bluuebunny/crossref_metadata_2025_split huggingface dataset:
One year tau progression measured with F‐18 MK6240 PET
Authors: Rowe Christopher C , Dore Vincent , Krishnadas Natasha , Mulligan Rachel S , Tyrrell Regan , Burnham Samantha C , Villemagne Victor LL 
Published: December 2020

AbstractBackgroundFor optimal design of anti‐tau trials, an understanding of the rate of tau progression in Alzheimer’s disease (AD) is important. Studies with Flortaucipir (F‐18 AV1451) PET have reported no detectable annual increase in beta‐amyloid (Ab) ‐ve cognitively normal (CN), 0.5%/yr increase in Ab +ve CN, mainly in entorhinal and posterior cingulate areas, and widespread cortical 3%/yr increase in Ab +ve MCI or dementia. Increase was greater with higher baseline tau and younger age. F‐18 MK6240 is a new tau tracer with higher target to background binding and no choroid plexus uptake, making it attractive for use in clinical trials. We aimed to define regional rates of MK6240 accumulation in CN, MCI and AD.MethodPET acquisition was performed 90‐110 minutes post injection of 200 MBq F‐18 MK6240 at baseline and 12 months later in 15 Ab ‐ve CN and 23 Ab +ve subjects (13 CN, 6 MCI, 4 mild AD). SUVR was calculated for the medial temporal region (Me) (i.e. entorhinal, amygdala, hippocampus, parahippocampal cortex) and temporoparietal cortex (Te) (i.e. inferolateral temporal and parietal cortex) using cerebellar grey matter as reference.ResultsMCI and AD were younger than CN (67.0 ±5 yrs vs 77.2 ±4). Ab ‐ve CN showed no change, Ab +ve CN showed a trend increase of 1.5%/yr in the medial temporal region, while MCI and AD showed an increase of 7%/yr in temporoparietal cortex with lesser increase in the medial temporal region of 4%/yr. (Table 1, Figure 1).ConclusionIn comparison to published data for AV1451, we found greater increase over one year in MK6240 binding in both the medial temporal and temporo‐parietal regions in Ab +ve CN, MCI and AD patients. However, given the strong relationships of age and baseline tau level to rate of increase, some of these comparative findings may be due to younger age in our MCI and AD participants. Future recruitment will address this issue.
Liraglutide treatment sustains neuronal glycolysis and prevents hyperinsulinemia‐induced neuronal senescence
Authors: Chow Hei‐Man , Herrup Karl 
Published: December 2020

AbstractBackgroundWe previously reported hyperinsulinemia during prediabetes could lead to neuronal insulin resistance and cell cycle‐induced senescence. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age‐related neurodegeneration and cognitive decline. Here we attempted to investigate if Liraglutide‐the FDA approved diabetes drug‐can prevent insulin‐induced senescence in neurons.MethodToxicity and optimal treatment strategies were first performed in primary neuronal culture (n=9). After that, optimal dosages of Liraglutide was co‐treated with long‐lasting insulin glargine for 72 hours. A series of post‐treatment biochemical, immunocytochemistry and electrophysiology analyses were performed.ResultLiraglutide treatment did not reveal toxicity to neurons even at micro‐molar dosage. Liraglutide co‐treatment with insulin substantially preserved glycolysis capacity in primary neuronal cultures. Initiation of drug treatment prior or simultaneously with insulin revealed almost equal protective on neurite morphology; synaptic protein abundance and distribution; electrophysiology properties and be able to suppress cell‐cycle associated senescence.ConclusionLiraglutide effectively prevents the entire range of structural and functional abnormalities in neurons induced by chronic exposure of insulin.
Regional microstructural alteration of the corpus callosum in preclinical Alzheimer’s disease
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Lee Jun Ho , Lee Younghwa , Ahn Hyejin , Joung Haejung , Jung Gijung , Lee Jun‐Young , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2020

AbstractBackgroundWhile previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics.MethodSeventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models.ResultWhen compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2).ConclusionThe findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD.
