201 research outputs found
Novel blood-based biomarkers and disease modifying therapies for Alzheimer's disease. Are we ready for the new era?
No full textRecent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer’s disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently
based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer’s disease, of
increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based
biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer’s disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements
Exploring functional connectivity patterns and their associations with amyloid and tau biomarkers across alzheimer's disease stages: a resting-state fmri study
No full textBackground: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and hallmark biomarkers: amyloid-beta (Aβ) plaques and neurofibrillary tau tangles. Functional connectivity, assessed via resting-state functional Magnetic Resonance Imaging (fMRI), has shown associations with Aβ and tau. However, its adoption is hindered by high data dimensionality, noise, and artefact susceptibility.
This study explored functional connectivity differences across clinically relevant AD groups, aiming to enhance our understanding of the link between brain function and AD neuropathology.
Methods and Data Analysis: Two datasets were used for cross-sectional analyses: dataset 1 was comprised of cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia of the Alzheimer’s Disease type (DAT) participants. Dataset 2 included CU only. Whole-brain region-of-interest (ROI)-to-ROI analysis was followed by a dual-approach of Multivariate Pattern Analysis and seed-based connectivity to identify regions and measure group differences in functional connectivity patterns. We then investigated whether AD biomarkers moderate functional connectivity and cognition relationships.
Lastly, network-level functional connectivity differences within and between the Default Mode network and medial temporal lobe (MTL) were measured between CU Aβ+ and Aβ- participants.
Results: Multivariate Pattern Analysis revealed functional connectivity differences between two out of three group comparisons. The left thalamus, precuneus, and frontal gyri sub-regions were identified as key ROIs. Tau (more than Aβ) moderated more relationships between functional connectivity and cognition, particularly among MCI participants.
In dataset 2, CU Aβ+ participants showed more relationships between MTL functional connectivity and regional tau burden. Specifically, among Aβ+, lower functional connectivity was associated with higher tau pathology, pointing towards early neurodegeneration.
Conclusions: These findings enhance our understanding of the interplay between brain function and AD pathology, reinforce tau as a biomarker closely linked to functional connectivity, and identify specific brain regions and networks with potential clinical applications in early AD diagnosis and therapeutic interventions.Open Acces
Correction for Prusiner et al., Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism
No full textCorrection for “Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism,” by Stanley B. Prusiner, Amanda L. Woerman, Daniel A. Mordes, Joel C. Watts, Ryan Rampersaud, David B. Berry, Smita Patel, Abby Oehler, Jennifer K. Lowe, Stephanie N. Kravitz, Daniel H. Geschwind, David V. Glidden, Glenda M. Halliday, Lefkos T. Middleton, Steve M. Gentleman, Lea T. Grinberg, and Kurt Giles, which was first published August 31, 2015; 10.1073/pnas.1514475112 (Proc. Natl. Acad. Sci. U.S.A. 112, E5308–E5317).
The authors note that Fig. 3 appeared incorrectly. The corrected figure and its legend appear below. The online version has been corrected
Ethnicity, cardiovascular disease & the risk of Alzheimer’s disease and related dementias (ADRD)
No full textBackground: It is widely known that South Asian and Black minority ethnic groups, in the United Kingdom, have a higher incidence and prevalence of cardiovascular disease and it is thought that this may in turn place these ethnic groups at a greater risk of developing dementia than the White ethnic groups. This study seeks to explore this theory further, using large scale population-based databases, in the United Kingdom.
Methods: All eligible participants over the age of 50 years from the CPRD database, that were free from a diagnosis of dementia at time of entry to the study, those with an ethnic coding were stratified into 5 different ethnic groups, White, Black, South Asian, East Asian and Mixed. Their trajectories were followed over the observation period from 1996 to the end of the study (2016). Cardiovascular Disease (CVD) and available lifestyle risk factor data relating to the development of dementia were also recorded over this period.
