bluuebunny/crossref_metadata_2025_split huggingface dataset:
Change in CAIDE dementia risk score and neuroimaging biomarkers during a 2‐year multidomain lifestyle randomized controlled trial
Authors: Stephen Ruth , Ngandu Tiia , Liu Yawu , Peltonen Markku , Antikainen Riitta , Kemppainen Nina , Laatikainen Tiina , Lötjönen Jyrki , Rinne Juha O. , Strandberg Timo , Tuomilehto Jaakko , Vanninen Ritva , Soininen Hilkka , Kivipelto Miia , Solomon Alina ,   The FINGER study group
Published: December 2020

AbstractBackgroundThe Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score was the first validated risk score estimating dementia risk based on a midlife risk profile. This exploratory study investigated associations of change in CAIDE score with change in neuroimaging biomarkers: brain magnetic resonance imaging (MRI) and Pittsburgh compound B‐positron emission tomography (PiB‐PET) measures during the 2‐year Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER).MethodFINGER targeted an at‐risk 60‐77 years old general population without dementia/substantial cognitive impairment. Data from baseline and 2‐year visits were used. 112 participants (59 intervention, 53 control) had repeated brain MRI measures (hippocampal, total gray matter, and white matter lesion volumes, and Alzheimer’s disease (AD) signature cortical thickness). Repeated PiB‐PET scans were available for 39 participants (18 intervention, 21 control). Linear regressions were used to test the association of CAIDE score change with change in MRI and PiB‐PET measures.ResultReduction in CAIDE score was associated less decline in hippocampus volume in the intervention group, but not the control group (randomization group x CAIDE change interaction β‐coefficient= ‐0.40; p=0.02). Associations for other MRI measures and amyloid accumulation on PiB‐PET scans were not significant.ConclusionReduction in estimated dementia risk as indicated by the CAIDE score change may result in more pronounced intervention benefits on hippocampus volume. Findings from this study should be verified in clinical trials with larger neuroimaging sample sizes and longer follow‐up.
Variation in retinal microvascular parameters is associated with mild cognitive impairment and Alzheimer’s disease
Authors: O'Neill Rachael Ann , Maxwell Alexander Peter , Hogg Ruth E , Passmore Anthony Peter , Quinn Nicola , Kee Frank , Young Ian , McKay Gareth , McGuinness Bernadette 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) is a neurodegenerative condition characterised by cognitive decline. Mild Cognitive Impairment (MCI) represents a transitional state between ageing normally and all forms of dementia, although those with MCI will not automatically convert to dementia. The retinal and cerebral microvasculature share similar embryological origins and physiological characteristics. Improved imaging technologies enable non‐invasive measurement of retinal microvascular parameters (RMPs). We investigated associations between RMPs and cognitive function in participants with AD and MCI.MethodRMPs (arteriolar/venular diameter, fractal dimension, vessel tortuosity) were measured from optic disc centred fundus images and analysed using semi‐automated software. Thirty‐four MCI and thirty‐two AD participants were recruited for the study from the Belfast Health and Social Care Trust memory clinics. Nine MCI and thirteen AD participants were excluded as their retinal images were of insufficient quality for image analysis. Associations were assessed by logistic regression with comparison to an age and sex‐matched control group from the NICOLA study as the reference category. Models were adjusted for potential confounders including smoking, diabetes, hypertension, total cholesterol and Mini Mental State Exam (MMSE) score. P<0.05 was considered significant.ResultData were included for 126 participants with cognitive function measures and sufficient retinal images. Twenty‐five participants had a clinical diagnosis of MCI and nineteen AD. Eighty‐two age and gender‐matched controls with no previous history of cognitive impairment, and MMSE and Montreal Cognitive Assessment scores >26/30 were included. Decreased arteriolar fractal dimension (OR: 0.30; 95%CI: 0.10, 0.91; P=0.03) was significantly associated with AD in all models. Decreased venular fractal dimension and both arteriole and venular diameter were significantly associated with MCI in all models (P <0.05). No further associations were detected (P >0.05).ConclusionOur findings identified variation in RMPs in association with MCI and AD in an older population. Additionally, previous studies have reported associations between reduced fractal dimension with MCI and AD. We were able to replicate these associations in unadjusted analyses, and following adjustment for confounders. These non‐invasive retinal measures may help identify mechanistic pathways of microvascular complications early in the disease process in individuals at increased risk of MCI and AD.
