bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of apolipoprotein ε4 allele as a predictor in the course and outcome in patients with subcortical vascular dementia
Authors: Issac Thomas Gregor , PT Sivakumar , Chandra S.R. , Christopher Rita , Rajan Jamuna G. , Philip Mariamma , Clinic Geriatric ,   Services, NIMHANS, India
Published: December 2020

Background

Vascular dementia (VaD) is the second most common dementia in elderly and the major contributor being Cerebral Small Vessel Disease (SVD) which has radiological manifestations of White Matter Hyperintensities(WMH), Cerebral Microbleeds and Lacunar infarcts. This study looks into the role of clinico‐demographic profile, genetic factors in terms of Apo E4 status and neuropsychological characteristics in predicting the course and outcome in patients with Subcortical VaD.

Method

A prospective cohort study involving 202 patients who were followed up at baseline and subsequently after 1 and 2 years’ time intervals following informed consent and IEC approval with attempt to understand the role of APOE4 positive status as a predictor for cognitive decline. Comparison of Neuropsychological test performance with ANOVA, regression analysis and survival analysis by plotting Kaplan Meier’s curve was done using SPSS v.21.

Result

The major risk factor identified was Hypertension in 92% followed by smoking in 76% and low socioeconomic status in 56% patients. 35.7% of the population had an APO E4 allele positivity. Regression analysis done showed APO E4 positive status as a significant independent predictor of poorer performance in neuropsychological test scores across time periods. However, survival analysis utilizing Kaplan Meir’s plot showed that unlike smoking and WMH (Odds ratio : 2.62) which increased mortality rates more than twofold, APO E4 did not contribute to increased mortality.

Conclusion

This study comprehensively looks into the role of APO E4 in VaD and identifies need for prevention of modifiable risk factors like smoking, hypertension, low SES, poor cognitive reserves and WMH which predicts cognitive decline in subcortical VaD and lead to early mortality in patients with VaD. Positive APO E4 allele status significantly affects performance in cognitive assessments but does not appear to predict mortality and hence risk modification needs to be tailored in patients with VaD.
Fukushimura BrainBank project, Japan
Authors: Kaneda Daita , Akatsu Hiroyasu , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Yamamoto Sakon , Yamamoto Takayuki , Yoshio Hashizume
Published: December 2020

Background

The Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes. Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who initially reported cortical Lewy bodies. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.

Method

For collecting CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections. All the medical records and radiological images from the nursing home to hospital are stored in the research institute, which make it possible for the researchers to access the psychological symptoms observed by carers in the long duration of the disease.

Result

The number of autopsy became over 30 cases per year. Most of the patients had dementia or chronic devastating cerebrovascular diseases. Of note, geriatric residents with mentally retardation or cerebral palsy from childhood were included. At the end of 2019, more than 720 of frozen brains with detailed medical record are stored in FBB and readily available for research. The neuropathology database share the same coding system for Japanese Brain Bank Network for Neuroscience Research (JBBNNR). We already have over 20 collaborators and supply our samples for more than 30 research institutes in Japan.

Conclusion

The challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions, especially from the point of view of nursing staffs.
Multimodal imaging reveals human cholinergic system functional and structural integrity in vivo
Authors: Nemy Milan , Grothe Michel , Barroso Jose , Teipel Stefan J. , Westman Eric , Ferreira Daniel
Published: December 2020

Background

Recent advances in the neuroimaging field have rekindled the interest for the human cholinergic system. As the widespread projections from the basal forebrain to the cortex play an important role in learning, memory and other cognitive processes that are significantly impaired in disorders such as Alzheimer’s disease, Dementia with Lewy Bodies, and Vascular Dementia, it is favourable to assess the affected pathways and cortical regions in vivo. However, research is still limited and different imaging modalities need to be combined to advance our current understanding of the complex interplay between anatomical, functional and physiological features of the human brain cholinergic system. We developed an advanced framework using deterministic fibre‐tracking methods using diffusion‐tensor imaging (DTI), and partitioning of the human basal forebrain on T1‐weighted structural MRI data supported by resting‐state functional MRI (rs‐fMRI) data.

Method

A total of 197 cognitively healthy individuals were recruited. The rs‐fMRI, DTI, and T1 data were processed with MRtrix3, DPARSFA, and SPM12 in order to track pathways rising from basal forebrain subdivisions towards rs‐fMRI identified cortical areas.

