Parkinson disease (PD) is a progressive disorder characterized by dopaminergic neurodegeneration in the brain. The development of parkinsonism is preceded by a long prodromal phase, and >50% of ...dopaminergic neurons can be lost from the substantia nigra by the time of the initial diagnosis. Therefore, validation of in vivo imaging biomarkers for early diagnosis and monitoring of disease progression is essential for future therapeutic developments. PET and single-photon emission CT targeting the presynaptic terminals of dopaminergic neurons can be used for early diagnosis by detecting axonal degeneration in the striatum. However, these techniques poorly differentiate atypical parkinsonian syndromes from PD, and their availability is limited in clinical settings. Advanced MRI in which pathological changes in the substantia nigra are visualized with diffusion, iron-sensitive susceptibility and neuromelanin-sensitive sequences potentially represents a more accessible imaging tool. Although these techniques can visualize the classic degenerative changes in PD, they might be insufficient for phenotyping or prognostication of heterogeneous aspects of PD resulting from extranigral pathologies. The retina is an emerging imaging target owing to its pathological involvement early in PD, which correlates with brain pathology. Retinal optical coherence tomography (OCT) is a non-invasive technique to visualize structural changes in the retina. Progressive parafoveal thinning and fovea avascular zone remodelling, as revealed by OCT, provide potential biomarkers for early diagnosis and prognostication in PD. As we discuss in this Review, multimodal imaging of the substantia nigra and retina is a promising tool to aid diagnosis and management of PD.
Although there is clinical demand for new technology that can accurately measure Parkinsonian tremors, automatic scoring of Parkinsonian tremors using machine-learning approaches has not yet been ...employed. This study aims to fill this gap by proposing machine-learning algorithms as a way to predict the Unified Parkinson's Disease Rating Scale (UPDRS), which are similar to how neurologists rate scores in actual clinical practice. In this study, the tremor signals of 85 patients with Parkinson's disease (PD) were measured using a wrist-watch-type wearable device consisting of an accelerometer and a gyroscope. The displacement and angle signals were calculated from the measured acceleration and angular velocity, and the acceleration, angular velocity, displacement, and angle signals were used for analysis. Nineteen features were extracted from each signal, and the pairwise correlation strategy was used to reduce the number of feature dimensions. With the selected features, a decision tree (DT), support vector machine (SVM), discriminant analysis (DA), random forest (RF), and
-nearest-neighbor (
NN) algorithm were explored for automatic scoring of the Parkinsonian tremor severity. The performance of the employed classifiers was analyzed using accuracy, recall, and precision, and compared to other findings in similar studies. Finally, the limitations and plans for further study are discussed.
Chronic alpha-synuclein (
) overexpression is a relatively homogenous and well-defined cause of parkinsonism and dementia. Parkinson's disease (PD), PD with dementia, dementia with Lewy bodies and ...multiple system atrophy all manifest in
multiplication families. Herein we summarize genealogic, clinical and genetic data from 59 families (25 not previously published) with parkinsonism caused by
multiplications. Longitudinal clinical assessments and genealogic relationships were documented for all family members. All probands were genotyped with an Illumina MEGA high-density genotyping array to identify copy number variants (CNV) and enable
multiplication breakpoints to be defined. Three
short tandem repeat (STR) markers were genotyped in all available samples to validate genomic dosage and inheritance. A web-application was built as a forum for future data sharing. CNV analysis identified 49 subjects with heterozygous
duplication (CNV3), 2 with homozygous duplication (CNV4) and 7 with a triplication mutation (CNV4). Clinical presentations varied greatly throughout the cohort.
dosage correlates with disease onset (mean age of onset CNV3: 46.9 ± 10.5 years vs. 34.5 ± 7.4 CNV4,
= 0.003). Atypical or more severe clinical courses were described in several patients and dementia was noted in 50.9% of the probands. Neither the multiplication size (average 2.05 ± 2.45 Mb) nor the number of genes included (range 1-50) was associated with motor symptom onset or dementia. Families with
multiplication are rare and globally-distributed. Nevertheless, they may both inform and benefit from the development of
targeted therapeutic strategies relevant to the treatment of all alpha-synucleinopathies.
