bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atypical case of VV1 Creutzfeldt‐Jakob disease subtype
Authors: Carrasco Adrianna , Okhravi Hamid 
Published: December 2020

AbstractBackgroundCreutzfeldt‐Jakob disease (CJD) is rare form of rapidly progressive dementia due to the presence of abhorrent prion protein and affects 1‐1.5 cases per million per year.1 An estimated 85% of these cases are sporadic, and the remaining 5‐15% develop CJD from inherited mutations of the prion gene.2 Sporadic CJD (sCJD) is further subdivided into six subtypes based on genetic polymorphisms, with the VV1 subtype occurring at a rate of 1 case per one‐hundredth million population per year. 3 These subtypes have been shown to correlate with age of onset, clinical course, disease features and duration4,5. Clinical characteristics of the VV1 subtype has been reported to show, early age of onset (39 years), disease duration of 15 months, elevated 14‐3‐3 and total tau in the CSF, absent PSWCs on electroencephalography (EEG), and magnetic resonance imaging (MRI) hyperintensities in the cerebral cortex with usual negative signal in the basal ganglia or thalamus.6,7,
MethodWe present an atypical case of the rarest VV1 sCJD subtype. Contrary to current data on VV1, our patient presented with an unusual age at onset (63 years), longer disease duration (20 months), and positive signal in the basal ganglia on MRI. The real‐time quaking‐induced conversion (RT‐QuIC) was negative.ResultPresenting clinical symptoms included paranoid thoughts and agitation, progressing with rapid memory decline, prosopagnosia, and later development of myoclonus and mutism. Other findings showed positive antithyroid peroxidase antibodies (anti‐TPO), absent PSWCs on EEG, positive 14‐3‐3 and elevated tau on CSF. High dose steroid therapy treatment was administered based on positive anti‐TPO findings, which failed to illicit any improvement and the patient continued to decline.ConclusionTo our knowledge, only two confirmed cases with the VV1 subtype, including our patient, have been reported to have a negative result on RT‐QuIC.8 This may indicate a unique characteristic to VV1 and aid in the diagnostic work up in suspected sCJD cases with this finding. However, given the rarity of our patient’s subtype, and the relatively novel RT‐QuIC, current data is based on a small number of cases and larger cohorts of confirmed VV1 cases with RT‐QuIC testing need to be reported.
Vasogenic edema in the frontostriatal tract and the anterior limb of the internal capsule predict cognitive decline in Alzheimer disease
Authors: Wang Qing , Chen Gengsheng , McKay Nicole Sarah , Gordon Brian A. , Hassenstab Jason , Morris John C. , Morris John C. , Benzinger Tammie L.S. , Wang Yong 
Published: December 2020

AbstractBackgroundWhereas the gray matter has long been regarded by neuroscientists as the major locus of cognitive function, white matter (WM) structures of the brain are increasingly recognized as critical for cognition. In particular, the frontostriatal tract (FST) and the anterior limb of the internal capsule (ALIC) play important roles in cognition function. In order to noninvasively quantify WM integrity, inflammation, and edema, a diffusion‐based MRI method, neuro‐inflammation imaging (NII), has recently been developed and validated. Specifically, NII‐derived extracellular water fraction (NII‐EWF) has been used as a surrogate biomarker of WM vasogenic edema in Alzheimer Disease (AD) (Figure 1). This study aimed to examine: (1) whether NII‐EWF in the FST and the ALIC is associated with cognitive ability; (2) whether the baseline NII‐EWF in the FST and the ALIC predict the cognitive decline in AD.Method172 Participants (121 amyloid negative healthy controls, 31 amyloid positive individuals w/ normal cognition and 20 individuals diagnosed as AD with a CDR of 0.5) enrolled in ongoing studies at the Knight ADRC at Washington University in Saint Louis underwent NII measures and a test battery of cognitive tests. Our measure of cognitive ability was Trail Making test, which is a subtask within our cognitive battery that assesses visual attention and working memory abilities. NII was acquired with multi‐b value scheme (bmax =1400s/mm2 and 25 directions). A random coefficient model was used to assess correlations between NII‐EWF and cognitive measures and to assess whether the baseline NII‐EWF is predictive of cognitive decline.ResultThe significant correlations between NII‐EWF and cognitive ability has been observed in both the FST (Figure 2A) and the ALIC (Figure 2B). The measure of NII‐EWF in both tracts has been found to be significantly predictive of the rate of cognitive decline (Figure 3).ConclusionOur findings suggest that NII‐EWF could be used as a predictor for cognitive decline in preclinical and early symptomatic AD. Given that the measure is acquired without using contrast agent and radioactive tracer, NII holds great promise as an accessible measure for quantifying WM pathologies and investigating their roles in the cognitive decline in AD.