Exploring the role of Amerindian genetic ancestry and ApoEε4 gene on Alzheimer disease in the Peruvian population
Authors: Cornejo‐Olivas Mario R. , Rajabli Farid , Veliz‐Otani Diego M. , Whitehead Patrice L. , Hofmann Natalia K. , Hamilton‐Nelson Kara L. , Illanes‐Manrique Maryenela , Milla‐Neyra Karina , Marca Victoria , Sarapura‐Castro Elison , Rivera‐Valdivia Andrea , Mejía Koni Katerin , Adams Larry D. , Mena Pedro Ramon , Vance Jeffery M. , Isasi Rosario , Cuccaro Michael L. , Beecham Gary W. , Meza‐Vega Maria , Castro‐Suarez Sheila , Custodio Nilton , Montesinos Rosa , Mazzetti Pilar , Pericak‐Vance Margaret A 
Published: December 2020

AbstractBackgroundThe ApoEε4 allele is a major risk factor for AD whose effect shows strong racial/ethnic differences. Among the populations ApoE shows the strongest effect in East Asians (EA) (ε3/ε4 odds ratio OR: 3.1–5.6; ε4/ε4 OR: 11.8–33.1) and has a relatively lower effect in non‐Hispanic Whites (NHW) (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9). The effect of ApoEε4 in populations with Amerindian (AI) ancestry is unknown. Peruvians with high AI (∼80%) genetic ancestry provide an opportunity to assess the effect of ApoEε4 in AD individuals with AI genetic ancestry. Our aim is to use data from the Peruvian population to assess the role of AI genetic ancestry and the ApoE gene on AD.MethodGenotyping including both ApoE and Illumina GSA array was performed in 147 Peruvians (54 AD cases and 93 cognitively intact (CI) controls). PC‐AiR and model‐based ADMIXTURE approach inferred population structure. To assess local ancestry, phasing using SHAPEIT (with 1kGP reference) was followed by RFMix (HGDP reference panels). Association between affection status and ApoEε4 dose was analyzed using logistic regression, adjusting for age, gender, PC1‐3.ResultAdmixture analysis showed that Peruvians have a substantial AI (62%) ancestral component (31% European, 4% African and 3% EA genetic ancestry). AD individuals have higher frequency of ApoEε4 allele than CI individuals (7.4% vs 3.7%, respectively, p‐value = 3e‐4). Logistic regression analysis showed ApoEε4 dose significantly associated with AD in Peruvians (OR = 4.92, CI: 2.07‐12.83, p = 6e‐4). The average of the local ancestry proportions around the ApoE were close to the average global ancestry proportions (AI:56%, EU:37% and AF:7%).ConclusionOur results showed that the risk for AD from ApoEε4 in Peruvians is higher than we have observed in NHW populations. Given the high admixture of AI in the Peruvian population, it suggests that the AI local ancestry is contributing to a strong risk for AD in ApoEε4 carriers. This would align with the current believed migration pattern of AI from East Asia, where ApoEε4 carriers have the highest ApoEε4 risk for AD. Further ascertainment is ongoing to identify additional AI ApoEε4 carriers to directly ascertain risk.
Effects of the novel FTD‐ALS gene CYLD on cell death mechanisms
Authors: Dobson‐Stone Carol , Lee Albert , Chung Roger S. , Hallupp Marianne , Boccanfuso Lauren , Oyston Lisa J. , Kwok John B. 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1‐16q12.2 for a large European Australian family with FTD‐ALS [Dobson‐Stone et al 2013, Acta Neuropathol 125:523‐533]. We have recently identified the p.M719V substitution in CYLD as the causal mutation at this locus. CYLD is a lysine‐63 deubiquitinase and CYLDM719V shows significantly increased deubiquitinase activity [Dobson‐Stone et al, Brain, accepted Dec 2019]. We sought to determine what biological pathways are affected by the presence of this mutation.MethodWe performed label‐free mass spectrometry quantitative proteomic analysis of HEK293 lysates overexpressing wild‐type (CYLDwt), FTD‐ALS mutant CYLDM719V or deubiquitinase‐inactive mutant CYLDD681G. We used Ingenuity Pathway Analysis to predict dysregulated biological pathways. We examined necroptosis in L929 cells overexpressing CYLDwt and CYLDM719V, measuring cell viability (ATP production) and cell death (membrane permeabilisation).Result276 proteins exhibited significantly altered expression when CYLDM719V was overexpressed, relative to CYLDwt. Pathway analysis predicted activation of apoptosis with CYLDM719V. This is likely related to deubiquitinase activity, as CYLDD681G was predicted to have the opposite effect. We are working to validate these findings by immunoblot and co‐immunoprecipitation analyses. CYLD has recently been identified as a mediator of another cell death pathway, necroptosis. We found a small but significant effect of CYLDM719V on cell viability after treatment with necroptosis inducer Z‐VAD‐FMK in L929 cells at 0.2 μM (8.8% decrease relative to control, Student’s t test p = 0.006), 2 μM (26.1% decrease, p = 0.0003) and 20 μM (38.6% decrease, p = 0.00005). CYLDwt showed significant effects only at higher doses (0.2 μM: 1.1% decrease, p = 0.396; 2 μM: 10.8% decrease, p = 0.049; 20 μM: 32.5% decrease, p = 0.0001).ConclusionOur study indicates that CYLDM719V may act in part by inappropriate activation of apoptosis and/or necroptosis, possibly via sensitising CYLD’s response to death stimuli. It remains to be seen which of these mechanisms is critical to CYLD’s effects on neurodegeneration in FTD and ALS, although our data lend support to the emerging research showing necroptosis as a plausible therapeutic target for ALS.
