bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a generalized deep learning framework for production scale segmentation of brain structures
Authors: McDougall Sean G , Delahanty Jeremy M , Sandoval Francisco , Knaack Alexander , Fletcher Evan , DeCarli Charles 
Published: December 2020

AbstractBackgroundWhole brain segmentation from magnetic resonance imaging (MRI) remains a vital step in analysis workflows. We developed a deep learning framework that dramatically reduces the computational and human resources required for removal of non‐brain tissues. Segmentation of brain structures is currently resource intensive and remains a bottleneck in the analysis pipeline. Here we report on the capabilities of our previously developed deep learning framework to segment three specific brain structures of varying difficulty.MethodWe trained and tested a deep learning framework on three brain structures of varying difficulty: the Hippocampus, Cortical Grey Matter, and Lateral Ventricles. Training set size differed between segmentation task based on ground truth availability: Hippocampus (8,780 train, 878 test), Cortical Grey Matter (8,900 train, 890 test), Lateral Ventricle (8,700 train, 870 test). Data sets were derived from the following studies: ADNI, ADC, Khandle, Sol‐Inca and 90plus. At the core of our framework is a tunable multi‐stage convolutional neural network (CNN). The configuration used for these experiments is the same as our top performing configuration used for whole brain segmentation, a 5 stage 13 layer encoder followed by a 6 layer fusion decoder. All experiments were performed on an NVIDIA DGX Station with four Tesla V100 16GB GPUs. For both training and testing we used ground truth masks generated by atlas‐based segmentation techniques followed by human quality control. We used the F1 score, or dice similarity coefficient, between each prediction and ground truth mask to evaluate the quality.ResultSample predictions and their corresponding ground truth masks are shown in Figures 1‐3. F1 score distributions are shown in Figure 4 indicating performance in diverse imaging cohorts. General performance is high, but varies amongst ROIs. Outliers are most likely explained by low quality data.ConclusionOur preliminary results suggest our current deep learning framework can generalize relatively well without modification to its configuration, although performance for each ROI varies. Further modifications to the framework are needed to achieve production scale quality as well as increased quality control of ground truth masks to reduce the number of outliers and improve general performance.
The Spanish revised interview for deteriorations in daily living activities in dementia 2: Everyday functioning needs in people with dementia in Colombia and Chile
Authors: Giebel Clarissa , Gaviria Ana , Leon Tomas , Samaniego Lorena Moreno , Gabbay Mark , Franco Jose 
Published: December 2020

AbstractBackgroundPeople with dementia (PwD) experience different levels of independence depending on the stage of dementia. Some PwD may struggle more with initiating activities than performing these, and vice versa. To capture this, the revised Interview for Deteriorations in Daily Living Activities in Dementia 2 (R‐IDDD2) has been developed and tested. The aim of this study was to adapt the R‐IDDD2 to Spanish populations to explore unmet everyday functioning needs in PwD living in Colombia and Chile.MethodBack‐to‐back translation was used to translate the tool into Spanish, with the new tool (R‐IDDD2‐S) having been piloted in five PwD and family carers. Small changes were made to the wording as a result. The tool asks family carers (sometimes also PwD) about the PwD’s ability to initiate 17 daily activities, including making a hot drink, and the ability to perform 20 activities. Carers are also asked to rate the PwD’s ability to perform individual sub‐tasks, such as ‘paying with cash’ for finance management. A total of 100 family carers are expected to participate. The QoL‐AD measures the PwD’ quality of life. Data were analysed using frequency analysis and correlation analysis.ResultTo date, 17 carers (5 in Colombia, 12 in Chile) have completed the R‐IDDD2‐S. PwD were on average 75 years old (+/‐10), female (82.4%), and living at home (100%). PwD struggled mostly to initiate using the computer, maintaining an active social life, and doing housework. For the performance of daily activities, PwD experienced the most difficulties when performing tasks of medication and finance management as well as shopping and using public transport. Higher levels of overall initiative and performance difficulties were associated with lower levels of quality of life of the PwD (pInitiative = .004; pPerformance = .006).ConclusionIn this ongoing study, the R‐IDDD2‐S highlights that PwD from Chile and Colombia seem to experience different needs when it comes to initiating and performing daily activities. By better understanding the various needs, and remaining abilities, PwD can be better supported in remaining as independent as possible in their own home for longer, and delay high cost dementia care services, such as care homes.
The ketogenic diet as a potential prevention or therapeutic strategy for AD
Authors: Craft Suzanne , Neth Bryan J , Mintz Akiva , Sai Kiran Solingapuram , Lockhart Samuel N , Cunnane Stephen , Whitlow Christopher T 
Published: December 2020