Microglial activation indexed by [11C]PBR28 is associated with synaptic depletion in the Alzheimer’s disease spectrum
Authors: Benedet Andréa Lessa , Ashton Nicholas J , Pascoal Tharick A. , Brinkmalm Ann , Nilsson Johanna , Kvartsberg Hlin , Mathotaarachchi Sulantha , Savard Melissa , Therriault Joseph , Tissot Cécile , Chamoun Mira , Blennow Kaj , Zetterberg Henrik , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundA large body of evidence supports the link between neuroinflammation and neurodegenerative conditions, including Alzheimer’s disease (AD). In AD, high expression of immune mediators have been associated with increased microglial reactivity. Several mechanisms were proposed to explain the relationship between microglial activation and synaptic plasticity/dysfunction. However, it remains unresolved whether neuroinflammation has a primary rather than a reactive contribution to synaptic deficits. Thus, in vivo human studies are extremely important to help deciphering the immediate causes of synaptic degeneration and the role of neuroinflammation in this context. Here we investigated, in the AD spectrum, the association between cerebrospinal fluid (CSF) biomarkers of synaptic depletion and microglial activation, indexed by [11C]PBR28 PET, using data from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort.Method70 participants (15 young controls, 27 normal controls (CN), 20 mild cognitive impairment (MCI) and 8 AD) were evaluated with cross‐sectional CSF biomarkers and [11C]PBR28 PET. The CSF biomarkers were quantified by in‐house immunoassays for neurogranin and neuromodulin (GAP‐43), whereas SNAP‐25 and synaptotagmin‐1 (SYT1) were quantified using an immunoprecipitation mass spectrometry method. Linear models were applied to evaluate group differences in CSF biomarker concentrations, adjusting for age and sex. Voxel‐wise linear regressions examined the association between CSF‐ and PET‐based measures. ROI‐based average SUVR was used to test the correlation between CSF biomarkers and [11C]PBR28SUVR.ResultAD participants had higher concentrations of CSF synaptic biomarkers compared with CN. Findings at the voxel level showed a good agreement between CSF biomarkers (Figure 1), with increased CSF biomarker levels being associated with greater [11C]PBR28uptake in the frontal, posterior cingulate, temporal and inferior‐parietal cortices. Amongst the biomarkers tested, CSF SNAP‐25 biomarkers showed the strongest correlations with [11C]PBR28 (RSNAP25_total=0.69; RSNAP25_long=0.67; Figure 2). Further results will indicate the relationship between sTREM2 and [11C]PBR28.ConclusionResults support a link between neuroinflammation and synaptic degeneration. Although causality could not be inferred, the findings corroborate a detrimental effect of neuroinflammation on synapses at later disease stages. Finally, the results also support CSF SNAP‐25as a biomarker to track synaptic dysfunction and degeneration in AD pathophysiology.