Results: A total of 1,091,242 individuals were included in the analytical sample, after exclusion of those with missing ethnicity data. There were a total of 174,546 (16.3%) cases of ascertained dementia. The white ethnic group had a higher mean age of dementia onset 81.8 years (SD 8.6) just ahead of the East Asian 80.3 years (8.9) ethnic group and the lowest mean age of onset seen in the Black ethnic group 76.3 years (SD 9.4). The fully adjusted Cox regression model (adjusting for all covariates including, socioeconomic status and education) revealed a lower risk of incident dementia in the Black [HR 0.83 (95% CI 0.74-0.93)] and South Asian ethnic groups [HR 0.55 (95% CI 0.49-0.61)], and the excessive risk in East Asian ethnic group was no longer found to be significant [HR 1.14 (95% CI 0.93-1.42)]. The East Asian ethnic group had a higher cumulative incidence of dementia than any other ethnic group when accounting for death as a competing risk [sdHR 1.37, (95% CI 1.18-1.58 for East Asian compared to White ethnicity]. However, overall cumulative incidence rates of dementia did not significantly change between the other ethnic groups when accounting for death as a competing risk.
Conclusion: The lower incidence of dementia seen in the Black and South Asian groups is intriguing and may be due to case under ascertainment amongst these ethnic groups, in view of their higher risk of cardiovascular disease. Understanding the differences for ethnic variation in dementia rates is not only vital for aetiological research but also for the development of prevention strategies, health service planning and resource allocation.Open Acces
Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project)
No full textCopyright © 2004 Excerpta Medica Inc. All rights reserved.Diego F. Wyszynski, Dawn M. Waterworth, Philip J. Barter, Jonathan Cohen, Y. Antero Kesäniemi, Robert W. Mahley, Ruth McPherson, Gérard Waeber, Thomas P. Bersot, Sanjay S. Sharma, Vikki Nolan, Lefkos T. Middleton, Scott S. Sundseth, Lindsay A. Farrer, Vincent Mooser, Scott M. Grund
Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson's Disease
No full textBackground
Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross‐sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug‐naive PD patients.
Methods
Twelve early drug‐naive PD patients and 16 healthy controls underwent a 3‐Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB‐J, [11C]SA‐4503, and [18F]BCPP‐EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1‐year follow‐up assessments.
Results
Reduced [11C]UCB‐J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug‐naive PD patients compared with healthy controls. [11C]UCB‐J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA‐4503 and [18F]BCPP‐EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB‐J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow‐up compared with baseline.
Conclusions
Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug‐naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow‐up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society
Is there an association between cancer and dementia in cohorts with and without T2DM? A national observational study
No full textBackground: Previous studies have suggested an inverse association and a hypothesized mutually protective effect between several forms of cancer and late-onset dementia (LOD). Type 2 diabetes (T2DM) is an established important risk factor for both diseases; however, the precise relationships between T2DM, cancer and LOD still remain poorly understood. This thesis investigates the relationship between different cancers and risk of LOD, and explores the role of prediabetes or T2DM in these associations.
Methodology: Using the Clinical Practice Research Datalink (CPRD), a massive UK primary care database, in years, 1998-2015, a sample of individuals ≥ 65 years old, with and without T2DM were identified. All individuals aged ≥ 65 years old, with and without a T2DM diagnosis were included in this analysis. Individuals with an LOD diagnosis prior to 65 years of age or prior to a T2DM diagnosis, were excluded. All study participants were followed up from the index date to the censor date. Participants were censored at point of LOD diagnosis, death, end of observation period (2015) or last data upload date (last date of follow-up), whichever came first. It was required that participants have been under observation by CPRD for > 1 year prior to cohort entry. Exploratory analyses were performed to investigate the incidence rates of LOD in both non-T2DM and T2DM cohorts. Cox proportional hazard models, with time-dependent covariates, were used to determine the risk of LOD in individuals with and without a cancer diagnosis in both non-T2DM and T2DM cohorts. The cause-specific hazard ratio (csHR) and sub-distribution hazard ratio (sdHR) for overall LOD and death in individuals with cancer were computed, to account for death as a competing risk.