AbstractBackgroundDiet is a powerful modulator of brain health. The ketogenic diet (KD), a very low carbohydrate diet, is remarkably effective in treating refractory epilepsy; 50‐70% of patients have >50% seizure reduction and 30% have >90% seizure reduction. Although the mechanisms underlying its effectiveness are not definitively known, reduction of neuronal hyperexcitability and neuroprotective effects of ketones have been demonstrated, as has reduction in AD pathology in rodent models. We tested the effect of a 6‐week Modified Mediterranean‐like KD (MMKD) compared with a low‐fat American Heart Association Diet (AHAD) on AD biomarkers and memory.MethodThe study used a randomized crossover design in which participants consumed either a MMKD (5‐10% of total daily calories obtained from carbohydrates) or the control AHAD (∼15% of calories obtained from fat per day) for 6 weeks, followed by a 6‐week washout period during which participants were instructed to resume their pre‐study diet, after which the second diet was consumed for 6 weeks. Diets were equicaloric with participants’ normal diet. Compliance was verified by measuring blood ketone levels. CSF collection, pseudocontinuous arterial spin label (pcASL) MRI, 11C‐AcAc/18F FDG Positron Emission Tomography (PET), and memory testing (Z score composite constructed from Story Recall and Free and Cued Selective Reminding Test) were performed at baseline and at the end of each intervention.ResultA total of 20 participants completed both diets, with 3 participants discontinuing the study early. Mean compliance rates for completers were 90% for the MMKD and 95% for AHAD. The MMKD was associated with increased CSF Aβ42 and decreased tau. Cerebral perfusion increased after the MMKD in AD regions of interest, and whole‐brain ketone uptake increased on 11C‐AcAc PET. No changes in these outcomes were observed following the AHAD. Memory performance improved after both diets.ConclusionThe MKKD intervention favorably influenced CSF AD biomarkers, cerebral perfusion, and memory. These results provide the basis for an ongoing Phase II study using a longer intervention in a larger sample of adults with MCI.
A strategic and cost efficient method for recruiting older adults at high risk for dementia
Authors: Ayers Emmeline , Blumen Helena M , Verghese Joe 
Published: December 2020

AbstractBackgroundWith no effective therapies to prevent, slow or stop the progression of Alzheimer’s Disease and related dementias, rates are expected to rapidly increase worldwide, increasing the necessity of research to examine interventions that alleviate symptoms and slow progression of cognitive decline. Strategic recruitment of individuals at high‐risk for developing cognitive impairment provides an opportunity to target study interventions for people who may show the greatest improvement in preventing and/or slowing progression of cognitive decline. The aim of the current study is to report a targeted and cost‐effective recruitment method to study “dementia‐at‐risk” older adults. We prospectively examined the association between “dementia‐at‐risk” status and incident dementia and pre‐dementia syndromes: Mild Cognitive Impairment (MCI) and Motoric Cognitive Risk (MCR) syndrome. MCR builds on operational definitions of MCI, substituting the cognitive criterion assessed by neuropsychological testing with slow gait. It is associated with increased risk for dementia and has only partial overlap with MCI.Method“Dementia‐at‐risk” was defined based on cut‐scores on either the Memory Impairment Screen (MIS) (scores >3≤6), a four‐item delayed free and cued recall test, and the AD8 (scores of ≥1), an eight‐item questionnaire that assesses memory, orientation, judgment, and function. Cox proportional hazard models adjusted for age, sex and education were used to examine the association between “dementia‐at‐risk” status and incident cognitive impairment in a sample of 446 cognitively healthy, community‐dwelling adults aged 65+ who completed telephone‐based versions of the MIS and AD8.ResultOver a mean follow‐up of 1.5 years, participants developed incident MCR (n=22), MCI (n=34) and dementia (n=3). “Dementia‐at‐risk” status (n=120) was associated with risk of any incident cognitive impairment (MCR, MCI and dementia) (adjusted Hazard Ratio (aHR): 2.37, 95% Confidence Interval (CI): 1.38‐4.07) as well as with incident MCI alone (aHR: 3.54, 95%CI: 1.79‐7.02). No association was found with incident MCR alone.ConclusionUse of cut‐scores on either the telephone‐based MIS or AD8 to screen for “dementia‐at‐risk” participants provides a cost‐effective and strategic way to target older adults who may benefit the most from interventions that prevent or slow progression of cognitive decline. Expanded screening methods to identify a larger at‐risk population are needed.
The behavioral effects of virally induced human tau expression in the locus coeruleus of TgF344‐AD rats
Authors: Galloway Claire , McCann Ryan , Kelberman Michael , Chawla Shivaang , Weinshenker David 
Published: December 2020