Design of a Phase 1/2 study of an AAV9‐based gene therapy for fronto‐temporal dementia patients with pathogenic GRN mutations (PROCLAIM trial)
Authors: Uspenskaya‐Cadoz Olga , Benoit Jamie , Mahoney Erin , Velaga Jenny , Sondergaard Patricia , Lowrey Mark , Sevigny Jeffrey 
Published: December 2020

AbstractBackgroundThe GRN gene encodes progranulin (PGRN), a secreted glycoprotein broadly expressed in the CNS and periphery in a variety of cells. PGRN is implicated in several physiological functions including as an activator of lysosome function, an anti‐inflammatory factor, a neurotrophic factor, and a growth factor. Patients suffering from fronto‐temporal dementia with GRN mutations (FTD‐GRN) carry a single mutation in the GRN gene, resulting in haploinsufficiency and an approximately 50% reduction in PGRN levels. GRN mutation carriers have an approximately 90% risk of developing FTD by age 75. FTD‐GRN is a rapidly progressing dementia with no approved treatment options. In FTD‐GRN patients, the delivery of a functional copy of the GRN gene by a recombinant adeno‐associated virus serotype 9 (rAAV9) directly to the CNS may normalize PGRN levels, potentially restoring lysosomal function and slowing neurodegeneration, thus resulting in modification of disease progression.MethodsPROCLAIM is a Phase 1/2 randomized, open‐label, ascending dose study to evaluate the safety and efficacy of PR006 in patients with FTD‐GRN. The study will evaluate three dose levels of PR006 in ascending dose cohorts. A total of 15 patients with symptomatic‐stage FTD ascertained by the CDR plus NACC FTLD sub of boxes score will receive PR006 at a low, mid or high dose, administered sub‐occipitally intra cisterna magna. The primary objective is to evaluate safety and tolerability of PR006, as well as to quantify the change in PGRN levels in blood and CSF. Secondary objectives are to assess pharmacodynamic effects of PR006 on neurofilament light chain protein, clinical decline assessed by the CDR plus NACC FTLD instrument, and immunogenicity. Exploratory objectives include the assessment of clinical symptom burden, MRI measures of cortical atrophy and white matter hyperintensities, and biomarkers of neuroinflammation and astroglial pathology.ResultThe PROCLAIM trial is planned to open patient enrollment in 2020.ConclusionPROCLAIM will assess dose, safety, tolerability, biomarker and efficacy effects of PR006 and inform its further clinical development.
Policy, practice, and public awareness: A review of national and international approaches to improve diagnosis and post‐diagnostic support for people living with dementia
Authors: Poole Marie , Wilcock Jane , Rait Greta , Brodaty Henry , Robinson Louise ,   COGNISANCE Programme Team
Published: December 2020

AbstractBackgroundInternational policy emphasises the importance of gaining a diagnosis and access to better support to for people living with dementia and those providing support. The COGNISANCE programme aligns with key policy objectives to advance dementia diagnosis and post‐diagnostic support across three continents.COGNISANCE comprises an international team from Australia, Canada, Netherlands, Poland and the UK. Researchers, people living with dementia, informal care partners, health and social care professionals and key national and international dementia organisations are working together to co‐design, deliver and evaluate toolkits and campaigns; to improve the dementia diagnostic process and post‐diagnostic support in partner countries. Our aim was to review existing evidence to inform the development of new international dementia toolkits and campaigns. The review included: national and international dementia plans/strategies; evidence‐based guidelines; and public awareness campaigns from our partner countries and international organisations.MethodUndertaking a qualitative approach, we applied scoping review framework methodology, conducted online searches for sources, and consulted with partner countries, national and international organisations. Where needed, documents were translated into English to ensure broad representation and facilitate analysis. Concepts relating to diagnosis, and post diagnostic support were extracted from each source and mapped. Thematic analysis of the evidence elicited core themes, components, and gaps in current approaches to improving diagnosis and post‐diagnostic support.ResultAnalysis of documents from five partner countries and four international organisations relating to diagnosis and post diagnostic support revealed 15 themes from 15 dementia strategies and 13 guidelines; and 13 themes from 13 national and international public awareness strategies. Core themes were awareness raising; information, care and support; diagnostic processes and community/social aspects of dementia. Analysis of national and international themes for diagnosis and post‐diagnostic support are indicative of central messages and target audiences; additionally, we have identified areas not yet prioritised.ConclusionDespite some cross‐country commonality in themes, considerable diversity and inconsistency remain in the key messages regarding dementia diagnosis and post diagnostic support. Awareness of current themes, emergent gaps, and alignment of key areas for different audiences will inform the co‐design of our new, international campaigns and toolkits.
