6 research outputs found
Impaired synaptic function is linked to cognition in Parkinson's disease
OBJECTIVE:
Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloidâβ species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloidâβ release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloidâβ, and presynaptic deposits of Îąâsynuclein. We expect a correlation between hypometabolism, CSF amyloidâβ, and the synapse relatedâmarkers CSF neurogranin and Îąâsynuclein.
METHODS:
Thirty patients with mildâtoâmoderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18FâfludeoxyglucoseâPET, and a neuropsychological test battery (repeated for the patients after 2 years).
RESULTS:
All subjects had CSF amyloidâβ 1â42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aβ, Îąâsynuclein, and neurogranin. All PET CSF biomarkerâbased cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mildâtoâmoderate Parkinson's disease compared to controls, correlated with amyloidâβ and Îąâsynuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group.
INTERPRETATION:
CSF Aβ, Îąâsynuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aβ and Îąâsynuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease
The genetic epidemiology of joint shape and the development of osteoarthritis
Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts forâ~â50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk
Alzheimerâs disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rgâ=â0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD
Whole-genome sequencing identifies rare genotypes in <em>COMP</em> and <em>CHADL</em> associated with high risk of hip osteoarthritis
Prevalence of the apolipoprotein E ξ4 allele in amyloid β positive subjects across the spectrum of Alzheimer\u27s disease
Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease
Introduction:
Apolipoprotein E (APOE) ξ4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.
Methods:
We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ξ4 prevalence in relation to age, sex, education, and geographical location.
Results:
The APOE ξ4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.
Discussion:
The APOE ξ4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location