Reduced transcallosal inhibition in Alzheimer’s disease compared to healthy controls
Authors: Agrawal Adesh Kumar , Mehta Urvakhsh M. , Naik Shalini S. , Thanki Milind Vijay , Mitra Sayantanava , Varghese Mathew 
Published: December 2020

AbstractBackgroundIn Alzheimer’s disease (AD), structural changes in the corpus callosum are known to precede clinical signs. Transcranial magnetic stimulation (TMS) can be used to study functional integrity of the corpus callosum through ipsilateral silent period (iSP). We examined iSP duration between patients with mild cognitive impairment (MCI)/AD and healthy controls.Method15 patients of AD (n = 10) and MCI (n = 5), and 15 healthy controls were recruited. All subjects completed clinical (Clinical Dementia Rating Scale, Instrumental Activities of Daily Living Scale for Elderly, Everyday Abilities scale for India, & Neuropsychiatric Inventory) and cognitive (Hindi Mental Status Examination, attention, working memory and semantic verbal memory) evaluations. Twenty single TMS pulses (suprathreshold pulse delivered to right motor cortex with the ipsilateral/right hand maintained in 20% of its maximal contraction) and twenty paired pulses (subthreshold priming pulse delivered 3ms before suprathreshold test pulse over left motor cortex) were delivered to assess inter‐cortical inhibition (iSP) and intra‐cortical inhibition (ICI) respectively.ResultiSP duration was significantly reduced (df = 27; t = ‐2.76; p‐0.01)) in the clinical group as compared to healthy controls. However, there were no significant differences in ICI. There was no significant association between iSP and clinical or cognitive performance.ConclusionThe presence of inter‐cortical rather than intra‐cortical inhibition deficits in AD supports the hypothesis of corpus callosum dysfunction in AD. A lack of association between iSP and severity indices suggest this measure may be examined as an early marker of AD.
Cerebrovascular disease influences hippocampal subfield atrophy in mild cognitive impairment
Authors: Wong Fennie , Yatawara Chathuri , Low Audrey , Wong Benjamin , Kandiah Nagaendran 
Published: December 2020

AbstractBackgroundDistinguishing between pure AD and AD with concomitant CVD is challenging due to overlapping pathogenesis such as cerebral accumulation of amyloid‐β (Aβ) plaques and neurofibrillary tangles. In recent years, hippocampal subfield volumes have been recommended over other neuroimaging markers of AD due to its functionally distinct nature and higher accuracy. However to date, patterns of hippocampal subfield atrophy in prodromal AD with and without concomitant CVD remain largely unexplored. This study investigates the associations and differences in hippocampal subfield volumes in mild cognitive impairment (MCI) with significant/non‐significant cerebrovascular disease (MCI+/‐CVD).Method176 MCI subjects (mean age=65.56 years, SD=8.77) underwent neuropsychological assessments and magnetic resonance imaging. White matter hyperintensities were quantified using modified Fazekas ratings. Subjects with Fazekas ratings of ≥ 8 were categorised as MCI+CVD. Demographics, brain volumetric measurements for grey and white matter volumes, periventricular and deep white matter hyperintensities and hippocampal subfields were examined in MCI+/‐CVD. Multiple linear regressions were conducted for MCI+CVD to examine predictions of hippocampal subfield volumes on cognitive performance.ResultMCI+CVD (N=39) performed worse than MCI‐CVD in all neuropsychological assessments. MCI+CVD had significantly smaller volumes in the hippocampal tail (p=.042), subiculum (p=.015), CA1 (p=.023), molecular layer (p=.009) and fimbria (p=.025). MCI+CVD had significant associations between hippocampal subfield volumes and cognitive performance: hippocampal tail with global cognition (p=.049) and visuospatial skills (p=.004); subiculum with global cognition (p=.026) and episodic memory (p=.001), molecular layer with global cognition (p=.049) and episodic memory (p=.010) and fimbria with episodic memory (p=.038).ConclusionMCI+CVD has significantly greater hippocampal subfield atrophy, with atrophy of the hippocampal tail, subiculum, molecular layer and fimbria correlating to poorer performance in global cognition, visuospatial skills and episodic memory. The findings of this study may guide future research in investigating longitudinal changes in hippocampal atrophy in MCI+/‐CVD and the corresponding implications on cognitive performance.