Result

We identified two functionally relevant subdivisions of the basal forebrain by clustering based on functional connectivity characteristics. The resulting subdivisions resemble cytoarchitectonically defined subdivisions as revealed by stereotactic mappings. Distinct white matter tracts originated from individual basal forebrain subdivisions towards cortical cholinergic areas, each of which showed differential associations with relevant cognitive functions.

Conclusion

Here we present a novel method of combination of MRI‐based techniques to assess and visualize the human cholinergic system in vivo. The ability to functionally subdivide the basal forebrain and model cognitive‐specific cholinergic pathways and cortical cholinergic areas opens new opportunities to investigate Alzheimer's disease and other neurodegenerative diseases with cholinergic involvement, with possible diagnostic and prognostic use.
APOE and sex‐stratified genome‐wide meta‐analyses of Alzheimer’s disease
Authors: Sáez María Eugenia , Moreno‐Grau Sonia , Madrid Laura , Ramirez Alfredo , Ried Janina S. , González‐Pérez Antonio , Ruiz Agustín ,   GR@ACE/DEGESCO Consortium, CHARGE Consortium, GERAD Consortium
Published: December 2020

Background

Genome‐wide studies have identified diverse susceptibility genes for Alzheimer’s disease, with the APOE locus being the major risk factor known so far. However, pathogenic mechanisms and the influence of other known AD loci or patient characteristics such as gender have been poorly explored. The ADAPTED IMI consortium, focused on exploring the APOE biology, has conducted the first genome‐wide meta‐analysis of AD stratified according to the three main APOE haplotypes. Additionally, we also explored the effect of gender on AD by performing sex‐stratified meta‐analysis.

Methods

APOE stratified meta‐analysis was performed in three stages comprising 39,186 human samples from sixteen datasets including ADNI, AddNeuroMed, ADGC, Mayo, Neocodex‐Murcia, NIA, ROSMAP, TGEN study for Stage I, GR@ACE and GERAD for Stage II and ARIC, CHS, FHS and RS (CHARGE consortium) for Stage III. Sex‐stratified meta‐analysis was performed on Stage I and Stage II datasets.

After quality control and imputation, association of genotype dosages with the AD case‐control status for each dataset was investigated through regression models adjusted by age, sex and the first four PC vectors, plus APOE status in the sex stratified analysis. Meta‐analysis was performed using the inverse variance weighing method. Results were summarized on gene‐level and explored for enrichment in known pathways and processes.

Results

In the combined analysis, we identified genome‐wide significant signals for APOE, BIN1, CLU, PICALM and a large intergenic region in 4p15 in the APOE ε4 stratum, and for ABCA7, BIN1 and PICALM in the APOE ε3 stratum, whereas no genome‐wide significant results were found in the APOE ε2 stratum. Sex‐stratified analysis identified genome‐wide significant signals for BIN1 and APOE as well as suggestive signals for PICALM, MYLK, SOX5 and SCEL in the female stratum. By contrast in males, only suggestive signals for BIN1, APOE, ZCCHC2, the ABI3BP/IMPG2 locus, ESRRB and the 19q13.4 leukocyte receptor cluster were identified. Accordingly, APOE‐ and sex‐specific pathways were highlighted.

Conclusions

This systematic stratified analysis led to the identification of loci associated with AD risk, which are specific for certain APOE haplotypes and specific combinations of APOE haplotypes and gender. This novel insight contributes to unravel the complex architecture of AD pathology.
Associations of dietary patterns and CSF biomarkers for Alzheimer’s disease in a population‐based sample of 70‐year‐olds
Authors: Samuelsson Jessica , Kern Silke , Zetterberg Henrik , Blennow Kaj , Rothenberg Elisabet , Wallengren Ola , Skoog Ingmar , Zettergren Anna
Published: December 2020

Background

Diet could be a modifiable factor in the prevention of Alzheimer’s disease (AD). Western‐style dietary patterns are considered to increase the risk, while Mediterranean‐style dietary patterns are considered protective. The aim of this study was to investigate the relation between dietary patterns and CSF biomarkers of relevance for AD.

Method

Data was derived from the population based Gothenburg H70 Birth Cohort Studies, Sweden (n=1203). CSF levels of β‐amyloid (Aβ)42, total tau, and phosphorylated tau were measured with ELISA. Dietary intake was determined by the diet history method (n=861). Principal component analysis were performed to reduce 21 food groups into factors representing dietary patterns. Logistic regression analyses, with CSF biomarkers as dependent variables (pathological, yes/no), and linear regression analyses with CSF biomarkers as continuous variables, were performed on the dementia‐free participants with both CSF and dietary data (n=269, 49% women). Analyses were adjusted for APOE ε4 status, energy intake, education, BMI and physical activity and sex. Analyses were also performed stratified by sex.

