bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frontal tau pathology underlies behavioural / dysexecutive clinical presentations of Alzheimer’s disease
Authors: Therriault Joseph , Pascoal Tharick A. , Savard Melissa , Benedet Andréa Lessa , Chamoun Mira , Tissot Cecile , Lussier Firoza Z. , Kang Min Su , Soucy Jean‐Paul , Massarweh Gassan , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundIncreasing attention is being directed to atypical clinical presentations of Alzheimer’s disease. The behavioural/dysexecutive variant of Alzheimer’s disease is a rare clinical syndrome presenting with behavioural changes, apathy and executive dysfunction, similar to frontotemporal dementia. While initial autopsy studies identified pathology in the frontal cortex, recent studies challenge the notion of frontal involvement in this condition.MethodWe assessed 14 cases of behavioural/dysexecutive Alzheimer’s disease recruited from a tertiary care memory clinic, all of whom had biologically defined Alzheimer’s disease (amyloid and tau positive). They were compared with 24 disease severity‐ and age‐matched amnestic Alzheimer’s disease patients and a group of 131 cognitively unimpaired (CU) elderly individuals. All subjects were evaluated with [18F]AZD4694‐PET (amyloid‐b), [18F]MK6240‐PET (tau), MRI, genotyping for apolipoprotein E (APOE) and neuropsychological testing.ResultVoxelwise contrasts against CU elderly identified patterns of frontal cortical tau aggregation in the behavioural/dysexecutive group, with peaks in the anterior cingulate, frontal insula and orbitofrontal cortices. Amnestic Alzheimer’s disease patients had larger differences in the lateral temporal, inferior parietal and posterior cingulate cortices. In contrast to tau‐PET, no differences were observed in the distribution of amyloid‐PET between both Alzheimer’s disease groups. Finally, voxelwise regressions demonstrated significant relationships between frontal cortical tau load and severity of executive dysfunction (FWE corrected at p<0.001), while memory dysfunction was related to temporal and parietal tau load (FWE corrected at p<0.001).ConclusionThe association between frontal tau pathology and behavioural / dysexecutive clinical presentations provides in vivo support for a “frontal variant” of Alzheimer’s disease as initially identified by autopsy studies. Our results also highlight the need for consensus clinical criteria for behavioural/dysexecutive Alzheimer’s disease.
Online medical education improves knowledge of clinical trial data and mechanism of action of therapies studied for the management of dementia‐related psychosis among neurologists and psychiatrists
Authors: Finnegan Thomas , Arnaud‐Hevi Lisette , Hanley Kelly 
Published: December 2020

AbstractBackgroundPsychosis is a consequence of dementia that occurs to varying levels depending on the type of dementia. Of note, it is estimated that up to 75% of people with dementia with Lewy bodies will experience psychosis compared with approximately 10% of people with frontotemporal dementia. Management of this condition is a challenge due to a lack of FDA‐approved therapies as well as the potentially serious adverse events associated with the medications currently employed. It is crucial that clinicians are aware of clinical outcomes and the mechanism of action of investigational approaches for the pharmacologic management of dementia‐related psychosis (DRP). An online educational activity was developed with the goal of improving knowledge among neurologists and psychiatrists regarding clinical trial outcomes for investigational therapies being studied in DRP.MethodAn online educational intervention was developed in the form of a 30‐minute video lecture with synchronized slides. Educational effectiveness was assessed with a repeated pairs pre‐/post‐ assessment study design in which each individual served as his/her own control. Responses to 3 knowledge‐based and 1 confidence‐based questions were analyzed. A chi‐square test assessed changes from pre‐ to post‐assessment. Cramer’s V was used to calculate the effect size of online education. Data from the assessment were collected between September 4, 2019 and November 25, 2019.ResultA comparison of responses from pre‐ to post‐assessment questions demonstrated a considerable educational effect for neurologists’ (n=365; V=0.17; P<.001) and a noticeable educational effect for psychiatrists’ (n=1155; V=0.15; P<.001). Participation in this educational intervention showed improvements for both groups in the following areas (P<.05): the mechanism of action of pimavanserin; the impact of pimavanserin on cognitive function in patients with Alzheimer disease; and the mechanism of action of memantine. Activity participation resulted in 36% of neurologists and 34% of psychiatrists reporting an increase in confidence in their ability to manage DRP.ConclusionThis study demonstrated the success of a targeted online, video lecture on improving neurologists’ and psychiatrists’ knowledge of the mechanism of and clinical trial outcomes for therapies studied for the management of DRP. Future education should continue to address the clinical developments and practical management of DRP.