AbstractBackgroundAberrant tau in the locus coeruleus (LC) is one of the first detectable neuropathological changes in Alzheimer’s disease (AD). Ubiquitous expression of mutant tau exacerbates pathological and cognitive impairments in rodent models of AD, but the consequences of wild‐type (WT) human tau expression in the LC is unknown. LC dysfunction has been linked to neuropsychiatric disorders and cognitive impairments that are relevant to AD, including sleep disorders, depression, anxiety, and memory loss. TgF344 AD rats are a transgenic rat model of AD that express APPSwe and PS1DE9 mutations and develop age‐dependent amyloid and tau pathology, neuroinflammation, cell death, and memory impairments that closely resemble humans with AD. We took advantage of this clinically‐relevant AD rat model to investigate the pathological and behavioral consequences of early human WT tau expression in the LC of TgF344 AD rats.MethodAt 2 months of age, TgF344 AD rats and WT littermates received bilateral LC infusions of human tau or mCherry control virus driven by the LC‐specific PRSx8 promotor. When rats were 6‐7 months of age, behavioral assays were administered to assess arousal (sleep latency), anxiety (open field, elevated plus maze, and novelty suppressed feeding), depression (forced swim task), and memory (Morris water maze and fear conditioning). Tau pathology in the LC was also evaluated by immunohistochemistry.ResultPreliminary analyses suggest that the behavioral consequence of human tau expression in the LC may interact with genotype. Specifically, TgF344‐AD rats that received human tau virus infusions had reduced freezing during cued and contextual fear conditioning tests compared to TgF344 AD rats that received control virus. By contrast, freezing behavior in WT rats was not influenced by human tau infusions in the LC. Additional analyses to evaluate group differences in measures of arousal, anxiety, and depression tasks are still being analyzed. Rats that received human tau virus showed tau pathology in the LC that was reminiscent of that observed in early human AD.ConclusionTau in the LC may contribute to early behavioral symptoms of AD that occur before widespread neuropathology and neurodegeneration occurs.
Three upstream ORFs in an alternative GRN 5′UTR influence downstream protein expression
Authors: Frydas Alexandros , Wauters Eline , Cacace Rita , van der Zee Julie , Van Broeckhoven Christine 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common subtype of dementia regarding people under 65 years. It is caused by degeneration of the frontal and temporal lobes of the brain and leads to behavioral and language impairments. Upstream open reading frames (uORFs) play an important role in controlling protein expression. Variants in these elements have been linked with certain diseases. We are investigating the role of uORFs in progranulin (GRN)‐associated FTD.MethodPatient sources are the Belgian FTD cohort (n = 366, age at onset (AAO): 63.3 ± 10.5y) and a cohort of GRN loss‐of‐function (LOF) mutation carriers (n = 112, 78 affected (AAO: 60 ± 7.1) and 34 unaffected). Targeted resequencing of uORF regions of GRN transcripts by amplicon target amplification assays (https://www.agilent.com). Reporter assays for characterization of GRN uORFs and identified variants.ResultsSequencing of uORF regions within two different GRN 5′ untranslated regions (UTRs) revealed 2 genetic variants (rs76783532, rs75193026) located in GRN uORFs. Variant rs75193026 is found in an alternatively spliced 5′UTR of the canonical GRN transcript, which contains 3 uORFs. Reporter assays showed that this variant significantly increases the levels of the downstream protein (Kruskal‐Wallis test, p‐value = 0.0184). Abolishment of each GRN uORF in the alternative 5′UTR led to a substantial increase of the levels of the downstream protein (Kruskal‐Wallis test, p‐value <0.05). Combined mutations of all 3 uORFs initiation sites showed a 10‐fold increase in protein expression (Kruskal‐Wallis test, p‐value < 0.0001).ConclusionDifferentially spliced GRN 5′UTR contains 3 uORFs that can potentially regulate expression of the downstream protein. The variant identified in the alternative 5′UTR appears to be functional based on the reporter assays, as it significantly increased protein expression. Estimation of mRNA changes in reporter assays will determine the impact of uORFs and the variant under study on transcriptional level. We are examining the possibility of uORF‐mediated translation by abolishing the canonical initiation codon of the downstream protein. We predict that our findings can contribute to novel mechanistic insights in GRN‐associated FTD.
Pathologic and cholinergic changes in the rostral prefrontal cortex of the oldest‐old
Authors: Maxwell Selena P. , Cash Meghan K. , Darvesh Sultan 
Published: December 2020

