sulcal cerebrospinal fluid volume compared with non‐ApoE4 carriers with slow gait. These differences remained significant despite controlling for covariates (e.g., demographic and clinical characteristics, including participant type).ConclusionOur results suggest that brain structural changes, attributable to Alzheimer’s pathology, may mediate the association between ApoE4 and slow gait among elderly individuals with pathological cognitive impairment.
The relationship of a white matter hyperintensities rating scale and cognition among Mexican Americans
Authors: Vintimilla Raul , King Kevin , Braskie Meredith N. , Yaffe Kristine , Toga Arthur W. , Johnson Leigh Ann , Hall James R. , O'Bryant Sid 
Published: December 2020

AbstractBackgroundWhite matter hyperintensities (WMHs) are a common manifestation of white matter damage. Mexican Americans (MAs) comprised 65% of the Latino population in the US, and they suffer a higher burden of cardiovascular risk factors that can influence the prevalence of WMHs. The purpose of this study was to examine the relationship between a WMHs rating scale and cognitive functioning in a sample of MA elders. This study extends the limited literature about WMHs and cognition in this underserved population.MethodWe studied 361 (266 females, mean age 61.86) cognitively normal MAs from the Health and Aging Brain Among Latino Elders Study (HABLE). MPR and Flair images were obtained using a 3T MRI system (Skyra, Siemens Healthineers). Quantification of WMHs was performed according to the King rating scale, which is based on the lesion size regardless of location. A one‐way ANOVA was conducted to examine the association of the King rating scale (low versus high scores) with the MMSE, logical memory I and II, Trails B, FAS, digit symbol substitution, and digit span scores. Age, sex, and education were entered as covariates in the model.ResultSubjects with low WMHs rating scale scores (grades 0 and 1 on the King scale) differ from subjects with high WMH rating scale scores (grades 2 and 3 on the King scale) in tests of global cognition and executive function. MMSE and Trails B mean scores were significantly lower in the high WMH rating scale group when compared with the low rating scale group. ANOVA revealed a difference between groups for MMSE, F(1,359) = 8.75, p = 0.003, and Trails B, F(1,335) = 20.73, p < 0.001, after adjusting for demographics. There was no association with other cognitive tests.ConclusionOur findings suggest a relationship between global cognition and executive function measures with WMHs, independent of age, sex, and education, among older non‐demented MAs.
Comparing versions of the memory binding test: Predictive validity for incident aMCI and incident dementia
Authors: Mowrey Wenzhu , Lipton Richard B. , Katz Mindy J. , Ramratan Wendy S. , Loewenstein David A. , Buschke Herman 
Published: December 2020

AbstractBackgroundThe Memory Binding Test (MBT) Version 1 demonstrated significant predictive validity for incident amnestic MCI (aMCI) and incident dementia. Version 2 of the MBT was developed to be briefer because brevity is essential for screening. Herein we aimed to compare the two versions in terms of predictive validity for aMCI and dementia, separately.MethodAs sub‐studies of the Einstein Aging Study (EAS), the two MBT versions were administered to two independent study samples between May 2003 and December 2007 at baseline, and these participants were followed up to Jan 2017 (For differences in versions see Table 1). The EAS enrolls a systematically recruited community sample of adults age over 70. The two versions were evaluated in parallel using the same methodologies. We evaluated a range of cut‐scores on the MBT score of choice, the Total Items in the Paired condition (TIP), including the empirical optimal cut‐score which maximized the sum of sensitivity and specificity from the cross‐sectional discriminative analyses. The predictive validity was assessed by Kaplan‐Meier curves, log‐rank tests and Cox regressions.ResultPredicting incident aMCI: Both versions were strong predictors of incident aMCI (Table 2): For the empirical optimal scores for TIP, hazard ratio (HR)=2.33, 95% CI: (1.26, 4.29), p=.007 for Version 1, HR=3.38, 95% CI: (1.09, 10.5), p=0.04 for Version 2; for a range of TIP scores (17−22): HR range: 2.27−6.07, p ≤ .01, for Version 1, and 2.67−5.91, p≤.04 for Version 2. Predicting incident dementia: Both versions were strong predictors of incident dementia (Table 3): For the empirical optimal scores for TIP, HR=8.32, 95% CI: (3.51, 19.7), p<.0001 for Version 1, HR=9.30, 95% CI: (3.43, 25.2), p<.0001 for Version 2; for a range of TIP scores (17−23): HR range: 3.09−8.32, p ≤ .003, for Version 1, and 6.40−9.30, p<.0001 for Version 2.ConclusionThe predictive validity for incident aMCI and incident dementia was strong and similar for the two versions of the MBT based on the overlapping confidence intervals. These results strongly support the hypothesis that poor performance on memory binding is an important marker for the early detection of aMCI and dementia.
Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease: A phase 2, double‐blind, randomized, placebo‐controlled trial
Authors: Turner Raymond Scott , Hebron Michaeline , Lawler Abigail , Mundel Elizabeth , Yusuf Nadia , Starr Nathan , Pagan Fernando , Torres‐Yaghi Yasar , Shi Wangke , Mulki Sanjana , Ferrante Dalila , Matar Sara , Liu Xiaoguang , Esposito Guiseppe , Berkowitz Frank , Jiang Xiong , Ahn Jaeil , Moussa Charbel E‐H 
Published: December 2020

AbstractBackgroundThe goal is to assess the safety, tolerability, and pharmacokinetics of nilotinib, and measure biomarkers in participants with mild to moderate dementia due to Alzheimer’s disease. We hypothesized that nilotinib is safe and detectable in cerebrospinal fluid. Nilotinib may alter disease biomarkers and potentially slow clinical decline.MethodThis is a single‐center, phase 2, randomized, double‐blind, placebo‐controlled study. Of 117 individuals approached, 13 declined, 51 were excluded, 51 were screened, and 37 were randomized 1:1 to placebo or nilotinib groups. The Alzheimer’s disease diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg vs matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg vs placebo for another 26 weeks.ResultOf the 37 individuals enrolled, 27 were women (73%), and the mean (SD) age was 70.7 (6.48) years. Nilotinib was safe and well‐tolerated, although more adverse events, particularly mood swings, were noted at the 300 mg dose (70.6%) vs placebo (0%) groups (p<.01). In the nilotinib group, amyloid burden was reduced in the temporal (‐0.08, 90% CI, ‐0.21 to ‐0.01, p=.04) and frontal lobes (‐0.19, 90% CI, ‐2.29 to ‐0.08, p<.001) compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months (566ng/ml, 90% CI, 135 to 1018, p=.02) and Aβ42 was reduced at 12 months (73.9 ng/ml, 90% CI, 14.3 to 137.9, p=.02) in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (‐27%) at 12 months and phospho‐tau181 was reduced at 6 months (‐31.6%) and 12 months (‐39.6%) in the nilotinib group.ConclusionNilotinib is safe and well‐tolerated, and achieves pharmacologically relevant brain concentrations. Biomarkers of Alzheimer's disease were altered in response to nilotinib treatment. These data support a larger, multi‐center, phase 3 study to determine the safety and efficacy of nilotinib in Alzheimer’s disease. ClinicalTrials.gov NCT02947893.