Connectivity‐based differentiation of agrammatic and logopenic variants of primary progressive aphasia using a whole brain data‐driven approach
Authors: Jenkins Lisanne M , Behn Jordan Quinn , Khan Raiyan R , Wang Lei , Rogalski Emily J , Greicius Michael D , Mesulam Marsel , Bonakdarpour Borna 
Published: December 2020

AbstractBackgroundPrimary progressive aphasia (PPA) is a syndrome of progressive language impairment caused by neurodegenerative disease. We previously showed using seed‐based connectivity analysis that connectivity between three language network regions is decreased in PPA. Furthermore, we showed selective connectivity disruptions corresponding to grammar, repetition, naming and comprehension deficits. The current investigation used a data driven approach to uncover signatures of resting state connectivity disruptions differentiating agrammatic PPA subtypes (PPA‐G) from logopenic PPA subtypes (PPA‐L).MethodOne hundred and six individuals participated in this study, for which 73 PPA patients were compared to 33 healthy controls (Table 1). Diagnosis of PPA subtype was made by clinical consensus using established criteria. Resting state functional MRI (rsfMRI) was collected using a Siemens 3T scanner over 10 minutes with eyes open. Data were analyzed using FSL tools. A group independent components analysis generated 30 independent components (ICs). Participant’s individual time series and component spatial maps were estimated using dual regression. Voxel‐wise non‐parametric permutation testing (n=5000) tested for significant differences in connectivity within each IC across groups. Follow‐up one‐way ANOVAs with Tukey post‐hoc tests were conducted.ResultPost hoc tests found PPA subgroup(s) had reduced connectivity than controls in three FSL‐identified ICs showing significant group differences (Figure 1). PPA‐L had significantly lower connectivity within IC1 in the cuneus. PPA‐G had significantly lower connectivity within IC14 in Broca’s area; and all three PPA subtypes had significantly lower connectivity within IC25 in the left middle temporal gyrus (MTG).ConclusionWe identified three components in which PPA subgroup(s) had lower connectivity than controls. In PPA‐G, but not PPA‐L, reduced connectivity was within Broca’s area, consistent with this region’s importance for fluency and grammar. In PPA‐L, but not PPA‐G, reduced connectivity was within the cuneus. This finding may seem surprising, however, it may reflect higher incidence in PPA‐L of Alzheimer pathology, which is known to have the precuneus as a major target of degeneration. All PPA subtypes had reduced connectivity within the posterior MTG, reflecting the common occurrence of atrophy in this area.