AI‐inferred gene expression trajectories mirror neuropathology and clinical deterioration in neurodegeneration
Authors: Medina Yasser Iturria , Khan Ahmed F , Adewale Quadri , Shirazi Amir H 
Published: December 2020

AbstractBackgroundWe lack robust minimally‐invasive molecular tests for early neurodegenerative detection, hindering the development of better treatment and therapies. Gene expression (GE) has been of crucial value for understanding neurodegenerative evolution, revealing disease‐specific differentiated genes/molecular‐pathways and networks. However, due to the large developing period of neurodegenerative disorders, we lack exhaustive longitudinal datasets covering the continuous molecular transitions underlying disease. Almost all our knowledge of the subjacent pathological mechanisms is based in data “snapshots” taken at a few disease stages.MethodWe collected in‐vivo GE samples from blood plasma of 744 subjects in the spectrum of late‐onset Alzheimer’s disease (LOAD) and from 1225 post‐mortem brains with LOAD or Huntington’s disease (HD), from ADNI, ROSMAP and HBTRC. The subjects have post‐mortem neuropathology evaluations (Braak, Cerad, Vonsattel staging) or amyloid/tau PET‐based quantifications. Next, we developed the GE contrastive Trajectory Inference (GE‐cTIF) algorithm, allowing the unsupervised machine‐learning identification of enriched GE temporal patterns in the diseased populations (e.g. LOAD) relative to a background population (healthy elderly). See Figure 1.ResultApplied to the in‐vivo samples (Figure 2), the individual molecular pathological scores predicted tau positivity (P<0.001, FEW‐corrected), amyloid positivity (P<0.001, FEW), tau‐amyloid comorbidity (P<0.001, FEW), clinical diagnosis (P<0.001, FEW), memory performance (P<0.001, FEW), executive function (P<0.001, FEW) and future clinical conversion (P<0.001). In the post‐mortem brains, the molecular scores were significantly predictive (P<0.001, FEW) of Braak, Cerad and Vonsattel stages. In addition, the proposed method allowed direct identification of genes and molecular pathways driving neurodegenerative progression. Notably, 85% and 90% of the highly predictive molecular pathways in the neurodegenerating brain (ROSMAP and HBTRC, respectively) were also among the most relevant pathways detected in the blood data (ADNI).ConclusionResults in three independent neurodegenerative datasets support the strong predictive power of GE‐cTI for predicting individual pathophysiology and cognitive decline. The obtained scores are direct measures of molecular integrity, calculated independently of phenotypic/clinical variables and able to be used as unbiased biomarkers in clinical applications. Our results have broad implications for uncovering dynamic mechanisms of molecular pathology, patient stratification in the clinic, and monitor response to personalized treatments.
