Tau as a Biomarker of Neurodegeneration Holper, Sarah; Watson, Rosie; Yassi, Nawaf
International journal of molecular sciences,
06/2022, Letnik:
23, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Less than 50 years since tau was first isolated from a porcine brain, its detection in femtolitre concentrations in biological fluids is revolutionizing the diagnosis of neurodegenerative diseases. ...This review highlights the molecular and technological advances that have catapulted tau from obscurity to the forefront of biomarker diagnostics. Comprehensive updates are provided describing the burgeoning clinical applications of tau as a biomarker of neurodegeneration. For the clinician, tau not only enhances diagnostic accuracy, but holds promise as a predictor of clinical progression, phenotype, and response to drug therapy. For patients living with neurodegenerative disorders, characterization of tau dysregulation could provide much-needed clarity to a notoriously murky diagnostic landscape.
Late-onset Alzheimer's disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer's disease before symptoms are established ...is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and metabolites, are emerging as powerful predictors of Alzheimer's disease at various timepoints within the disease course, including at the preclinical stage. In this review, we discuss recent advances in such blood biomarkers for determining disease risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their risk profile. We summarize studies analyzing protein biomarkers, as well as report on recent proteomic- and metabolomic-based prediction models. Finally, we discuss how a combination of multi-omic blood biomarkers can potentially be used in memory clinics for diagnosis and to assess the dynamic risk an individual has for developing Alzheimer's disease dementia.
The diagnosis of dementia with Lewy bodies presents specific challenges in clinical practice, with no readily available disease‐specific biomarkers. This leads to delays in diagnosis, exposure to ...inappropriate treatments, and may be a contributor to poorer outcomes for patients and their caregivers.
There has been renewed interest in developing technologies for the measurement of dysregulated alpha‐synuclein, with some of these techniques yielding promising early results. Further validation of these techniques and exploration their transferability to blood‐based technologies is underway.
Much work has been conducted on using fluid biomarkers to understand the overlap of dementia with Lewy bodies with other neuropathologies and its clinical significance. In particular, the prevalence and impact of comorbid amyloid‐beta and tau pathology in dementia with Lewy bodies has been investigated most thoroughly. In addition, overlap with other important neuropathologies including cerebrovascular disease and neuroinflammation is an area of active investigation.
Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, ...review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.
Dementia with Lewy bodies (DLB) is characterized by relative preservation of the medial temporal lobe compared with Alzheimer disease (AD). The differential involvement of the hippocampal subfields ...in both diseases has not been clearly established, however. We aim to investigate hippocampal subfield differences in vivo in a clinical cohort of DLB and AD subjects.
104 participants (35 DLBs, 36 ADs, and 35 healthy comparison HC subjects) underwent clinical assessment and 3T T1-weighted imaging. A Bayesian model implemented in Freesurfer was used to automatically segment the hippocampus and its subfields. We also examined associations between hippocampal subfields and tests of memory function.
Both the AD and DLB groups demonstrated significant atrophy of the total hippocampus relative to HC but the DLB group was characterized by preservation of the cornu ammonis 1 (CA1), fimbria, and fissure. In contrast, all the hippocampal subfields except the fissure were significantly atrophied in AD compared with both DLB and HC groups. Among DLB subjects, CA1 was correlated with the Recent Memory score of the CAMCOG and Delayed Recall subscores of the HVLT.
DLB is characterized by milder hippocampal atrophy that was accompanied by preservation of the CA1. The CA1 was also associated with memory function in DLB. Our findings highlight the promising role of hippocampal subfield volumetry, particularly that of the CA1, as a biomarker for the distinction between AD and DLB.
Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from ...2013-2018, and to determine factors predicting choice of initial treatment.
Cohort of new-users (N = 4,887) of anti-Parkinson medication aged ≥ 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex.
Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged ≥ 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged < 65 years, rates of treatment initiation with DAs (37%) and levodopa (37%) were similar in 2013/2014 but initiation with DA exceeded levodopa thereafter. Among men aged < 65 years, treatment initiation with levodopa (44%-49%) remained more frequent than initiation with DAs (29%-32%) throughout the study period.
Treatment initiation with levodopa was most frequent among persons aged ≥ 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.
To compare magnetic resonance imaging (MRI) patterns of cortical thinning in subjects with dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and normal aging and investigate the relationship ...between cortical thickness and clinical measures.
Study participants (31 DLB, 30 AD, and 33 healthy comparison subjects) underwent 3-Tesla T1-weighted MRI and completed clinical and cognitive assessments. We used the FreeSurfer analysis package to measure cortical thickness and investigated the patterns of cortical thinning across groups.