Adherence to a Mediterranean diet is associated with better cognitive performance many years later in the PRIME cohort
Authors: McGrattan Andrea , Mcevoy Claire T , Woodside Jayne V , Linden Gerry , Passmore Anthony Peter , Holmes Clive , Patterson Christopher , Teeling Jessica , McGuinness Bernadette 
Published: December 2020

AbstractBackgroundGreater adherence to a Mediterranean Diet (MD) has been associated with reduced cognitive decline and dementia risk. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) recruited 10,600 European male participants between 1991 and 1993 aged 50‐59 years. The aim of this study was to examine the association between adherence to a MD (at baseline) and subsequent cognitive performance.MethodDietary data was collected via a short, self‐administered 16‐item Food Frequency Questionnaire; an adapted version of the traditional MD Score was also developed (aMDSR) and median values of intake for each MD component were used as the cut‐off point to calculate the aMDSM. In 2017, follow‐up cognitive assessments using the Addenbrooke’s Cognitive Examination – Revised (ACER) commenced within the Belfast cohort (n=405).ResultFor aMDSM, those in the Low MD category scored lower on all cognitive tests compared to the High MD category, with significant differences reported for ACE‐R (p = 0.001), ACE‐R sub domain of memory (p = 0.038), fluency (p = 0.001) and visuospatial skills (p = 0.030). For participants with a ACE‐R score below 88, suggestive of cognitive impairment, there were 19.3% in the Low MD category and 7.2% in the High MD category (p = 0.004). There were 7.4% in the Low MD category and 2.7% in the High MD category who obtained an ACE‐R score below 82, indicative of probable dementia, with no statistically significant difference between categories (p=0.09). In an adjusted model for age, education and cardiovascular risk factors, this significant difference was maintained, with those in the High MD category being 56% less likely to have an ACE‐R score of <88/100 (OR 0.442, 95% CI 0.241‐0.810, p=0.008) compared to those in the Low MD category. For participants with a ACE‐R score below 82, indicative of probable dementia, there were 7.4% in the Low MD category and 2.7% in the High MD category with no statistically significant difference between categories (OR 0.661, 95%CI 0.269‐1.621, p=0.37) .ConclusionIn the PRIME Belfast cohort, higher adherence to a MD was associated with better cognitive performances 26 years later in some but not all analyses.
APOE4 packs a punch in women: Sex‐specific vulnerability for tau and neuroinflammation
Authors: Wang Yi‐Ting , Kang Min Su , Therriault Joseph , Pascoal Tharick A. , Lussier Firoza Z , Savard Melissa , Benedet Andréa Lessa , Tissot Cecile , Arias Jaime Fernandez , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundThe role that sex plays in Alzheimer’s disease (AD) has long been the subject of intense investigation. Considerable amount of literatures showed a disproportionally high prevalence of AD in women. Moreover, sex differences were observed in disease manifestation, rates of cognitive decline, cerebral atrophy, as well as the response to treatments, suggesting that sex serves as a crucial factor in the disease heterogeneity. APOE is the strongest genetic risk factor for sporadic AD, with the ε4 allele conferring increased risk. It was found that female ε4 carriers show stronger risk for clinical AD. Other studies showed that female ε4 carriers have higher p‐tau levels in cerebrospinal fluid and show worse memories than male ε4 carriers. Despite evidence supports APOE has a stronger association among women compared with men, limited work has evaluated the effects of ApoE4 on AD core neuropathology including amyloid, tau and microglial activation in a sex‐specific manner.MethodThis was a cross‐sectional study in APOE ε4 carriers with AD (n=31), MCI (n=23), cognitively normal controls (n=47) and young healthy controls (n=9) from the TRIAD study at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid load, tau neurofibrillary tangles and microglia activation were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694), [18F]MK6240 and [11C]PBR28 respectively.ResultNo significant difference was found in age, education and MMSE score between male and female subjects. Female ε4 carriers showed significant higher tau burden in hippocampus (P<0.01), entorhinal cortex (P<0.05) and parahippocampal cortex (P<0.05) compared to male ε4 carriers. A sex‐specific vulnerability for tau and neuroinflammation was observed. More specifically, in amyloid‐positive female ε4 carriers, higher tau burden was found to be strongly associated with worse cognitive function assessed by Mini‐Mental State Examination (MMSE). In addition, an positive correlation between amyloid load and microglial activation level was also identified in female APOE ε4 carriers.ConclusionWe provide striking evidence that female is more vulnerable for the effects of APOE ε4 on tau and neuroinflammation, suggesting APOE may modulate AD pathology in a sex‐specific manner, particularly in the presence of amyloidosis.