Proteomic similarities in Alzheimer’s disease and epilepsy brains highlight the important role of tau
Authors: Pires Geoffrey , Leitner Dominique , Kanshin Evgeny , Askenazi Manor , Friedman Daniel , Devinsky Orrin , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor 
Published: December 2020

AbstractBackgroundAlzheimer's Disease (AD) patients are more likely to experience epileptic seizures, and cognitive impairment is a frequent comorbidity in patients with epilepsy. Emerging findings indicate a common link between epilepsy and AD, however our understanding of the pathological changes shared between these two diseases is limited. Therefore, our aim was to determine whether there are common protein changes associated with both epilepsy and AD using an unbiased proteomics approach.MethodWe used label‐free mass‐spectrometry to quantify protein differences in the human epileptic hippocampus (epilepsy vs controls; n=14/group) and compared these results to differentially expressed proteins in AD generated by a meta‐analysis of the 10 most comprehensive AD proteomics studies.Result777 proteins were significantly altered in the hippocampus in epilepsy. A significant proportion of these protein changes were also observed in AD (263/777 similar protein changes; p<0.0001). Proteins altered in both epilepsy and AD were predominantly excitatory neuron specific proteins (enrichment p<0.0001). Network analysis showed that proteins altered in both epilepsy and AD were most significantly involved in remodelling of epithelial adherens junctions (17/57 proteins, p=2.37x10‐16), clathrin‐mediated endocytosis signalling (21/160 proteins, p=2.98x10‐12) and phagosome maturation (17/114 proteins, p=4.81x10‐11), suggesting that the endosomal/lysosomal system dysfunction is a key factor for both epilepsy and AD pathogenesis. Shared protein alterations also indicated a decrease in synaptic proteins (enrichment p=6.52x10‐21), confirming that synapse loss or dysfunction is a common feature of both diseases. Interestingly, tau was identified as the most significant upstream regulator of proteins altered in both epilepsy and AD (p=4.53x10‐36). Furthermore, there was a significant overlap between proteins altered in both epilepsy and AD and proteins present in our recently generated phosphorylated tau interactome (32/125 pTau interactome proteins, p<0.0001). Together, this suggests that tau may have an important pathological role in both epilepsy and AD.ConclusionAD and epilepsy have many common protein changes in the brain. Tau may have an important role in mediating many of these common protein changes in AD and epilepsy.
Idiopathic normal pressure hydrocephalus as a novel window for Alzheimer’s disease
Authors: Leinonen Ville , Rauramaa Tuomas , Malm Tarja , Luikku Antti J. , Junkkari Antti , Koivisto Anne M. , Hiltunen Mikko 
Published: December 2020

AbstractBackgroundIdiopathic normal pressure hydrocephalus (iNPH) is characterized by gait apraxia, cognitive deterioration and urinary incontinence. Differential diagnosis with other neurodegenerative disorders like Alzheimer’s disease (AD) can be challenging. Furthermore, AD‐related brain pathology is frequent comorbidity and can predict subsequent clinical AD. Here we aim to describe a diagnostic and treatment protocol of iNPH optimized for prediction of clinical outcome, especially future AD, and research value on neurodegenerative diseases.MethodSince 1993 until the end of 2019, 990 patients with possible NPH underwent diagnostic right frontal cortical brain biopsy during intraventricular pressure measurement or CSF shunt surgery. Brain biopsies are routinely evaluated by immunohistochemistry against amyloid‐β (Aβ) and hyperphosphorylated tau (HPτ). Patients are follow‐up until death to gain all available outcome data.ResultWe have found an increased occurrence of clinical AD (up to 25%) in previously shunted iNPH patients as compared with rate of dementia in general population (15%). Cortical biopsy with Aβ pathology (seen in around 40% of all biopsies) during shunt insertion was the best predictor of future comorbid AD. These patients would be ideal for clinical trials of potential preventive therapies.ConclusionDiagnostic work‐up of NPH offer large amount of CSF, repeated brain imaging and cognitive testing. Most importantly, CSF shunt surgery open an ethically sustainable window to living brain including various comorbid neuropathological findings by chance. Along with optimized patient care, Kuopio iNPH work‐up (Figure) offer unique platform for biomarker discovery and validation.
Biopsychosocial determinants of cognitive impairment in a representative sample of English older population
Authors: Cadar Dorina , Abell Jessica , Steptoe Andrew 
Published: December 2020

AbstractBackgroundTo investigate various biopsychosocial determinants of cognitive health in later life, using the neuropsychological battery of tests administered in the Harmonised Cognitive Assessment Protocol Sub‐Study of the English Longitudinal Study of Ageing (ELSA‐HCAP).MethodELSA‐HCAP is a neuropsychological sub‐study of 1273 participants completed in 2018, as part of an international research collaboration designed to better measure and identify neurocognitive disorders in representative population‐based samples. ELSA‐HCAP was administered to participants across all range of cognitive abilities, but we oversampled those identified as having low cognitive scores in the most recent ELSA waves. The HCAP respondent interview covered a broad range of cognitive domains (memory, language, executive function, psychomotor speed, problem‐solving, and numeracy) known to be affected by the ageing process. We also linked ELSA‐HCAP with the previous measures collected across ELSA waves, including biomarkers, psychosomatic and social economic information of these individuals collected in ELSA main waves 4 years before in 2016. We used Structural Equation Modelling (SEM) to estimate direct and indirect associations between Apolipoprotein (APOE) e4 status, education, wealth, inflammatory markers, chronic conditions, quality of life, depression and overall cognitive performance based on multiple domains, as well as the potential mediating effects.ResultHigher levels of education and increased quality of life were protective of the overall cognition, independent of the level of wealth. Depression and chronic conditions were strong predictor of cognitive impairment. We also found significant effects of age and sex, with women showing a slight cognitive advantage compared to men. We did not found an effect of APOE4 allele on cognitive impairment in this study. We find a pathway between higher levels of education leading to higher wealth, which impacting the number of chronic conditions and indirectly impacting on the overall cognition. We also found an indirect effect of inflammatory markers via chronic conditions and depressive symptoms.ConclusionIn a subset sample of a nationally representative sample of English population, we found that specific psychosocial risk factors were associated with the overall cognition in later life. Biological inflammatory markers were indirectly associated with overall cognition via depressive symptoms and chronic conditions pathways.
