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Cortical dysfunction in non-demented Parkinson's disease patients: a combined (31)P-MRS and (18)FDG-PET study.
Regional cerebral phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) was performed in 10 non- demented Parkinson's disease patients and nine age-matched control subjects. Five of the patients undergoing (31)P-MRS and four additional Parkinson's disease patients had cerebral 2-[(18)F]fluoro-2-deoxy-D-glucose PET ((18)FDG-PET), the results of which were compared with those of eight age-matched control subjects. All Parkinson's disease patients underwent neuropsychological testing including performance and verbal subtests of the Wechsler Adult Intelligence Scale-Revised, Boston Naming Test, Controlled Oral Word Association test (FAS Test) and California Learning Test to exclude clinical dementia. (31)P MR spectra from right and left temporo-parietal cortex, occipital cortex and a central voxel incorporating basal ganglia and brainstem were obtained. (31)P MR peak area ratios of signals from phosphomonoesters (PMEs), inorganic phosphate (P(i)), phosphodiesters (PDEs), alpha-ATP, gamma-ATP and phosphocreatine (PCr) relative to beta-ATP were measured. Relative percentage peak areas of PMEs, P(i), PDEs, PCr, and alpha-, beta- and gamma-ATP signals were also measured with respect to the total (31)P-MRS signal. Significant bilateral increases in the P(i)/beta-ATP ratio were found in temporoparietal cortex (P = 0.002 right and P = 0.014 left cortex) for the non-demented Parkinson's disease patients compared with controls. In the right temporoparietal cortex, there was also a significant increase in the mean relative percentage P(i) (P = 0.001). (18)FDG-PET revealed absolute bilateral reductions in glucose metabolism after partial volume effect correction in posterior parietal and temporal cortical grey matter (P < 0.01 and P < 0.05, respectively) for the Parkinson's disease group, using both volume of interest analysis and statistical parametric mapping. There were significant correlations between right temporoparietal P(i)/beta-ATP ratios and estimated reductions in performance IQ (r = 0.96, P < 0.001). Left temporoparietal P(i)/beta-ATP ratios correlated with full scale IQ and verbal IQ (r = -0.82, P = 0.006, r = -0.86, P = 0.003, respectively). In summary, temporoparietal cortical hypometabolism was seen in non-demented Parkinson's disease patients with both (31)P-MRS and (18)FDG-PET, suggesting that both glycolytic and oxidative pathways are impaired. This dysfunction may reflect either the presence of primary cortical pathology or deafferentation of striato-cortical projections. (31)P-MRS and (18)FDG-PET may both provide useful predictors of future cognitive impairment in a subset of Parkinson's disease patients who go on to develop dementia.
Atypical parkinsonism in Afro-Caribbean and Indian origin immigrants to the UK.
This article reviews evidence for the occurrence of atypical parkinsonism in Afro-Caribbean and Indian ethnic minority subjects living in western countries, particularly the UK. Current information on the frequency, pattern, and prevalence of Parkinson's disease and parkinsonism in these communities is unclear and controversial. While several workers have suggested that there is a low prevalence of Parkinson's disease in populations of African origin, other workers have suggested a higher prevalence of Parkinson's disease in African Americans. Furthermore, little information is available in relation to the pattern of parkinsonism in these subjects. A recent phenomenologic study of parkinsonism in the French West Indies by Caparros-Lefebvre and colleagues has indicated a significantly increased frequency of atypical parkinsonism in local non-white subjects. Since 1995, we have been studying the pattern and frequency of parkinsonism in Afro-Caribbean and Indian (originating from the Indian subcontinent) patients living in the UK, with London serving as the coordinating center. Our results indicate that there is a three- to fourfold increase in the frequency of occurrence of sporadic atypical parkinsonism characterized by levodopa hyporesponsiveness, bradykinesia-dominant disease, and early cognitive dysfunction in these patients even after exclusion of patients with clinically probable multiple system atrophy, progressive supranuclear palsy, and Lewy body dementia. These findings are similar to observations made in the French West Indies. Ongoing studies in India suggest that atypical parkinsonism also affects local patients, and the pattern of parkinsonism tends to differ from Afro-Caribbean subjects in the UK. Studies are currently underway to unravel the mechanism of increased frequency of atypical parkinsonism in these ethnic groups and include genetic studies addressing polymorphisms of enzymes metabolizing levodopa, dietary neurotoxin screen and functional imaging studies of the striatum using positron emission tomography. Furthermore, the contribution of diabetes mellitus and hypertension, commonly seen in these ethnic groups, is also being examined.
Evidence for cortical dysfunction in clinically non-demented patients with Parkinson's disease: a proton MR spectroscopy study.