Comparison of two analytical platforms for blood‐based surrogate biomarkers of amyloid pathology
Authors: De Meyer Steffi , Schaeverbeke Jolien , Gille Benjamin , Verberk Inge M.W. , Luckett Emma Susanne , Thijssen Elisabeth H. , Gabel Silvy , Mauroo Kimberley , Bruffaerts Rose , Stoops Erik , Vanderstichele Hugo Marcel , Teunissen Charlotte E. , Vandenberghe Rik , Poesen Koen 
Published: December 2020

AbstractBackgroundFormation of amyloid plaques and fibrillary tau tangles in brain are key pathological hallmarks in Alzheimer’s disease (AD). Surrogate biomarkers of these hallmarks have been established in CSF. However, a less invasive sample source would simplify the recruitment and the follow‐up of response in clinical trials targeting the pathological hallmarks in AD. We assessed the performances of two analytical platforms for plasma beta‐amyloid (Aβ) species and total tau (t‐tau) as surrogates of amyloid‐PET status.MethodsPlasma Aβ1‐42 and Aβ1‐40 were quantified in cognitively healthy controls (n=160, age[mean]=69, 46% female) and amnestic MCI (aMCI) patients (n=41, age[mean]=71, 43% female) by i) the Simoa Amyblood platform (Amsterdam UMC and ADx NeuroSciences) and ii) an ELISA platform (Euroimmun, Lubeck, Germany) employing identical antibody pairs. Plasma t‐tau was quantified with a prototype ELISA (ADx NeuroSciences). The same biomarkers were also measured in CSF (ELISA [Euroimmun]). Controls underwent [18F]‐flutemetamol PET and aMCI patients received [18F]‐florbetaben PET (SUVRcomp cut‐off for amyloid positivity=1.38 and 1.29, respectively). Spearman correlations between CSF and plasma biomarkers were calculated and the performance of plasma biomarkers to identify amyloid PET positivity was determined through ROC analysis. Bonferroni correction adjusted for multiple comparisons.ResultsFor ELISA, the strongest correlations were found among amyloid biomarker ratios between plasma and CSF within the aMCI cohort (r=0.6561‐0.8123, p<0.0023); most of these correlations were also present in controls, albeit weaker (r=0.4308‐0.5498, p<0.0078). Using Amyblood, correlations were weaker than for ELISA, most not surviving Bonferroni correction (Table 1). All plasma biomarker ratios could differentiate between amyloid‐PET positive and amyloid‐PET negative subjects in both cohorts (AUC[range]=0.719‐0.876, p<0.0001). Plasma t‐tau identified amyloid positivity only in the aMCI cohort (AUC[range]=0.818, p<0.0001), while plasma Aβ1‐42 could do so only in controls (AUC[range]=0.676‐0.679, p<0.0027). Within the aMCI cohort, Aβ1‐42/Aβ1‐40 performed better than Aβ1‐42 when measured with Amyblood (p=0.0064). No differences in performances were observed between platforms for any biomarker (p>0.543) (Table2). Logistic regression analysis including age, gender and APOEε4 as covariates did not significantly improve performances.ConclusionMeasuring amyloid species with blood‐based immunoassays renders good performance to assess amyloid PET status, especially in aMCI. To this end, Amyblood did not outperform ELISA.