Effect of comprehensive, individualized, person‐centered management on antidepressant usage in advanced Alzheimer’s persons in a 28‐week, randomized, controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Torossian Carol , Saad Muhammad , Dafflisio Gianna , Vedvyas Alok , Reisberg Barry 
Published: December 2020

AbstractBackgroundWe published results of a clinician‐blind, parallel‐group study of Comprehensive, Individualized, Person‐Centered Management (CI‐PCM) in moderate‐to‐severe, community‐residing, Alzheimer’s persons (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). CI‐PCM intervention subjects (n=10) showed 967% greater global improvement than subjects randomized to Usual Community Care (UCC, n=10). Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted (BEHAVE‐AD‐FW) total scores showed significant benefit in the intervention group at week 28 (p<0.05). Kettunen asserts, (Eur J Clin Pharmacol, 2018), “Among persons with AD, antidepressants are used for treatment of BPSD…their effectiveness in this indication is modest.” Casey states, (Pharmacy & Therapeutics, 2015), “Antidepressants…are widely used in dementia for depressed mood, anxiety, agitation, and apathy.” Bui recommends, (Cochrane for Clinicians, American Family Practice, 2012), “…antidepressants should be used [in patients with dementia] only if all other nonpharmacologic interventions for neuropsychiatric symptoms are unsuccessful.” Herein, we examine the effect of the CIPCM program on antidepressant usage and the Behavioral and Psychological Symptoms of Dementia (BPSD) as measured with the BEHAVE‐AD‐FW.MethodInvestigators blinded to treatment group assignment reviewed subject charts (N=20), for antidepressant usage, and BEHAVE‐AD‐FW total and category F scores, which measure tearfulness and depressed mood. Costs of antidepressant usage, and BEHAVE‐AD‐FW total, and category F scores for each group were compared.ResultThere were no significant differences in antidepressant usage or BEHAVE‐AD‐FW total or category F scores between groups at baseline. At all study visits, 50% of subjects in each group took antidepressants. At week 28, community physicians prescribed CI‐PCM subjects less or the same dose of antidepressants, and prescribed comparator subjects the same or greater doses, and additional antidepressants. BEHAVE‐AD‐FW category F scores for UCC comparators were persistently elevated and worsened by week 28, whereas, CI‐PCM group scores improved to zero, indicating no depressive symptoms.ConclusionFor CI‐PCM subjects, total BPSD symptomatology declined significantly (p<0.05), antidepressant usage declined, and tearfulness and depressed mood resolved, by week 28. In contrast, UCC subjects increased antidepressant usage, paid 4.42 times more for antidepressants, and had worsening of behavioral disturbances and depressive symptoms. CI‐PCM is an effective nonpharmacologic intervention that reduces antidepressant usage in advanced AD persons with BPSD.
PET differences between cognitively unimpaired stable and declining subtypes: Multiple approaches show higher amyloid and tau among those with sub‐clinical cognitive decline
Authors: Koscik Rebecca L. , Jonaitis Erin M. , Betthauser Tobey J. , Hermann Bruce P. , Clark Lindsay R. , Mueller Kimberly D. , Du Lianlian , Birdsill Alex C. , Chin Nathaniel A. , Christian Bradley T. , Johnson Sterling C. 