Objectives
To investigate peripapillary retinal nerve fiber layer (pRNFL) changes in patients with progressive supranuclear palsy (PSP).
Methods
We included 21 PSP patients (36 eyes) who underwent ...peripapillary optical coherence tomography (OCT) scans at 2.5 ± 1.3 years of disease, without ophthalmologic co-morbidities. We compared pRNFL thicknesses in PSP eyes with age-matched 22 controls (22 eyes) using generalized estimating equation model adjusting for intra-subject inter-eye correlations, age and sex. We also analyzed the correlation between the pRNFL thickness and clinical severity using Spearman’s correlation. In twelve PSP patients with 3 T brain MRI volumetric scan within 1 year of OCT exam, we investigated the correlation between the pRNFL thickness and brain atrophy using Pearson’s correlation.
Results
PSP patients had global pRNFL thinning compared to controls (beta = − 6.436,
p
= 0.025). Global pRNFL thickness correlated with Hoehn & Yahr stages (
r
= − 0.487,
p
= 0.025), and nasal pRNFL thinning showed a trend of correlation (uncorrected
p
< 0.05). Exploratory correlation analysis between global pRNFL thickness and nonmotor items in the PSP rating scale showed a trend toward association with sleep disturbances (uncorrected
p
= 0.008) and urinary incontinence (uncorrected
p
= 0.031), although not significant after Bonferroni correction (all 28 items). The patients had significant atrophy in the posterior cingulate cortex, third ventricle, pallidum, and midbrain with reduced midbrain-to-pons ratio, but no correlation was found between pRNFL thickness and brain volumes.
Conclusion
The pRNFL seems to be affected in PSP, which is more severe with advanced disease stages. Retinal investigation in a larger longitudinal cohort would help elucidate the pathophysiological role of retinal thinning in PSP.
Placebo response in degenerative cerebellar ataxias (CAs) has never been studied despite the large number of randomized controlled trials (RCTs) that have been conducted. In this descriptive review, ...we aimed to examine the placebo response in patients with CAs. We performed a literature search on PubMed for RCTs on CAs that were published from 1977 to January 2020 and collected data on the changes from the baseline to the endpoint on various objective ataxia-associated clinical rating scales. We reviewed 56 clinical trials, finally including 35 parallel-group studies and excluding 21 cross-over studies. The included studies were categorized as follows: (1) studies showing significant improvements in one or more ataxia scales in the placebo groups (
n
= 3); (2) studies reporting individual placebo responders with improvements in one or more ataxia scales in the placebo groups (
n
= 5)—the overall proportion of placebo responders was 31.9%; (3) studies showing mean changes in the direction of improvement in at least one ataxia scale in the placebo groups, though not statistically significant (
n
= 19); (4) studies showing no placebo response in any of the ataxia scales in the placebo groups (
n
= 4); (5) studies where data on the placebo groups were unavailable (
n
= 9). This review demonstrated the placebo response in patients with CAs on various objective ataxia scales. Our study emphasizes that the placebo response should be considered when designing, analyzing, and interpreting clinical trials and in clinical practice in CA patients.
Subthalamic nucleus deep brain stimulation (STN DBS) is effective against freezing of gait (FOG) in Parkinson's disease (PD); however, whether this effect persists over the long term is debated. The ...aim of the current study was to investigate the long-term effect of STN DBS on FOG in patients with PD.
Data on 52 cases in which PD patients received bilateral STN DBS were obtained from a prospective registry. The authors blindly analyzed FOG incidence and its severity from the videotapes of a 5-m walking task at the baseline and at the 1-, 2-, and 5- or 7-year follow-up visits. They also compared the axial score from the Unified Parkinson's Disease Rating Scale (UPDRS) part III, UPDRS part II (UPDRS-II) item 14, and the FOG questionnaire (FOG-Q). Postoperatively, video-based FOG analysis and the axial score were evaluated under 4 conditions (off-medication/off-stimulation, off-medication/on-stimulation, on-medication/off-stimulation, and on-medication/on-stimulation), and UPDRS-II item 14 and the FOG-Q score were evaluated under 2 conditions (off-medication/on-stimulation and on-medication/on-stimulation).