OBJECTIVES: To investigate whether proton magnetic resonance spectroscopy (1H MRS) can detect cortical dysfunction in non-demented patients with Parkinson's disease, and to correlate changes with cognitive function on formal neuropsychological testing. METHODS: Multivoxel 1H MRS was performed in 17 patients with levodopa treated idiopathic Parkinson's disease with out clinical dementia, and 10 age match ed control subjects. Measurements of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine+phosphocreatine (Cr), and Cho/Cr were obtained from right and left temporoparietal cortex and occipital cortex. Fourteen patients with Parkinson's disease underwent a full battery of neuropsychological testing including performance and verbal subtests of the WAIS-R, Boston naming test, FAS test, and California verbal learning test. RESULTS: There were significant temporoparietal cortex reductions in NAA/Cr ratios in right and left averaged spectra of the patients with Parkinson's disease (p=0.012 after Bonferroni correction) and in spectra contralateral to the worst clinically affected limbs of the patients with Parkinson's disease compared with controls (p = 0.003 after Bonferroni correction). There was a significant correlation between reduction in NAA/Cr ratios and measures of global cognitive decline, occurring independently of motor impairment (p=0.019). CONCLUSIONS: This study suggests that 1H MRS can detect temporoparietal cortical dysfunction in non-demented patients with Parkinson's disease. Further longitudinal studies are needed to investigate whether these 1H MRS changes are predictive of future cognitive impairment in the subset of patients with Parkinson's disease who go on to develop dementia, or occur as part of the normal Parkinson's disease process.
Limb contractures in levodopa-responsive parkinsonism: a clinical and investigational study of seven new cases.
We describe six patients with classical levodopa-responsive Parkinson's disease (PD) and one case of levodopa-responsive familial juvenile dystonia-parkinsonism with fixed contractures of the hands, feet or legs. In most patients contractures became established over a short period (2 months-2 years) but a considerable time after onset of parkinsonism (mean 13 years). Mean disease duration was 17 years, and all patients had severe levodopa-induced dyskinesias, either biphasic or peak dose, in the affected limb prior to onset of the contracture. Nerve conduction studies excluded peripheral ulnar nerve lesions in all patients with one exception, who was found to have a mild bilateral ulnar entrapment neuropathy. Transcranial magnetic stimulation performed in five of the seven patients showed shorter mean central motor conduction time in the affected than in the unaffected limb. Results of magnetic resonance imaging of the brain performed in a subgroup of patients were normal, with no evidence to suggest multiple system atrophy, cerebral infarction or focal abnormalities of the basal ganglia. We conclude that hand and feet contractures are not necessarily restricted to parkinson plus syndromes and may complicate otherwise typical PD in the absence of a structural or peripheral nervous cause. Striatal dopaminergic deficiency, particularly long-standing, may have a role in the pathogenesis of limb contractures in PD.
A Heterogeneous Sensing Suite for Multisymptom Quantification of Parkinson's Disease.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting millions worldwide. Bespoke subject-specific treatment (medication or deep brain stimulation (DBS)) is critical for management, yet depends on precise assessment cardinal PD symptoms - bradykinesia, rigidity and tremor. Clinician diagnosis is the basis of treatment, yet it allows only a cross-sectional assessment of symptoms which can vary on an hourly basis and is liable to inter- and intra-rater subjectivity across human examiners. Automated symptomatic assessment has attracted significant interest to optimise treatment regimens between clinician visits, however, no wearable has the capacity to simultaneously assess all three cardinal symptoms. Challenges in the measurement of rigidity, mapping muscle activity out-of-clinic and sensor fusion have inhibited translation. In this study, we address all through a novel wearable sensor system and machine learning algorithms. The sensor system is composed of a force-sensor, three inertial measurement units (IMUs) and four custom mechanomyography (MMG) sensors. The system was tested in its capacity to predict Unified Parkinson's Disease Rating Scale (UPDRS) scores based on quantitative assessment of bradykinesia, rigidity and tremor in PD patients. 23 PD patients were tested with the sensor system in parallel with exams conducted by treating clinicians and 10 healthy subjects were recruited as a comparison control group. Results prove the system accurately predicts UPDRS scores for all symptoms (85.4% match on average with physician assessment) and discriminates between healthy subjects and PD patients (96.6% on average). MMG features can also be used for remote monitoring of severity and fluctuations in PD symptoms out-of-clinic. This closed-loop feedback system enables individually tailored and regularly updated treatment, facilitating better outcomes for a very large patient population.
