Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories.

BACKGROUND: Detection of the pathological and disease-associated alpha-synuclein (αSynD) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson's disease (PD). We recently showed that αSynD can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes. METHODS: OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data. RESULTS: The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83-1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability. CONCLUSIONS: Our study provides evidence that OM-αSynD may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.

Assessment of APOE in atypical parkinsonism syndromes.

Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 × 10-30; ε2: OR: 0.21, 95% CI: 0.13-0.34; p = 5.39 × 10-10) and LBD (ε4: OR: 2.94, 95% CI: 2.34-3.71, p = 6.60 × 10-20; ε2: OR = OR: 0.39, 95% CI: 0.26-0.59; p = 6.88 × 10-6). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE ε4 decreases survival in a dose-dependent manner in Alzheimer's disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE ε4 allele with increased risk for LBD, and importantly demonstrate that APOE ε2 reduces risk of this disease.

Simultaneous assessment of cognitive and affective functions in multiple system atrophy and cortical cerebellar atrophy in relation to computerized touch-panel screening tests.

Cognitive impairment and affective dysfunction of multiple system atrophy (MSA) and cortical cerebellar atrophy (CCA) have not been simultaneously examined comparing standard test batteries and a sensitive tool to detect subtle cognitive decline in patients. In the present study, we simultaneously examined cognitive and affective ability in MSA with predominant cerebellar ataxia (MSA-C, n=25), MSA with predominant parkinsonism (MSA-P, n=8), and CCA (n=14) patients using computerized touch panel screening tests. Mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), frontal assessment battery (FAB), and Montreal cognitive assessment (MoCA) scores were significantly lower in MSA-C patients than in age-and gender-matched normal controls. One MSA-C patient showed a decrease in the regional cerebral blood flow (rCBF) of the frontal lobe. MSA-P patients showed no such cognitive decline. Only FAB and MoCA scores were significantly lower in the CCA patients. MSA and CCA patients also showed a mild to moderate depressive state. Touch-panel screening tests demonstrated a significant decline of beating devils game in all three disease groups including MSA-P patients, and a significant extension of the flipping cards game only in MSA-C patients. The present study demonstrated different cognitive and affective functions among MSA-C, MSA-P, and CCA patients, and a sensitive screening method for cognitive assessment using touch-panel tests.

Quantitative assessment of subcortical atrophy and iron content in progressive supranuclear palsy and parkinsonian variant of multiple system atrophy.

It is a matter of debate whether increased brain iron levels are the cause or only the consequence of neurodegenerative process in degenerative parkinsonism. The aim of this study is to characterize disease-related changes in volumes and iron-related R2 values of basal ganglia and thalamus. 13 patients with progressive supranuclear palsy (PSP), 15 with a parkinsonian variant of multiple system atrophy (MSA-p), 29 with Parkinson's disease (PD), and 21 age-matched controls underwent 3-Tesla MRI. The R2 values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. Voxel-based analysis was also performed to visualize a topographical correlation of R2 value and volume. The PSP group had significantly higher R2 values in globus pallidus and caudate nucleus (p < 0.05), whereas the MSA-p group had higher R2 values in putamen (p < 0.001) than PD and controls. The globus pallidus in PSP and the putamen in MSA-p were the most significant areas of atrophy to differentiate PSP, MSA-p and PD (AUC = 0.856, 0.832, respectively, p < 0.001). The R2 values in both structures increased in parallel with the extent of atrophy. They were negatively correlated with volumes in putamen (r = -0.777, p < 0.001) and globus pallidus (r = -0.409, p = 0.025) of MSA-p, and globus pallidus (r = -0.4, p = 0.043) of PSP. Voxel-based analysis identified higher R2 values in more severely atrophic sub-regions in these structures. We observed topographical differences of iron deposition as well as atrophy between MSA-p and PSP. Increased iron levels were related to the structural atrophy in basal ganglia. Our results imply that iron accumulation is likely an epiphenomenon of the degenerative process.

Symptom prevalence, severity and palliative care needs assessment using the Palliative Outcome Scale: a cross-sectional study of patients with Parkinson's disease and related neurological conditions.

