Detection of alpha-synuclein conformational variants from gastro-intestinal biopsy tissue as a potential biomarker for Parkinson's disease.

AIMS: Gastrointestinal (GI) α-synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well-characterized cohort of PD patients and healthy controls (HC). METHODS: With immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS-PLA), we targeted oligomeric aSyn species specifically; and with paraffin-embedded tissue blot (AS-PET-blot) we aimed to detect fibrillary, synaptic aSyn. RESULTS: A total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS-PLA (cellular and diffuse signal) and with AS-PET-blot (aSyn-localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC. CONCLUSIONS: Our study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

Cortical structural involvement and cognitive dysfunction in early Parkinson's disease.

Magnetic resonance imaging (MRI) studies in early Parkinson's disease (PD) have shown promise in the detection of disease-related brain changes in the white and deep grey matter. We set out to establish whether intrinsic cortical involvement in early PD can be detected with quantitative MRI. We collected a rich, multi-modal dataset, including diffusion MRI, T1 relaxometry and cortical morphometry, in 20 patients with early PD (disease duration, 1.9 ± 0.97 years, Hoehn & Yahr 1-2) and in 19 matched controls. The cortex was reconstructed using FreeSurfer. Data analysis employed linked independent component analysis (ICA), a novel data-driven technique that allows for data fusion and extraction of multi-modal components before further analysis. For comparison, we performed standard uni-modal analysis with a general linear model (GLM). Linked ICA detected multi-modal cortical changes in early PD (p = 0.015). These comprised fractional anisotropy reduction in dorsolateral prefrontal, cingulate and premotor cortex and the superior parietal lobule, mean diffusivity increase in the mesolimbic, somatosensory and superior parietal cortex, sparse diffusivity decrease in lateral parietal and right prefrontal cortex, and sparse changes to the cortex area. In PD, the amount of cortical dysintegrity correlated with diminished cognitive performance. Importantly, uni-modal analysis detected no significant group difference on any imaging modality. We detected microstructural cortical pathology in early PD using a data-driven, multi-modal approach. This pathology is correlated with diminished cognitive performance. Our results indicate that early degenerative processes leave an MRI signature in the cortex of patients with early PD. The cortical imaging findings are behaviourally meaningful and provide a link between cognitive status and microstructural cortical pathology in patients with early PD.

Apathy in rapid eye movement sleep behaviour disorder is common and under-recognized.

BACKGROUND AND PURPOSE: Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population. METHODS: Eighty-eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated. RESULTS: A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy. CONCLUSIONS: Apathy is common in RBD and is underestimated by a single self-report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.

A comparison of (18)F-dopa PET and inversion recovery MRI in the diagnosis of Parkinson's disease.

OBJECTIVE: To quantify structural changes in the substantia nigra of patients with PD with inversion recovery MRI and to compare these with striatal dopaminergic function measured with (18)F-dopa PET. METHODS: The authors studied 10 patients with PD and eight age-matched control subjects with a combination of MR sequences previously reported to be sensitive to nigral cell loss. Striatal regions of interest were defined on T1-weighted MRI coregistered to (18)F-dopa PET in all subjects. RESULTS: Discriminant function analysis of the quantified MR nigral signal correctly classified 83% of the combined PD patient/control group; three of 10 PD cases were incorrectly classified as "normal" (Wilks' lambda = 0.724, p > 0.05). Discriminant function analysis correctly classified 100% of PD patients and control subjects with (18)F-dopa PET based on mean caudate and putamen K(i) values (Wilks' lambda = 0.065, p < 0.001). Correlations between mean putamen K(i) and rostral and caudal nigral MR signal changes and mean caudate K(i) and caudal nigral MR signal changes were found (r = -0.76, -0.69, -0.80, p < 0.05). CONCLUSION: (18)F-dopa PET is more reliable than inversion recovery MRI in discriminating patients with moderately severe PD from normal subjects. However, the structural changes detected within the substantia nigra of patients with PD found using inversion recovery MRI correlate with measures of striatal dopaminergic function using (18)F-dopa PET.

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.

Motorcycle emissions and fuel consumption in urban and rural driving conditions.

This work reports sampling of motorcycle on-road driving cycles in actual urban and rural environments and the development of representative driving cycles using the principle of least total variance in individual regions. Based on the representative driving cycles in individual regions, emission factors for carbon monoxide (CO), hydrocarbons (HC), nitrogen oxides (NO(x)=NO+NO(2)) and carbon dioxide (CO(2)), as well as fuel consumption, were determined using a chassis dynamometer. The measurement results show that the representative driving cycles are almost identical in the three largest cities in Taiwan, but they differ significantly from the rural driving cycle. Irrespective of driving conditions, emission factors differ insignificantly between the urban and rural regions at a 95% confidence level. However, the fuel consumption in urban centers is approximately 30% higher than in the rural regions, with driving conditions in the former usually poor compared to the latter. Two-stroke motorcycles generally have considerably higher HC emissions and quite lower NO(x) emissions than those of four-stroke motorcycles. Comparisons with other studies suggest that factors such as road characteristics, traffic volume, vehicle type, driving conditions and driver behavior may affect motorcycle emission levels in real traffic situations.

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.

Late onset levodopa responsive Huntington's disease with minimal chorea masquerading as Parkinson plus syndrome.

Huntington's disease is characterised by hyperkinetic movements, mainly chorea, cognitive dysfunction, and psychiatric abnormalities. Non-dopa responsive parkinsonism occurs in the later stages of choreic disease or as the predominant feature of juvenile patients (Westphal variant). Late onset Huntington's disease presenting as levodopa responsive parkinsonism is rare. A series of four patients with late onset Huntington's disease presenting as levodopa responsive parkinsonism and cardiovascular dysautonomia, initially misdiagnosed as multiple system atrophy (MSA) in three patients, is reported. Levodopa treatment did not unmask significant chorea. These cases suggest the presence of a distinct phenotypic variant of Huntington's disease to be added to the differential diagnosis of other akinetic rigid syndromes.

Correlating rates of cerebral atrophy in Parkinson's disease with measures of cognitive decline.

We studied eight clinically non-demented PD patients and ten age-matched controls with serial volumetric T1-weighted MRI. All PD patients underwent full neuropsychological testing at baseline and follow up scans. Sub-voxel coregistration of the serial MRI scans with quantification of changes in total brain substance and ventricular size per year was performed. The PD patients had significant reductions in both percentage and absolute annual brain volume loss when compared to age-matched controls (p < 0.001). There were significant correlations between reductions in percentage brain volume loss and estimated reductions in performance IQ (r = 0.841, p = 0.004) and full scale IQ (r = 0.63, p = 0.049), measured by subtracting IQ measures at time of follow up scan from premorbid estimates. In conclusion, PD patients have a significant rate of median brain volume loss [10.35 (range) 6.69-16.90 ml/year] with no significant loss seen in age-matched controls, and these changes correlate with global measures of cognitive decline. Further longitudinal studies could evaluate whether serial volumetric MRI is a useful technique in predicting the preclinical onset of dementia in Parkinson's disease patients, and its role in the assessment of putative treatments for slowing disease progression.

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.

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.