During the off-medication state, the on-stimulation condition improved FOG outcomes, except for video-based FOG severity, up to the last follow-up compared with the baseline. Video-based FOG outcomes and the axial score during the off-medication state were improved with the on-stimulation condition up to the last follow-up compared with the off-stimulation condition. During the on-medication state, the on-stimulation condition did not improve any FOG outcome compared with the baseline; however, it improved video-based FOG outcomes up to the 2-year follow-up and the axial score up to the last follow-up compared with the off-stimulation condition.
Our findings suggest that STN DBS has a long-term effect on FOG in the off-medication state. However, STN DBS did not show a long-term effect on FOG in the on-medication state, although it had a short-term effect until the 2-year follow-up.
To investigate the longitudinal change of non-motor symptoms according to the age at onset in Parkinson's disease (PD).
This cohort study using the Parkinson's Progression Markers Initiative data ...included 405 patients with early PD. They were classified into late-onset (age at onset ≥ 70 years, n = 63), middle-onset (50 to 69 years, n = 268), and young-onset (<50 years, n = 74) groups. Non-motor symptoms were assessed with well-validated instruments covering neuropsychiatric, sleep-related, and autonomic symptoms yearly over 5 years of follow-up. Dopamine transporter imaging was also performed at baseline and the 1-, 2-, and 4-year follow-up visits.
The late-onset group had a mean decrease of 0.35 more points per year in the Montreal Cognitive Assessment (MoCA) scores (p = 0.008) and increases of 0.32 more points in the 15-item Geriatric Depression Scale scores (p = 0.002) and 0.72 more points in the State-Trait Anxiety Inventory-state scores (p = 0.022) compared to the middle-onset group. The young-onset group had a mean decrease of 0.22 fewer points per year in the MoCA scores (p = 0.002) than the middle-onset group. The other non-motor progression did not differ among the groups. No significant differences were found between the late-onset, middle-onset, and young-onset groups in the changes of striatal DAT binding ratios.
Compared to middle-onset PD, late-onset PD showed a faster progression of cognitive impairment along with depression and anxiety, and young-onset PD showed a slower progression of cognitive impairment in the early phases of the disease. These differences do not appear to be associated with the longitudinal changes in striatal dopaminergic activities.
•Late-onset PD showed faster decline in cognitive impairment, depression, and anxiety compared to middle-onset PD.•Young-onset PD showed a slower progression of cognitive impairment compared to middle-onset PD.•These differences do not appear to be related to the longitudinal changes in striatal dopaminergic activities.
The current study was designed to determine whether the degree of presynaptic striatal dopamine depletion can predict the later development of freezing of gait (FOG) in Parkinson's disease (PD).
This ...retrospective cohort study included 390 de novo patients with PD without FOG at baseline. The participants were divided into tertiles according to the baseline dopamine transporter (DAT) uptake of each striatal subregion, and the cumulative risk of FOG was compared using the Kaplan-Meier method. Cox proportional hazard models were used to assess the predictive power of DAT uptake of striatal subregions for the development of FOG.
During a median follow-up period of 4.0 years, 143 patients with PD (36.7%) developed FOG. The severe reduction group of DAT uptake in the caudate nucleus and putamen had a significantly higher incidence of FOG than that of the mild and moderate reduction groups. Multivariate Cox regression analyses showed that DAT uptakes in the caudate nucleus (hazard ratio HR 0.551; 95% confidence interval CI 0.392–0.773; p = 0.001) and putamen (HR 0.441; 95% CI 0.214–0.911; p = 0.027) predicted the development of FOG. In addition, male sex, higher postural instability and gait difficulty score, and a lower Montreal Cognitive Assessment score were also significant predictors of FOG.
Our finding suggests that presynaptic striatal dopaminergic denervation predicts the later development of FOG in de novo patients with PD, which may provide reliable insight into the mechanism of FOG in terms of nigrostriatal involvement.
•We examined the development of FOG in relation to the striatal dopaminergic denervation in 390 de novo patients with PD.•Lower levels of initial DAT activities in the caudate nucleus and putamen were significant predictors of FOG.•Male sex, higher PIGD score, and lower MoCA score also independently predicted FOG.
Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the ...same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency);
mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.
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