Published: December 2020

AbstractBackgroundBiomarker‐related cognitive decline begins well before mild cognitive impairment (MCI), yet detecting subclinical decline is challenging. The presence of differences in AD biomarkers between cognitively unimpaired stable and declining subtypes (CU‐S and CU‐D) might indicate validity evidence for CU‐D criteria. This study examines whether brain amyloid and tau biomarkers differed across concurrent determinations of CU‐S, CU‐D and MCI/Dementia statuses using consensus conference and algorithm‐based cognitive statuses.MethodWRAP participants with >=3 Preclinical Alzheimer’s Cognitive Composite (PACC3) scores, free of dementia at baseline PACC3, and >=1 positron emission tomography (PET) [C‐11]Pittsburgh Compound B (PiB) scan were included (n=269); n=215 also had [F‐18]MK‐6240 tau scans. The mean(sd) age at last cognitive assessment was 67.0(6); PET PiB and MK scans occurred within means of 1.6(2) and .8(1.1) years of cognitive assessment. Cognitive statuses of CU‐S, CU‐D, and MCI/Dementia were assigned via consensus conference review. Six algorithm‐based cognitive status indicators were also examined (3 PACC3 composite‐based and 3 based on combinations of individual tests; for all, CU‐D range = centiles [4, 16), or ∼1 to 1.75 SD below expected; see Table 1). We compared continuous Global PiB DVR and MK‐6240 regional SUVR outcomes across cognitive statuses using analysis of variance and proportions PiB+ (Global PiB DVR>1.2) across cognitive statuses using Fisher’s exact tests. Significant omnibus tests (p<.05) were followed with pairwise comparisons.ResultTable 1 shows cognitive statuses by determination method. All omnibus tests comparing biomarkers across CU‐S, CU‐D and MCI groups were significant. CU‐D had higher proportion PiB+ than CU‐S for 4 of 7 methods (Figure 1). CU‐D differed from CU‐S on average Global PiB DVR (5 methods; Figure 2), MK‐6240 entorhinal cortex SUVR (6 methods, Figure 3), and MK‐6240 hippocampus SUVR (6 methods, Figure 4).ConclusionReaching a clinical diagnosis of Alzheimer’s or other dementia is the culmination of years of brain changes and initially subtle cognitive decline. The observed increased PET amyloid and tau pathology among cognitively unimpaired‐declining participants, particularly in cognitive status determination methods using longitudinal patterns, suggest CU‐D criteria can be sensitive to preclinical changes. Detecting subclinical cognitive decline may improve opportunity for early intervention that could ultimately delay clinical impairment.
Patterns of brain atrophy in dysexecutive amnestic mild cognitive impairment raise confidence about prodromal AD dementia
Authors: Junquera Fernández Almudena , García Estefanía , Parra Mario A. , Fernández Guinea Sara 
Published: December 2020

AbstractBackgroundPrediction models aimed at detecting risk of progression from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) dementia increase their accuracy when impaired executive functions enter the analysis. This suggests that impaired executive functions in MCI are likely linked to the prodromal stages of AD dementia. Neuroimaging assessment of such patients would allow exploring if they show AD related patterns of brain atrophy. We hypothesized that AD sensitive brain regions would show discrimination between dysexecutive amnestic MCI (maMIC) and healthy controls.MethodWe analysed 32 healthy controls and 23 MCI patients. Patients were divided in single domain amnestic MCI, multidomain amnestic MCI (i.e., with the dysexecutive component), and non‐amnestic MCI. Brain volume data entered regression models to analyse which brain regions predict group membership (control vs maMCI). Stepwise lineal regression model was then conducted to identify the brain regions with better prediction power.ResultsFour variables were able to predict group membership in simple lineal regression models: entorhinal cortex, lingual gyrus and parahippocampal gyrus in the left hemisphere and fusiform gyrus in the right hemisphere. The entorhinal cortex provided the most accurate model (F(1, 42) = 14.19, p=0.001, R2=0.24). Linear regression models were run with performance on executive function tasks including tests of switching, planning, verbal fluency and working memory. The most accurate model returned Letters and Numbers and categories fluency (F(2, 44) = 21.35, p=0.000, R2=0.48) suggesting that working memory and category generation are the functions contributing to the dysexecutive profiles observed in maMCI patients.ConclusionDysexecutive profiles in multidomain amnestic MCI together with neuroimaging volumetric analysis increase the probability of identifying the prodromal stages of AD dementia.