Result

Four dietary patterns were derived from the principal component analysis. A western‐style dietary pattern, a Mediterranean‐style dietary pattern, a mixed dietary pattern with alcoholic beverages and a dietary pattern of high fat dairy products, eggs and refined cereal products. The odds ratio of having pathological values of total tau was higher among those with a higher compliance to a western‐style dietary pattern (OR 1.37; 95%CI 1.02‐1.85). The linear regression model indicate the same trend (r2=0.06, B=0.04, p=0.08). When stratified by sex, the odds ratio of having pathological values of phosphorylated tau was higher for men with a higher intake of high fat dairy products, eggs and refined cereal products (OR 3.38; 95%CI 1.22‐9.36). There were no associations between the other dietary patterns and CSF biomarkers.

Conclusion

Our results indicate an association between western‐style dietary patterns and increased levels of total tau and phosphorylated tau. There was no relation between a healthier Mediterranean‐style dietary pattern and CSF biomarkers for AD, however.
Sulcal morphology as predictor of cognitive decline over a 3‐year period in elderly at risk to develop Alzheimer’s disease
Authors: Mortamais Marion , Gutierrez Laure Anne , Balem Marianne , Bars Emmanuelle Le , de Champfleur Nicolas Menjot , Bouyahia Ali , Chupin Marie , Perus Lisa , Fischer Clara , Vellas Bruno , Andrieu Sandrine , Mangin Jean‐Francois , Berr Claudine , Gabelle Audrey ,   MAPT/DSA study group
Published: December 2020

Background

Cerebral sulci openings have been consistently observed as larger in Alzheimer’s disease (AD) patients than in cognitively normal elderly. However, it remains unknown whether large openings may have predictive value of cognitive trajectories. We aimed to determine whether sulci openings might be predictors of changes in cognition over a 3‐year period in elderly people at risk to develop AD (at‐AD‐risk).

Method

Participants were recruited in memory and research centers in France between 2008 and 2011 in the framework of the MRI‐Multidomain Alzheimer Preventive Trial (MRI‐MAPT) ancillary study. They were non‐demented community‐dwelling women and men aged ≥ 70 years, and presented memory complaints and frailty criteria. In 20 sulci distributed throughout the brain, openings were extracted from Magnetic Resonance Imaging (MRI) T1‐weighted images obtained at baseline in 433 participants, using the Morphologist pipeline of BrainVISA [http://brainvisa.info, version 4.5.1]. Cognition was evaluated at baseline, 6, 12, 24, and 36 months of follow‐up with a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini‐Mental State Examination (MMSE) orientation items, Digit Symbol Substitution Test, and Category Naming Test). Linear mixed regression models explored the composite score variation over time according to the baseline openings magnitude.

Result

At baseline, participants were on average 74.8 (4.0) years old. The mean MMSE was 28.1 (1.5) and the mean composite cognitive score was 0.11 (0.62). Sulci openings were categorized into tertiles (T1, T2, T3) for the statistical analyses. The participants showing the largest openings (T3) in the left anterior inferior temporal sulcus presented a greater decline in the composite cognitive score over the 3‐year period of follow‐up (β=‐0.07, 95%CI [‐0.12; ‐0.02]) than the participants with lower openings values.

Conclusion

Large openings of sulci within the lateral temporal area of the brain might be predictors of cognitive decline within 3 years in at‐AD risk individuals. These results may have strong applications in clinical setting and for preventive strategies.
Interneuron hyperexcitability as both causal factor and risk factor in Alzheimer’s disease
Authors: Hijazi Sara , Heistek Tim , Scheltens Philip , Mansvelder Huibert D. , Smit August B. , van Kesteren Ronald E.
Published: December 2020

Background

Neuronal network dysfunction is increasingly recognized as an early sign of Alzheimer’s disease (AD). This is seen for instance as neuronal hyperexcitability, a disturbance of excitation/inhibition balance and altered oscillatory activity and synchrony, both in patients and in mouse models of AD. The causes and functional implications of these network alterations are currently only starting to be revealed.

Methods

We tested the contribution of hippocampal parvalbumin‐positive interneurons to early neuronal network dysfunction in an APP/PS1 mouse model of AD. Patch clamp analysis was performed to measure neuronal excitability and synaptic connectivity. Chemogenetics was used to specifically restore PV cell excitability in APP/PS1 mice, or induce PV cell hyperexcitability in wildtype mice. A Morris water maze test was used to determine the consequences of these manipulations for learning and memory.