Implication of ferroptosis iron‐dependent programmed cell death mechanism in neurodegeneration
Authors: Plascencia‐Villa German , Perry George 
Published: December 2020

AbstractBackgroundBesides the abnormal accumulation of hyperphosphorylated tau, amyloid‐β plaques and neuroinflammation, progressive synaptic loss and neuronal cell death are persistent pathological hallmarks related to the development of neurodegeneration. However, the cellular pathways/mechanisms that trigger neuronal death in AD remain largely undefined. A detailed understanding and description of the molecular mechanisms related to neuronal loss processes in affected AD will be invaluable to the identification and development of new effective therapeutic targets. A novel form of iron‐dependent regulated cell death process termed ferroptosis was recently identified. Misregulated ferroptosis pathways have been speculated to trigger neurodegeneration, but the cellular mechanisms and signaling are not completely understood.MethodDifferentiated neurons were treated (0‐200uM) with different ferroptosis inductors or ferroptosis inductors+inhibitors to determine molecular responses. We employed analytical and advanced imaging techniques, including bioassays, transcriptomics, optical/confocal/electron microscopy and mass spectrometry to determine and compare cell responses, pathways and other features characteristic of ferroptosis. Then AD brain tissues were analyzed to image ferroptotic cells and transcriptomic profiles of pathways altered in ferroptosis.ResultSome of the ferroptosis‐like biochemical and morphological features have been observed in AD: glutathione reduction, alterations in glutamate/cystine antiporter (Xc‐), lipid peroxidation, mitochondrial dysfunction, MAPK/ERK activation, GPX4 downregulation, and altered redox homeostasis. We determined that ferroptosis is activated in AD as a probable mechanism underlying neuronal loss in neurodegeneration, describing the mechanisms and cellular pathways involved. The results obtained showed alterations in cystine‐glutamate exhcnage, iron metabolism, glutathione metabolism and mevalonate pathway in neurons treated with ferroptosis inductors, particularly correlating with high oxidative stress and neuronal death, these responses were ameliorated when ferroptosis inhibitors were added to the neurons. These observations of altered ferroptosis were confirmed in AD brain and by determining their transcriptomic profiles of ferroptotic pathways.ConclusionDetermine the molecular mechanisms related to ferroptosis in neuronal cells. Remarkably, the experimental approach allowed (1) establish a relationship between neuronal death and neurodegeneration in the context of ferroptosis, (2) impact our understanding of the AD pathogenesis and cell death mechanisms, and (3) determine novel strategies for early diagnosis and therapeutic interventions that target the molecular pathways of ferroptosis.
The interaction of amyloid and tau on decreased cortical neurite density in preclinical Alzheimer’s disease
Authors: Vogt Nicholas M , Hunt Jack F.V. , Adluru Nagesh , Van Hulle Carol A , Chin Nathaniel A. , Carlsson Cynthia M. , Ma Yue , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik , Alexander Andrew L , Blennow Kaj , Bendlin Barbara B 
Published: December 2020

AbstractBackgroundBoth MCI and AD dementia are associated with decreased cortical microstructure as measured by neurite orientation dispersion and density imaging (NODDI). Specifically, in MCI, neurite density index (NDI) – but not cortical thickness – is decreased in several key AD regions, suggesting NODDI may be more sensitive than conventional structural imaging for detecting early neurodegenerative changes. Given that AD pathology accumulates for years before cognitive and clinical symptoms arise, in this study, we tested the hypothesis that cognitively unimpaired individuals with greater AD pathology (as measured in CSF) will have decreased cortical microstructure in AD signature brain regions.Method219 cognitively unimpaired individuals (66.8±7.5 yrs, 58.9% female, 38.9% APOE4‐positive) underwent MRI (multi‐shell diffusion‐weighted for NODDI microstructure; T1‐weighted for cortical thickness) as well as CSF AD biomarker quantification (Aβ40, Aβ42, and pTau via ELISAs). The NODDI model was fit using optimized parameters for GM (intracellular parallel diffusivity=1.1μm2/ms), and cortical thickness (CT) was calculated using CAT12. Mean NDI and CT were extracted from a bilateral composite AD signature region as well as individual subregions (Fig1A). Linear regression models (controlling for age and sex) tested both main effects and the interaction of CSF Aβ42/Aβ40 and pTau levels on cortical measures (separate models for NDI and CT).ResultWhile there were no main effects of CSF Aβ or pTau levels on NDI or CT, there was a significant Aβ‐by‐pTau interaction on NDI in the composite AD signature region, such that individuals with higher burden of amyloid showed lower NDI as a function of pTau (Fig1B). Notably, this interaction was not observed for cortical thickness. Examining individual subregions showed that this interaction effect was observed bilaterally and was strongest in inferior parietal, inferior temporal, and fusiform subregions (Fig1C&D).ConclusionIn cognitively unimpaired individuals with higher amyloid burden, higher pTau was associated with lower NDI – but not thickness – in AD signature cortical regions. These results suggest that amyloid alone (in the absence of tau pathology) is not associated with microstructural changes, and that NDI is a particularly sensitive marker for early AD‐related cortical changes occurring prior to gross atrophy or development of cognitive impairment.
In vivo validation of a lead compound targeting tau self‐association in two mouse models of tauopathy
Authors: Moe James G. , Lopez Patricia , Jimenez Heidy , Adrien Leslie , Davies Peter , Davidowitz Eliot J. 