Results: Separate analyses amongst 217,335 individuals with T2DM and 739,061 without T2DM were performed. The mean age (SD) of individuals with T2DM at cohort entry was 71.62 (7.09) years (47.3% females) vs.70.80 (7.66) years (56.9 % females) in the non-T2DM cohort. During follow-up, a total of 165,272 (22 %) and 32,022 (15 %) cancer cases and 51,733 (7 %) and 11,450 (5%) LOD cases were identified in the non-T2DM and T2DM cohorts, respectively. In the non-T2DM cohort, 10,602 (6 %) had both LOD and cancer diagnosis vs. 1,172 (4%) in the T2DM cohort. The incidence rate of LOD was higher in females in both non-T2DM and T2DM cohorts (non-T2DM: 7.15 per 1,000 person years in males and 10.04 per 1,000 person years in females; T2DM: 6.96 per 1,000 person years in males and 10.57 per 1,000 person years in females). There was a higher risk for LOD in cancer individuals in the
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non-T2DM cohort [HR 1.16, 95 % CI (1.13-1.20)]. Conversely, in the T2DM cohort, there was a significantly lower risk for developing LOD in lung cancer participants vs. no cancer group [HR 0.52, 95 % CI (0.29-0.94)]. In the presence of death as a competing risk for LOD, lung cancer showed an even more intensified “protective relationship” (sdHR 0.11 (95% CI 0.06, 0.21), when compared to the cause specific hazard ratios (csHR of 1.16 (95% CI 1.13, 1.20). The cumulative incidence function curves showed that in the presence of death, there is a protective effect of cancer on LOD incidence in both cohorts (not observed for csHRs).
Conclusion: Examining the cause-specific and sub distribution hazard models led to the conclusion that the inverse association observed between cancer, lung cancer and LOD, especially in the T2DM cohort, is most likely due to mortality selection. Careful consideration of statistical model specifications is imperative, particularly in older adult population research, where mortality is inevitable.Open Acces
What can artificial intelligence bring to Alzheimer\u2019s disease clinical trials? A first perspective
No full textAssociations of diabetes control and anti-diabetes medications with the risk of dementia in patients with diabetes: a cohort study based on the UK Clinical Practice Research Datalink
No full textBackground: Type 2 diabetes (T2D) is a well-established risk factor for dementia. However, the role of glycaemic control in the development of dementia has been less well substantiated. Metformin, a first-line anti-diabetes drug, has been suggested as a promising disease-modifying agent for dementia, but the evidence of its beneficial effect has been partial and inconsistent.
Methods: A series of large-scale cohort studies were conducted based on the UK Clinical Practice Research Datalink (CPRD) between 1987 and 2018. Time-varying Cox proportional hazards model was adopted to estimate associations of longitudinal HbA1c levels and diabetic complications with dementia incidence among T2D patients. Risk of dementia incidence was then compared between patients initially treated with metformin and those initially treated with sulfonylureas or patients receiving no anti-diabetes drugs during registration.
Results: During a median of six years follow-up, 28,627 incident dementia cases were observed among 457,902 T2D patients. Patients with recorded hypoglycaemia or microvascular complications had higher risk of dementia compared to those without such complications (HR=1.30 [95% CI: 1.22-1.39] or 1.10 [95% CI: 1.06-1.14]). Time-varying HbA1c was associated with increased dementia risk (HR=1.08, 95% CI: 1.07-1.09 per 1% HbA1c increment). Both conventional Cox regression and propensity score weighting analysis showed metformin initiators had lower risk of dementia compared with sulfonylurea initiators (HR=0.91 [95% CI: 0.87-0.95] and 0.88 [95% CI: 0.81-0.96]) or patients receiving no anti-diabetes drugs (HR=0.86 [95% CI: 0.83-0.90] and 0.94 [95% CI: 0.90-0.99]). HbA1c and diabetic complications during follow-up only partially mediated the inverse metformin-dementia association.
Conclusions: This thesis highlights the importance of effective glycaemic management in maintaining cognitive health among diabetes patients and provides evidence on a beneficial effect of metformin for dementia prevention. Metformin may reduce dementia risk beyond its effect on diabetes control, thus has the potential of being repurposed for dementia prevention in the general population.Open Acces
Novel PET biomarkers to disentangle molecular pathways across age-related neurodegenerative diseases
No full textThere is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers
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