Cortical thinning in AD was found predominantly in the temporal and parietal areas extending into the frontal lobes (N = 63, df = 59, t >3.3, p <0.005, FDR-corrected). In DLB, cortical thinning was less diffuse with focal areas of cortical change predominantly affecting posterior structures (inferior parietal, posterior cingulate, and fusiform gyrus) (N = 64, df = 60, t >3.6, p <0.005, FDR-corrected). The average reduction in cortical thickness in medial temporal lobe structures was less in DLB (6%-10%) than in AD (15%-24%), and similar to the reduction in cortical thickness observed in other regions including inferior parietal, precuneus, and posterior cingulate (6%-9%). Associations between cortical thickness and clinical measures (MMSE and verbal fluency) were also observed in DLB (N = 31, df = 27, t >2.8, p <0.01 uncorrected).
Cortical thickness may be a sensitive measure for characterising gray matter loss in DLB and highlights important structural imaging differences between the conditions.
Preventive zinc supplementation provided as a stand-alone dispersible tablet, or via home fortification as multiple micronutrient powders (MNPs), has been considered a potential strategy to prevent ...zinc deficiency and improve health (including immune) outcomes among children in low- and middle-income countries. However, the impact of zinc supplementation on immune profiles has not been well characterized. We sought to define the effect of zinc supplementation on peripheral blood gene expression and cytokine levels among young children in Dhaka, Bangladesh. In a sub-study of a large randomized, controlled, community-based efficacy trial where children 9–11 months of age received one of the following interventions on a daily basis for 24 weeks: (1) MNPs containing 10 mg of zinc; (2) dispersible tablet containing 10 mg zinc; or (3) placebo powder, we used RNA sequencing to profile the peripheral blood gene expression, as well as highly sensitive multiplex assays to detect cytokine profiles. We profiled samples from 100 children enrolled in the parent trial (zinc MNPs 28, zinc tablets 39, placebo 33). We did not detect an effect from either zinc intervention on differential peripheral blood gene expression at the end of the intervention, or an effect from the intervention on changes in gene expression from baseline. We also did not detect an effect from either intervention on cytokine concentrations. Exploratory analysis did not identify an association between undernutrition (defined as stunting, underweight or wasting) and peripheral blood gene expression. Zinc interventions in children did not produce a gene expression or cytokine signature in the peripheral blood. However, this study demonstrates a proof of principle that sensitive multi-omic techniques can be applied to samples collected in field studies.
Percent whole brain volume change (PBVC) measured from serial MRI scans is widely accepted as a sensitive marker of disease progression in Alzheimer's disease (AD). However, the utility of PBVC in ...the differential diagnosis of dementia remains to be established. We compared PBVC in AD and dementia with Lewy bodies (DLB), and investigated associations with clinical measures.
72 participants (14 DLBs, 25 ADs, and 33 healthy controls (HCs)) underwent clinical assessment and 3 Tesla T1-weighted MRI at baseline and repeated at 12 months. We used FSL-SIENA to estimate PBVC for each subject. Voxelwise analyses and ANCOVA compared PBVC between DLB and AD, while correlational tests examined associations of PBVC with clinical measures.
AD had significantly greater atrophy over 1 year (1.8%) compared to DLB (1.0%; p = 0.01) and HC (0.9%; p < 0.01) in widespread regions of the brain including periventricular areas. PBVC was not significantly different between DLB and HC (p = 0.95). There were no differences in cognitive decline between DLB and AD. In the combined dementia group (AD and DLB), younger age was associated with higher atrophy rates (r = 0.49, p < 0.01).
AD showed a faster rate of global brain atrophy compared to DLB, which had similar rates of atrophy to HC. Among dementia subjects, younger age was associated with accelerated atrophy, reflecting more aggressive disease in younger people. PBVC could aid in differentiating between DLB and AD, however its utility as an outcome marker in DLB is limited.
Visuoperceptual deficits are common in dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Testing visuoperception in dementia is complicated by decline in other cognitive domains and ...extrapyramidal features. To overcome these issues, we developed a computerized test, the Newcastle visuoperception battery (NEVIP), which is independent of motor function and has minimal cognitive load.We aimed to test its utility to identify visuoperceptual deficits in people with dementia.
We recruited 28 AD and 26 DLB participants with 35 comparison participants of similar age and education. The NEVIP was used to test angle, color, and form discrimination along with motion perception to obtain a composite visuoperception score.
Those with DLB performed significantly worse than AD participants on the composite visuoperception score (Mann-Whitney U = 142, p = 0.01). Visuoperceptual deficits (defined as 2 SD below the performance of comparisons) were present in 71% of the DLB group and 40% of the AD group. Performance was not significantly correlated with motor impairment, but was significantly related to global cognitive impairment in DLB (rs = -0.689, p <0.001), but not in AD.
Visuoperceptual deficits can be detected in both DLB and AD participants using the NEVIP, with the DLB group performing significantly worse than AD. Visuoperception scores obtained by the NEVIP are independent of participant motor deficits and participants are able to comprehend and perform the tasks.
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