Published: December 2020

AbstractBackgroundTau self‐association is the initial step in the formation of toxic tau oligomers and larger aggregates. Our program is highly differentiated in that it targets tau self‐association with small molecules to block the formation of all forms of tau aggregates, whereas other tau aggregation inhibitor programs have largely focused on inhibiting formation and/or dissociating large and relatively inert fibrils which could generate toxic tau oligomer seeds. Relative to immunotherapeutic approaches, small molecules are agnostic to specific post‐translational modifications, conformational changes or strains of tau aggregates, and have superior access to their target in the CNS.MethodPreventive and therapeutic blinded studies in htau and JNPL3 transgenic mice were performed at an independent laboratory. Mice were treated for four months by administration of our lead compound in feed. For preventive studies, treatment was from 3 to 7 months‐of‐age; for preventive studies, treatment was from 7 to 11 months‐of‐age for JNPL3 and 9 to 13 months‐of‐age for htau. To quantify levels of Sarkosyl‐insoluble tau, self‐associated tau, and phosphorylated tau in the treated and control groups of mice ELISAs were performed. Immunohistochemistry determined levels of conformationally altered and hyperphosphorylated tau. Motor and cognitive behavioral testing are being performed as part of the ongoing therapeutic studies.ResultThe lead compound reduced self‐associated tau and caused a statistically significant, linear, dose‐dependent reduction of the levels of sarkosyl‐insoluble tau aggregates and phosphorylated insoluble tau aggregates in relationship to the levels of compound in the brain in male htau mice. The study of female JNPL3 mice showed dose‐dependent reduction below baseline and vehicle levels of self‐associated tau, insoluble tau aggregates and phosphorylated tau. The compound was well tolerated at all therapeutic doses; there were no adverse events due to the compound.ConclusionThe lead compound reduced both soluble and insoluble phosphorylated tau aggregates in the htau mouse model representing tau aggregation in AD and in the JNPL3 mouse model of inherited tauopathy. These studies validated both the screening approach against tau self‐association as a target and the in vivo efficacy of the small molecule lead compound.
Cellulose ethers reduce amyloid‐beta pathology in in vitro and in vivo Alzheimer’s disease model
Authors: Ali Tahir , Klein Antonia N. , Vu Alex , Gilch Sabine 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent cause of dementia. Neuropathologically, AD is characterized by amyloid‐beta (Aβ) aggregation. This is thought to be a primary pathological event impairing cellular homeostasis, neurotransmitters, inflammatory response, induces misfolding of other proteins and consequently leads to synaptic/neuronal loss. To date, no therapeutics are available to cure AD. Hence, we aimed to determine the therapeutic effects of cellulose ether (CE)‐based compounds for the treatment of AD.MethodWe tested different concentrations of the CE TC‐5RW in vitro for its effect on Aβ aggregation by Thioflavin T assay. Similarly, we performed MTT assays to determine cell viability of human neuroblastoma (SH‐SY5Y) cells treated with Aβ aggregates formed in the presence or absence of TC‐5RW. In vivo, transgenic 5xFAD (expressing human APP and PSEN1 transgenes harboring in total 5 mutations associated with familial AD) mice were treated at the age of 6 weeks with a single subcutaneous injection of TC‐5RW at a dosage of 4g/kg. Following this treatment, the mice were euthanized at the age of 10 months and brains were harvested for further biochemical (Western blotting) and immunohistochemical analyses.ResultOur in vitro Thioflavin T assay results indicated that TC‐5RW had beneficial effects and at 0.25 % and 1 % TC‐5RW concentrations inhibited Aβ aggregation and accumulation. The MTT results showed that TC‐5RW increased cell viability of Aβ exposed SH‐SY5Y cells. Likewise, in vivo, the treatment with TC‐5RW significantly reduced the amount of oligomeric and monomeric forms of Aβ in the brains of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. We performed Aβ6E10 immunofluorescence staining to analyse the number of Aβ plaques, and Aβ immunoreactivity in the hippocampus and cortex of the mice. The treatment with TC‐5RW significantly alleviated the number of Aβ plaques and immunofluorescence reactivity in the hippocampus and cortex of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. These in vitro and in vivo results indicate that TC‐5RW reduces Aβ pathology.ConclusionTaken together, our results and the safety profile (FDA approved) of CEs, suggest that these compounds have promising potential for the development of therapeutics against AD.