AbstractBackgroundThe oldest‐old are a continually expanding population of people 85 years of age and older. While the majority of this population expresses some degree of cognitive impairment typically associated with the aging brain, including executive dysfunction, a subset do not present with cognitive deficits. It is hypothesized that decreased cortical cellular and synaptic density, and neurotransmitter production in the aging frontal lobe contributes to executive dysfunction. The rostral prefrontal cortex (rPFC) is a region involved in executive function in part due to high cholinergic innervation. This study aims to characterize the neuropathologic and cholinergic changes in the rPFC in the oldest‐old.MethodMale and female formalin‐fixed human rPFC of cognitively intact individuals over the age of 85 will be examined compared to sex‐ and age‐matched Alzheimer’s disease rPFC. Disease‐associated neuropathological load will be examined with immunohistochemical staining using specific antibodies for β‐amyloid (Aβ) species (total Aβ, Aβ1‐40, Aβ1‐42, protofibril and fibril oligomers), tau species (total tau, 3R, and 4R), α‐synuclein, and phosphorylated‐TDP‐43. The cholinergic system will be evaluated using histochemical staining for butyrylcholinesterase and acetylcholinesterase, and immunohistochemical staining with a specific antibody for choline acetyltransferase.ResultPreliminary results indicate a high prevalence of abnormal intraneuronal Aβ aggregation in a subset of neurons of the middle laminar layers of several oldest‐old brains. One of these brains has concurrent abnormal tau aggregates in the white matter.ConclusionThe results of this study will further our understanding of the mechanisms that allow a subset of the oldest‐old to maintain normal cognitive function despite age related changes to neural elements and the presence of disease‐associated pathology. Abnormal sequestering of disease associated proteins may indicate neuroprotective mechanisms which prevent loss of function in the rPFC.
Cognitive dysfunction is common in middle‐aged adults with type 2 diabetes in South Africa
Authors: Bobrow Kirsten , Kornblith Erica S , Gouse Hetta , Robbins Reuben N , Yaffe Kristine , Farmer Andrew J , Levitt Naomi 
Published: December 2020

AbstractBackgroundType 2 diabetes (T2DM) is a leading, potentially modifiable risk factor for cognitive impairment and dementia. However, very little is known about the burden of cognitive impairment in adults with T2DM in low‐ and middle‐income settings. We describe patterns of cognitive functioning and impairment in adults with T2DM in primary care in Cape Town, South Africa.MethodsParticipants were recruited from a final study visit of a randomized control trial study that assessed adherence support for T2DM (ISRCTN7076880) using brief‐messages. Participants completed a standardized neuropsychological test battery previously adapted for use in South Africa that assessed seven cognitive domains: learning (verbal and visual), delayed recall/memory (verbal and visual), working memory, processing speed, executive function, language, and fine motor skills. Linear regression was used to adjust individual raw test scores for age, sex and education. We used the standardized residuals from the models as a standard score and defined impairments as >1 standard deviation below the mean. Logistic regression models were fitted to explore associations between demographics, health behaviors, and glycaemic control and the number of domains impaired (≥2.)ResultsEighty participants (75% women) with a mean age of 55 years (SD=11) and 9.2 (SD=3.4) years of education were enrolled. Mean HbA1c was 83 mmol/mol (SD=1.1) and duration of type 2 diabetes was 8 years (SD=6). Eight participants (11%) had co‐morbid HIV. Impairment was present across all cognitive domains. Proportion impaired varied by domain and test from 5% to 15%. One third of participants were impaired in only one domain, and one third in two or more. Male sex was significantly associated with impairment in two or more domains. Glycemic control, HIV‐status, self‐rated health, mood or premorbid functioning did not significantly predict impairment by type or number of domains impaired.ConclusionCognitive impairment is common among middle‐aged adults with T2DM being managed in primary care in South Africa. Further research is required to clarify predictors, and by implication management of cognitive impairment in people with T2DM in low‐and middle‐income settings.
Low systolic blood pressure modifies the association of amyloid‐β with tau neuropathology
Authors: Oveisgharan Shahram , Capuano Ana W. , Kapasi Alifiya , Buchman Aron S. , Schneider Julie A. , Bennett David A. , Arvanitakis Zoe 
Published: December 2020