Genome‐wide association study of progression in Alzheimer's disease
Authors: Katzourou Ioanna , Leonenko Ganna , Williams Julie , Holmans Peter , Escott‐Price Valentina 
Published: December 2020

AbstractBackgroundThe rate of disease progression is an important factor to consider regarding Alzheimer’s disease (AD), as people with a rapid decline are considerably more likely to require additional care resources. The rate of progression in AD has been found to vary widely between individuals, with numerous factors driving this heterogeneity. In this project, a genome‐wide association study (GWAS) was performed to investigate the presence of a genetic liability to faster progression in patients with AD.MethodsA subset of 543 individuals with AD from the Cardiff MRC centre cohorts that have been assessed at multiple timepoints was used in this analysis. A progression score for each individual was approximated by a random slope from a random effects regression model of Mini Mental State Examination (MMSE) using all available MMSE measurements. The score was subsequently used in a GWAS of progression. Quality control analysis was performed following standard GWAS protocols resulting in 304,448 variants to be included in the analysis.ResultsThe sample was 67.37% female, with mean age at recruitment being 80.2 years. Mean MMSE was 17.03 at first assessment and 11.54 at last assessment, and mean number of assessments was 3.16. After correcting for multiple testing, no variant was found to be significantly associated with progression in this GWAS. Furthermore, apolipoprotein E (ApoE) genotype was not associated with progression.ConclusionPreliminary results show that, after Bonferroni correction for multiple testing, no variant was significantly associated with progression in AD. Suggestive associated variants were found in chromosome 20:5843812 (p‐value = 3.12 × 10−7), 1:62271962 (p‐value = 6.30 × 10−7), 10:15452800 (p‐value = 1.65 × 10−6) and 5:117646945 (p‐value = 2.40 × 10−6). Moreover, ApoE genotype was not found to affect the rate progression, the lowest p‐value in the ApoE region (19:44905791 ‐ 19:44909393) being 0.23. This non‐significant result might indicate that the genetic risk for accelerated cognitive decline within AD is separate from the genetic risk for developing AD. The sample size is one of the main limitations of this study. Replication in a larger dataset is necessary in order to validate these findings and uncover the presence of genetic variants that affect the rate of decline in AD.
A characterisation of amyloid status and cognition in late‐life depression
Authors: Golemme Mara , Loreto Flavia , Patel Neva , Win Zarni , Tam Henry , Sadiq Dilman , Nijran Kuldip , Malhotra Paresh A. , Perry Richard J. 
Published: December 2020

AbstractBackgroundThe link between late‐life depression and Alzheimer’s disease (AD) has long been investigated, however it is still unclear whether depression acts as a risk factor, a prodromal feature or a comorbid condition in AD. Clarifying the nature of this link has important implications in the early intervention and diagnosis of AD. The relatively recent introduction of in‐vivo brain biomarkers for AD pathology offers the chance to explore the relationship between depression and pathologically‐confirmed neurodegeneration. Here, we examined the association among objective cognitive functioning, self‐reported cognitive failures and AD pathology in patients with late‐life depression.MethodSixty‐three older adults with no formal diagnosis of cognitive impairment underwent a comprehensive cognitive assessment and Amyloid‐PET Imaging at the Imperial Memory Unit. Participants were classified into two groups, according to the presence (n=33, mean age=71.82 ±4.98) or absence (n=30, mean age=71.30 ±5.80) of late‐life depression. Late‐life depression was confirmed through validated questionnaires (GDS ≥ 6 and/or HDRS ≥ 12) and medical history review. Amyloid‐PET images were qualitatively read as amyloid positive or amyloid negative by two experienced nuclear medicine radiologists (NMRs). Equivocal scans (6%) were read by a third independent NMR. Cognitive data in the two groups were compared using non‐parametric tests.ResultsAmyloid status did not differ significantly between the two groups (p=.367), with 3 (9%) depressed and 5 (17%) non‐depressed participants reported as amyloid‐positive. Despite higher levels of self‐reported cognitive failures (p<.001), the depressed group did not differ from the non‐depressed group in a global measure of cognition (MMSE depressed: 28.09±1.69; non‐depressed: 28.93±4.66) and showed worse performance in 4 (Word List short‐delay recall, Digit Span backward and forward, Coding) of the 17 cognitive measures administered. Follow up data, currently being collected at our Unit, will add information about the long‐term trajectory of cognition in late life depression.ConclusionsIn our sample, depressive symptoms were associated with a limited number of cognitive measures but not with AD pathology. This suggests that depression seems to have a limited role in the early diagnosis of AD. Future studies should examine the role of specific features of depression and of other widespread neuropsychiatric symptoms (e.g., anxiety) in AD.