Higher perceived age‐related gains and losses relate to lower objective cognitive scores
Authors: Sabatini Serena , Ukoumunne Obioha , Ballard Clive , Collins Rachel , Anstey Kaarin J. , Diehl Manfred , Brothers Allyson , Corbett Anne , Hampshire Adam , Brooker Helen , Clare Linda 
Published: December 2020

AbstractBackgroundAwareness of age‐related changes (AARC), including perceived losses (e.g., memory decline) and gains (e.g., wisdom), comprise an important component of the aging process. Indeed, subjective perceptions of aging and health can reveal critical information not captured by objective measures. In particular, growing biomarker evidence suggests that subjective cognitive decline (SCD) may be a risk state for dementia. However, whether perceived age‐related gains confer cognitive protection is not known. We examine the extent to which perceived age‐related gains and losses explain variability in cognitive performance across three stages of older adulthood.MethodWe used cross‐sectional data from the PROTECT cohort (assessment in 2019); 6,377 UK residents (age range= 51‐95 years, mean age= 66.1 years, 75.9% women) without dementia completed measures of depression, AARC gains and losses, and undertook cognitive tasks. Structural equation modeling (SEM) was used to test whether AARC gains and losses predict scores on objective cognitive tasks. In the model, we included depressive symptoms as a mediator of the associations of AARC losses with scores on cognitive tasks. We also controlled for potential confounders. We tested the same model among three sub‐samples of individuals aged 50 to 60 (N= 1,628), 61 to 70 (N= 3,076), and 71 and over (N= 1,673).ResultThe model fit the data well among all three groups. The correlation between AARC gains and losses was negligible, yet higher levels of both predicted poorer cognitive scores among all groups. Associations of gains and losses with verbal reasoning were small to moderate, whereas associations with remaining cognitive tasks were of negligible size. Depressive symptoms mediated the effect of AARC losses on verbal reasoning in the two older groups.ConclusionAs hypothesized, individuals with higher perceived losses demonstrated poorer cognition. In contrast, higher perceived gains did not confer protection; rather, perceived gains were also associated with lower cognitive performance. This unexpected pattern of results, seen across all age groups, underscores the complexity of mapping perceived experiences onto objective outcomes, and emphasizes the importance of considering subjective aging more broadly when refining the clinical construct of SCD as a reliable marker of cognitive decline.
Cognitive impairment and dementia among older prisoners: A report from an Italian prison
Authors: Fabbo Andrea , Neviani Francesca , Petrella Stefano , Beretta Roberto , De Salvatore Luigi , Mussi Chiara 
Published: December 2020

AbstractBackgroundPrison population is aging. Older prisoners are increasing and age‐related problems are a new challenge for the prison officers. Dementia is under detected among old prisoners although life style, substance abuse, custody condition, jail environment increase dementia risk. Older prisoners either may be affected by dementia before the crime or develop dementia during the detention. In Italy in 2017 there were 3700 older prisoner aged 60 and over and 776 aged 70 and over.MethodIn Sant’Anna prison in Modena district currently there are 19 prisoners over 65. In our district is possible to require psychogeriatric evaluation for older prisoners .ResultsSince 2017 10 prisoners in sex offender section have been evaluated (mean age 73,7 ds 8,6): 4 of them (30%) have been identified as people with dementia (20% vascular dementia and 10% mixed dementia) and 30% have been diagnosed as neurocognitive minor disorder. 1 of them 87 years old (10%) had Alzheimer disease (MMSE20/30) at the moment of the crime. He needs to be supported by a younger prisoner who is now involved in his care, as educational program.ConclusionIn our preliminary experience all older prisoners examined have challenging behaviour related to dementia or cognitive impairment, evaluated with NPI scale (mean 25, 3 min 18 max 38). This is a preliminary picture of Italian dementia reality in prison. This topic deserves future attention.