Multiple sclerosis in Japan appears to be a milder disease compared to the UK
© 2015, Springer-Verlag Berlin Heidelberg. Multiple sclerosis (MS) is relatively common in the West, but rare in Japan. In the literature, there are few comparative data regarding disease severity throughout the world. The objective of this study was to compare disability in patients from a UK and a Japanese MS cohort. We retrospectively analysed the clinical features of patients with MS from a UK and Japanese MS centre. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Expanded Disability Status Scale score according to disease duration, was used as a marker of disease severity. One thousand one hundred forty-eight UK patients and 104 Japanese patient were identified representing the relative national prevalence. Demographics and disease duration did not differ between the groups. Median MSSS was significantly different between the two groups (Japan 3.34 vs. UK 5.87, p < 0.001). Primary progressive MS was more common in the UK (12.9 %) than in the Japanese cohort (3 %, p = 0.044). The majority of Japanese patients (83.7 % vs. UK 17 %) had been exposed to disease modifying treatments (DMTs). Exposure to DMTs did not show a significant effect on disability. In conclusion, this study suggests that MS in Japan may be associated with less disability than in UK. More Japanese patients were treated with DMTs. Differences in treatments do not seem to explain the disparity in disability severity. This suggests either genetic or environmental influences on disease severity.
FEATURES IN IDIOPATHIC RBD MIRROR THOSE OBSERVED IN PD
<jats:sec><jats:title>Introduction</jats:title><jats:p>Patients with idiopathic RBD have an increased risk of developing a defined neurodegenerative disorder, the majority developing PD. Is it possible to detect features of PD in RBD, before a diagnosis of PD is established?</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Fifty-seven patients with polysomnography-proven idiopathic RBD and seventy-four control and drug-naïve PD subjects were recruited. All participants underwent a thorough motor and non-motor assessment, and were screened for mutations in glucocerebrosidase (GBA) genes. Visual working memory was separately assessed in 21 RBD, 15 drug-naïve PD and 21 controls using a serial order task testing both recall precision and the pattern of impairment.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>RBD patients had increased motor and postural impairment compared to controls. Non-motor deficits (hyposmia, constipation, depression, anxiety) were similar between RBD and PD cases. Furthermore, there was a significant deficit of working memory memory recall precision in PD and RBD, with the pattern of deficit being similar in both groups.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>RBD is associated with motor and non-motor impairment often seen in early PD. The pattern of visual working memory impairment in RBD is equivalent to that observed in early PD. These results support the hypothesis that idiopathic RBD is representative of prodromal sporadic PD.</jats:p></jats:sec>
IMPACT & TREATMENT OF NON-MOTOR SYMPTOMS IN EARLY PARKINSON'S DISEASE
<jats:sec><jats:title>Objective</jats:title><jats:p>To delineate treatment and quality of life of non-motor symptoms (NMS) in early Parkinson's disease (PD) and first-degree relatives.</jats:p></jats:sec><jats:sec><jats:title>Background</jats:title><jats:p>Non-motor symptoms (NMS) are an important prodromal feature of Parkinson's disease (PD). However, their frequency, treatment rates and impact on health-related quality of life (HRQoL) in the early motor phase is unclear.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>769 population-ascertained PD subjects within 3.5 years of diagnosis and 287 control subjects were assessed. Validated severity questionnaires were employed to assess NMS symptoms across the following domains: (1) neuropsychiatric (2) gastrointestinal (3) sleep (4) sensory (5) autonomic (6) sexual. Health related quality of life (HRQoL), functional status and management were also evaluated.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>NMS were common in early PD. More than half of the PD cases had hyposmia, pain, fatigue, sleep disturbance or urinary dysfunction. PD cases had worse HRQoL scores than controls (OR 4.1, p<0.001) with depression, anxiety and pain being stronger drivers than MDS-UPDRS motor scores. Quality of life is affected in early PD, although 23% of participants reported no problems. NMS were rarely treated in routine clinical practice.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Despite their major impact on HRQoL, NMS are usually under-recognised and treated. The use of screening tools could improve recognition and treatment of NMS in early PD.</jats:p></jats:sec>
NEUROIMAGING OF IDIOPATHIC REM SLEEP BEHAVIOR DISORDER
<jats:sec><jats:title>Introduction</jats:title><jats:p>Resting-state functional magnetic resonance imaging (rs-fMRI) studies have previously shown significantly impaired connectivity in patients within the early motor phase of Parkinson's disease. Is it possible to detect the same imaging signature of Parkinson's in RBD subjects, before a clinical diagnosis of Parkinson's disease is established?</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Twenty-six patients with polysomnography-proven RBD and twenty-two age- and sex-matched healthy controls were recruited into the study. All subjects underwent a comprehensive structural and resting-state MRI protocol.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Voxel-based morphometry analysis did not yield any significant grey matter differences between the two groups. Similarly, no significant differences of fractional anisotropy were found using white matter tract analysis. Rs-fMRI revealed decreased coactivation within the basal ganglia network (involving the caudate, putamen, globus pallidus bilaterally) and the sensorimotor network (precentral gyrus) of patients with RBD. A small area of increased coactivation was found in the default mode network of patients with RBD.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our findings support the presence of basal ganglia dysfunction in patients with RBD, likely representing the prodromal stages of Parkinson's disease. Clinical and neuroimaging follow up is necessary to assess the clinical utility of resting state fMRI to predict the onset of Parkinson's disease in RBD subjects.</jats:p></jats:sec>