Accelerated forgetting is sensitive to β‐amyloid pathology and cerebral atrophy in cognitively normal 72‐year‐olds
Authors: Lu Kirsty , Pavisic Ivanna M. , James Sarah‐Naomi , Street Rebecca E. , Keuss Sarah E. , Buchanan Sarah M. , Wagen Aaron , Storey Mathew , Parker Thomas D. , Lane Christopher A. , Keshavan Ashvini , Murray‐Smith Heidi , Cash David M. , Malone Ian B. , Coath William , Wong Andrew , Henley Susie M.D. , Crutch Sebastian J. , Fox Nick C. , Richards Marcus , Schott Jonathan M. 
Published: December 2020

AbstractBackgroundAccelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge, no studies have investigated whether AF is sensitive to preclinical AD pathology in cognitively‐normal older adults.MethodParticipants in the Insight 46 study, a sub‐study of the British 1946 birth cohort, completed baseline cognitive and neuroimaging assessments at age 69‐71. For the follow‐up visits (∼29 months later), we complemented the clinic visit assessments of Complex Figure Drawing and the Face‐Name test (FNAME‐12) with a 7‐day delay version administered by telephone (Figure 1). AF scores were calculated as the percentage of material retained after 7 days, relative to retention after 30 minutes. Cerebral atrophy between baseline and follow‐up was quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status at baseline (positive / negative) was determined from 18F‐Florbetapir‐PET.As follow‐up assessments are still underway, preliminary interim analyses have been conducted based on 195 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). Multivariable regression models were used to investigate the effects of β‐amyloid status and BBSI on AF, and to explore interactions between these two predictors, adjusting for potential confounders including prospectively‐collected measures of childhood cognitive ability and education.ResultDespite no statistically‐significant differences after a 30‐minute delay, β‐amyloid‐positive participants retained a lower percentage of Complex Figure material over 7 days (71.8% vs. 80.7%, p=0.010) and a trend to a lower percentage of FNAME‐12 material (69.4% vs. 77.2%, p = 0.083) (Table 2, Figure 2). Higher education predicted better retention of the Complex Figure. Among β‐amyloid‐positive participants only, greater cerebral atrophy predicted poorer retention of the Complex Figure (Table 2, Figure 3).ConclusionThese results provide novel evidence of AF in cognitively‐normal β‐amyloid‐positive 72‐year‐olds. AF may be a sensitive outcome measure for therapeutic trials in preclinical AD, as it may reveal subtle memory decline at an earlier stage than traditional assessments. The interaction between β‐amyloid pathology and cerebral atrophy merits longitudinal investigation.
Therapeutic support in the final stage of life: Quality of life/quantity of life—A case report
Authors: Tapia Sara E , Olivares Claudia A 
Published: December 2020

AbstractBackgroundTo describe the challenges as speech therapists of accompanying a person with Alzheimer's disease, especially when they are close to death, it is important to talk about quality of life and decision making. As therapists and people, it is important to question what our role is at this stage. What are the considerations we should have? What is the limit between quantity and quality of life? The use of gastrostomy in advanced stages deserves analysis and discussion.Methodqualitative, case report, descriptive, participant observation.Result72‐year‐old CS patient with Alzheimer's disease 12 years ago, accompanied by a speech therapist 5 years ago. Constant work is done to educate the family about communication and food, with critical issues such as changing the way of feeding (oral or gastrostomy) and maintaining tasting for pleasure. They face complex realities at the medical, ethical and emotional levels.Conclusionit is difficult to face death, and to know what is the limit of our role as therapist?, the decision? When do we limit the freedom to decide to die? Issues such as the information that affected people and families handle about their health situation, obstinacy or therapeutic cruelty become relevant when talking about autonomy, the possibility of deciding will always be mediated by the information handled by the person and the true freedom of decision. That is why we question our participation, respecting the freedoms and autonomies of all beyond our professional knowledge and scientific evidence that confronts us permanently with more ways to extend life.