In a randomized, delayed-start trial of levodopa in Parkinson’s disease, with one group receiving the drug for 80 weeks and the other starting at 40 weeks, the difference between the groups in the ...progression of symptoms was not significant.
Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical ...parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.
We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.
Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.
Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.
Summary Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently ...defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.
Abstract
Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson’s disease (PD), a recent ...meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores at baseline and 6–12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation.
Objective
Selective focal MR‐Signal (diffusion‐) changes in the CA‐1 sector of the hippocampus have been described in transient global amnesia (TGA), but the pathophysiological substrate of these ...lesions is largely unknown. As several imaging and epidemiological findings point to a vascular origin an analysis of the temporal evolution of the hippocampal apparent diffusion coefficient (ADC) changes may offer new understanding of the pathomechanisms of TGA.
Methods
The time course of the ADC of hippocampal DWI lesions in TGA patients was studied using serial 3 T high‐resolution MR‐imaging within 1‐10 days as well as 4‐6 months after TGA. ADC values from 76 MR‐studies were analyzed and expressed as ratio ADC (rADC) in reference to the unaffected hemisphere.
Results
Twenty‐nine patients with TGA showed 34 DWI lesions with corresponding T2 lesions in the CA‐1 sector of the hippocampal cornu ammonis within a time window of 24‐72 h after onset. Ratio ADC decreased below 1.0 (0.66 ± 0.08) 24 h after the acute TGA episode and did show a further significant decrease to 0.57 ± 0.1 after 3 days (p < 0.05). After 72 h, rADC increased and normalized around day 10 with rADC values of 1.0 (p < 0.05).
Interpretation
The temporal evolution of the rADC in hippocampal signal changes in TGA shows a time course previously described for ischemic lesions in human stroke patients. This might imply a vascular origin of diffusion changes leading to a transient perturbation of memory relevant circuits in the hippocampus. Ann Neurol 2007
The EARLYSTIM Study compared deep brain stimulation (DBS) with best medical treatment (BMT) over 2-years, showing a between-group difference of 8.0 from baseline in favor of DBS in health-related ...quality of life (HRQoL), measured with the PDQ-39 SI (summary index). This study obtained complementary information about the importance of the change in HRQoL as measured by the PDQ-39, using anchor-based (Patient Global Impression of Change, PGIC) and distribution-based techniques (magnitude of change, effect size, thresholds, distribution of benefit) applied to the EARLYSTIM study data. Anchor-based techniques showed a difference follow-up-baseline for patients who reported "minimal improvement" of -5.8 -9.9, -1.6 (mean 95%CI) in the DBS group vs -2.9 -9.0, 3.1 in the BMT group. As the vast majority (80.8%) of DBS patients reported "much or very much improvement", this difference was explored for the latter group and amounted to -8.7 for the DBS group and -6.5 in the BMT group. Distribution-based techniques that analyzed the relative change and treatment effect size showed a moderate benefit of the DBS on the HRQoL, whereas a slight worsening was observed in the BMT group. The change in the DBS group (-7.8) was higher than the MIC (Minimally Important Change) estimated value (-5.8 by the anchor; -6.3 by triangulation of thresholds), but not in the BMT (0.2 vs. -3.0 to -5.4, respectively). Almost 90% of the patients in the DBS group declared some improvement (58.3% and 56.7% beyond the estimated MIC), which was significantly different from the BMT group whose proportions were 32.0% and 30.3%, respectively. The number needed to treat to improve greater than or equal to1 MIC by DBS vs BMT was 3.8. Change in depression, disability and pain influenced the improvement of the DBS group. DBS improved HRQoL in a high proportion of patients to a significant and moderate degree, at 2 years follow-up.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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