Results

We found that hippocampal PV interneurons become hyperexcitable in APP/PS1 mice at an early disease stage, at 3‐4 months of age. Reducing PV cell excitability restores neuronal network properties and rescues learning and memory deficits. These effects are long‐lasting and are paralleled by a significant reduction in soluble amyloid‐beta concentrations and amyloid plaque load. Conversely, when we chemogenetically induced PV cell hyperexcitability in wildtype mice, animals developed network dysfunction and learning and memory impairments similar as observed in APP/PS1 mice. Interestingly, these impairments were transient, but could be reinstated by a singly low‐dose injection of amyloid‐beta directly into the hippocampus.

Conclusion

Hippocampal PV interneuron hyperexcitability is an early phenomenon in APP/PS1 mice and causally contributes to the development of other AD‐like symptoms, such as neuronal network dysfunction, cognitive impairment and amyloid pathology. Interestingly, hyperexcitable PV neurons also renders healthy hippocampal circuitry vulnerable to amyloid‐beta‐induced toxicity. These findings thus establish PV cell hyperexcitability as both a causal factor and a risk factor in AD.
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

Background

The 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).

Method

FINGER 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.

Result

Reduction 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.

Conclusion

Reduction 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

Background

Alzheimer'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.

Method

RMPs (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.

Result

Data 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).

Conclusion

Our 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

Background

The 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.

Methods

PROCLAIM 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.

Result

The PROCLAIM trial is planned to open patient enrollment in 2020.

Conclusion

PROCLAIM 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

Background

International 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.

Method

Undertaking 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.

Result

Analysis 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.

Conclusion

Despite 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

Background

We 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.

Method

We 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.

Result

Applied 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).

Conclusion

Results 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

Background

The 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.

Methods

A 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.

Results

The 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.

Conclusion

Preliminary 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

Background

The 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.

Method

Sixty‐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.

Results

Amyloid 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.

Conclusions

In 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

Background

Accelerated 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.

Method

Participants 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.

Result

Despite 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).

Conclusion

These 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

Background

To 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.

Method

qualitative, case report, descriptive, participant observation.

Result

72‐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.

Conclusion

it 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.
Exploring the feasibility and acceptability of a comprehensive resilience‐building psychosocial intervention (CREST) for people with dementia in the community: A non‐randomised feasibility study
Authors: Doyle Priscilla A , Gallagher Niamh , Smyth Siobhán , Casey Dympna
Published: December 2020

Background

A dementia diagnosis can prevent people from participating in society, leading to a further decline in cognitive, social and physical health. However, it may be possible for people with dementia to continue to live meaningful lives and continue to participate actively in society if a supportive psychosocial environment exists. This feasibility study seeks to create such an environment by determining the feasibility of conducting a multifaceted complex resilience‐building psychosocial intervention for people with dementia and their caregivers living in the community.

Method

Ten participants with dementia and their primary caregivers living in the community were recruited and received the CREST intervention. The intervention provided (a) a 7‐week cognitive stimulation programme (CST) followed by an 8‐week physical exercise programme for people with dementia and (b) a 6‐week educational programme for caregivers. Members of the wider community were invited to a dementia awareness programme and GP practices to a dementia‐training workshop. Trained professionals delivered all intervention components. Outcomes assessed the feasibility and acceptability of all study processes such as: recruitment; intervention content and delivery; and data collection methods.

Result

Recruiting participants was difficult, with local community organisations/groups proving more successful than GP practices. Preliminary results indicate that participants (people with dementia and carers) enjoyed the content of the CREST intervention, that the delivery method and timing worked well and overall they found the programme beneficial. Carers reported that the educational programme provided them with valuable information which was accessible and easy to understand. However, the group activities and learning from each other was identified as crucial to their enjoyment and learning. The people with dementia likewise enjoyed the CST and exercise components, some reporting that the CST enhanced their concentration and that exercising with an exercise buddy was more sociable and enjoyable.

Conclusion

The evidence from participants indicates that CREST is feasible and acceptable to carers and people with dementia in the community.
Hippocampal metabolism and memory impairment in diet‐induced insulin‐resistant mice are reversed by diet normalization
Authors: Garcia‐Serrano Alba M. , Duarte Joao M.N.
Published: December 2020

Background

Epidemiological evidence suggests that obesity and type 2 diabetes (T2D) increase the risk for dementia. Brain metabolic dysfunction plays a role in obesity and T2D‐induced memory impairments. We aimed at investigating the potential for reversibility of metabolic alterations in the hippocampus and cortex, as well as memory performance in mice fed a high‐fat and high‐sucrose diet (HFHSD) that develop a metabolic syndrome with insulin resistance, progressing to T2D.