BACKGROUND: Palliative care is rarely being offered to patients with Parkinson's disease. AIM: To assess symptom prevalence, severity and palliative care needs in advanced stages of Parkinsonism. DESIGN: A cross-sectional survey using a palliative care assessment tool, the Palliative Outcome Scale was administered to patients. SETTING/PARTICIPANTS: Eight-two patients with a diagnosis of idiopathic Parkinson's disease, multiple systems atrophy or progressive supranuclear palsy were included in the study. RESULTS: Their mean age and disease stages 3-5 Hoehn and Yahr were 67 years and 4.1, respectively. Patients reported a mean of 10.7 (standard deviation = 3.9) physical symptoms. Over 80% had pain, fatigue, day time somnolence and problems with mobility. Other symptoms in 50%-80% included constipation, loss of bladder control, swallowing difficulties, drooling, breathlessness and sleep problems. Symptoms rated as causing severe problems were pain, fatigue, constipation and drooling. Assessment of mood revealed 70% of the patients felt anxiety and 60% had felt depressed. Eight-five per cent felt their families were anxious or worried about them. Thirty-eight per cent would have liked more information and 42% had practical problems that still needed to be addressed. There was a positive correlation between number of symptoms and disease severity (r = 0.39, p = 0.01). The total mean Palliative Outcome Scale score was 13.6 (standard deviation = 6.1), suggesting moderate palliative care needs. CONCLUSION: This is the first study to describe the care needs of people with Parkinson's disease using the Palliative Outcome Scale tool. The burden of symptoms and concerns was high in advanced stages of disease. It might be appropriate that people severely affected by these conditions should be considered for referral to specialist palliative care services.

Assessment of dementia in patients with multiple system atrophy.

BACKGROUND AND PURPOSE: We investigated dementia in patients with multiple system atrophy (MSA) in order to characterize the prevalence and nature of impairments in these patients. METHODS: Fifty-eight MSA patients were recruited in our institution between April 1996 and December 2006 and investigated. RESULTS: Of 58 patients, 10 were diagnosed with dementia. There were no significant differences in age at onset, gender, duration of disease, or severity of cerebellar dysfunction between patients with and without dementia. The early and delayed heart to mediastinum (H/M) ratios obtained with (123)I-metaidobenylguanidine (MIBG) cardiac scintigraphy were significantly decreased in patients with dementia compared with those without dementia. Of the 10 patients with dementia, three were found to have cognitive decline that preceded onset of motor symptoms. White matter lesions were evident in these patients, whilst frontal atrophy was prominent in patients whose cognitive decline was preceded by onset of motor symptoms. CONCLUSIONS: Dementia in patients with MSA may be more common than previously thought, furthermore, we speculate that clinical features of dementia in these patients might be heterogeneous.

Assessment of cortico-spinal tract impairment in multiple system atrophy using transcranial magnetic stimulation.

OBJECTIVE: Among Parkinsonian syndromes, pyramidal signs suggesting cortico-spinal impairment are a hallmark of multiple system atrophy (MSA). Although it is crucial to diagnose correctly this disease to choose the appropriate treatment, the available diagnostic criteria lack sensitivity. Cortical excitability patterns assessed by transcranial magnetic stimulation (TMS) do not differentiate Parkinsonian disorders. TMS using triple stimulation technique (TST) accurately detects cortico-spinal impairment. We hypothesized that this technique could detect such impairment in MSA patients. METHODS: The TST was applied along with single and paired-pulse TMS to 31 patients fulfilling the diagnostic criteria for MSA-P (n=10), MSA-C (n=4), progressive supranuclear palsy (PSP; n=6) and Idiopathic Parkinson's disease (IPD; n=11) and 11 control subjects. RESULTS: Single and paired-pulse TMS patterns did not differ between any patient group. The TST pattern was abnormal in five MSA-P, one MSA-C and one PSP patients but not in IPD patients or controls. The mean TST ratio for MSA-P (86.6%) was significantly different from IPD (99.1%; p<0.05) whereas ratios for MSA-C (92.1%) and PSP (93.3%) were not different from IPD or controls (99.5%). CONCLUSIONS: These results suggest that TST is effective to assess cortico-spinal impairment in MSA. SIGNIFICANCE: TST might be useful for the diagnosis of atypical Parkinsonism.

Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort.

Among 367 subjects, the authors analyzed 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple-system atrophy, and atypical parkinsonism and 200 healthy control subjects for FMR1 premutation alleles. None of the subjects carried alleles within the premutation range. These findings suggest that in the absence of other supportive clinical or imaging features, the cost-effectiveness of routine fragile X tremor/ataxia syndrome screening in this Asian cohort with movement disorders was low.

Near-infrared spectrophotoscopy of finger venules in assessment of autonomic dysfunction.

The authors evaluated morphologic changes in the venules of the finger using near-infrared spectrophotoscopy in patients with autonomic dysfunction, such as familial amyloidotic polyneuropathy and multiple-system atrophy. Abnormalities of the venules, such as tortuosity, irregular venous caliber, and microaneurysm-like change, and a linear negative correlation between the degree of orthostatic hypotension and the degree of vasoconstriction of the venules were observed.