AbstractBackgroundFew pathological studies have examined the association of the vascular risk factors with Alzheimer’s disease (AD) pathology. In this clinical‐pathologic study, we examined the association of vascular risk factors with the amyloid‐β and tau depositions, hallmarks of AD pathology.MethodWe leveraged post mortem data of 1580 participants from two longitudinal community‐based studies of older adults. Amyloid‐β and tau were quantified by postmortem examination. Vascular risk factors were summarized by calculating the Framingham risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid‐β and tau levels, and examined if the FRS modified the association of the amyloid‐β with tau.ResultOn average, participants were nearly 90 years old at the time of death and two thirds were women. The FRS was not associated wtih amyloid‐β (r = ‐0.01, p = 0.844), or tau levels (r = 0.02, p = 0.412). However, the FRS as a whole, and specifically the systolic blood pressure (SBP) component, modified the association of the amyloid‐β with the tau, such that the association was stronger at lower levels of FRS, and lower SBP specifically. Taking levels of SBP into account showed that the slope of tau accumulation per unit increase in the amyloid‐β was 40% steeper in participants who had a SBP < 120 mmhg, compared to those with a 130 ≤ SBP < 140 (estimate of slope difference = 0.197, S.E. = 0.087, p = 0.024).ConclusionLower levels of SBP in late‐life is associated with a stronger association of amyloid‐β with tau neuropathology. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.
Methylation status and sulfur amino acids as risk factors for cognitive decline over 15 years: A longitudinal, population‐based study
Authors: Hooshmand Babak , Refsum Helga , Smith A David , Grande Giulia , Marseglia Anna , Laukka Erika J , Bäckman Lars , Fratiglioni Laura 
Published: December 2020

AbstractBackgroundImpairment of methylation status and raised values of homocysteine and cysteine may be modifiable risk factors for cognitive decline. We aimed to investigate the association of vitamin B12, folate, and sulfur amino‐acids with cognitive decline in a large sample of community dwelling older adults.MethodFrom the Swedish National Study of Aging and Care in Kungsholmen (SNAC‐K), 2900 dementia‐free individuals at baseline aged 60‐102 years with comprehensive assessments and Mini‐mental state examination (MMSE) were recruited. A total of 2202 participants underwent repeated MMSE assessments up to 5 occasions over 15 years. The association of baseline vitamin B12, holotranscobalamin, folate, homocysteine, methionine, cystathionine, cysteine, glutathione, and methylation status (defined as serum methionine/homocysteine ratio) with rate of cognitive decline was examined using linear mixed models, adjusted for several potential confounders, including common vascular risk factors.ResultAfter adjusting for age, sex, education, creatinine, albumin, smoking status, systolic blood pressure, and APOEε4 status, raised baseline serum total homocysteine and cysteine values were associated with faster rate of cognitive decline: for the highest quartile compared with the lowest, β coefficient and standard error (SE) were ‐0.0058 (0.002) for homocysteine (p=0.004) and ‐0.0051 (0.002) for cysteine (p=0.014) In contrast, a better methylation status was associated with less MMSE decline over 15 years: β (SE) was 0.0058 (0.002) for the highest quartile compared with the lowest (p=0.004). Furthermore, elevated methionine values tended to slow rate of cognitive decline (p=0.079). No relationships were found for other sulfur amino acids, vitamin B12 or folate.ConclusionMarkers of methylation status and raised cysteine values were related to more rapid cognitive decline over 15 years, suggesting that optimizing homocysteine, cysteine, and methionine values may be important in reducing the risk of cognitive decline in older adults.