Method

Age matched control mice were fed a control diet with 10% fat (CD). Diabetic mice were exposed to HFHSD (60%‐fat in chow, plus 20% sucrose in drinking water) for 6 months. A group of mice was fed the same diet for 4 months, followed by a dietary switch to the 10%‐fat diet for 2 months (RD). Metabolic profiles of the hippocampus and cortex were measured longitudinally by magnetic resonance spectroscopy (MRS) at 9.4T before dietary interventions, and after 4 and 6 months. Glucose tolerance tests were performed at the same time points. Memory performance was assessed at the end of the study through an object relocation and novel object recognition tasks.

Result

HFHSD‐fed mice developed overweight, glucose intolerance and insulin resistance, which recovered to control values upon diet reversing (all P<0.01 for RD vs. HFHSD). HFHSD‐fed mice showed poorer memory performance in both object recognition tasks (both P<0.001 vs. CD). Mice in the RD group showed memory performance similar to controls. At 4 months of HFHSD, the hippocampal metabolic profile showed a prominent increment in taurine concentration (P<0.01 vs. baseline). This change persisted until the end of the study in HFHSD mice (P<0.01 vs. baseline), but recovered to baseline levels in mice of the RD group (P<0.05 vs. HFHSD). These metabolic changes were not observed cortex.

Conclusion

We conclude that T2D and T2D‐induced memory impairment are promoted by a diet rich in fat and sugar. As in other T2D models, the diabetic hippocampus shows increased concentration of taurine in the MRS‐detected metabolic profile. Brain alterations were reversed upon dietary switch from HFHSD to a regular diet.
Health utility in preclinical and prodromal AD compared to controls: EQ5D data from the Swedish Biofinder Study
Authors: Gustavsson Anders , Raket Lars Lau , Lilja Mathias , Rutten‐Jacobs Loes , Fues‐Wahl Hanna , Bagijn Marloes , Hansson Oskar , Palmqvist Sebastian
Published: December 2020

Background

Health utility values (e.g. as assessed with EuroQoL 5 domains, EQ5D) are central for the health economic evaluation of candidate treatments for Alzheimer's disease (AD). Currently available estimates in early stages of disease including preclinical and prodromal AD are limited, and do not separate patients by biomarker status.

Method

Baseline data from the longitudinal Swedish BioFINDER study on patients in different stages of AD and cognitively healthy controls were analyzed. Subjects were either cognitively unimpaired healthy elderly controls sampled from a population‐based cohort, or patients with cognitive complaints (subjective cognitive decline (SCD) or mild cognitive impairment (MCI)), but without dementia, referred to memory clinics. Health utility was assessed with EQ5D (3 level version) recalculated into a utility index with the UK tariff; higher scores representing higher utility. Cerebrospinal fluid amyloid biomarker positive subjects were defined as prodromal AD if they met criteria for MCI and otherwise defined as preclinical AD.

Result

Five‐hundred‐ninety‐nine non‐dementia subjects aged between 60 and 88 years were assessed at baseline. Individuals with SCD or MCI reported lower health utility (n=245, mean=0.78, 95% CI 0.75‐0.80) compared to cognitively healthy elderly controls (n=354, mean 0.90 95% CI 0.88‐0.91), regardless of biomarker status. Prodromal AD patients reported higher health utility (n=79, mean=0.81, 95% CI 0.77‐0.85) compared to amyloid‐negative MCI patients (n=54, mean=0.71, 95% CI 0.64‐0.77). Prodromal AD patients were less often smoking, fewer had prior ischemic heart disease and were less often treated with anti‐depressants, compared to amyloid‐negative MCI patients. Subjects with preclinical AD reported health utility (n=114, mean 0.86, 95% CI 0.83‐0.88) which were similar to amyloid‐negative cognitively unimpaired (i.e. SCD and controls) (n=305, mean=0.87, 95% CI 0.86‐0.89).

Conclusion

Health utility was lower in biomarker confirmed preclinical and prodromal AD patients compared to cognitively healthy controls. The analysis suggests that amyloid biomarker status is an important determinant of health utility in patients with MCI. This may be explained by more severe co‐morbidities in biomarker negative patients. In particular, the cause of their cognitive symptoms (e.g. cardiovascular disease) may be associated with a greater impact on their quality of life in early stages of disease.