Transcranial magnetic stimulation for differential diagnostics in patients with parkinsonism

Objective –  We investigated transcranial magnetic stimulation (TMS) parameters in patients with parkinsonism, particularly in the early stages of the disease.
Subjects and methods –  We performed TMS in 48 patients with PD, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). We measured motor threshold (MT), latency ( L ), motor-evoked potential amplitude and central motor conduction time (CMCT) and cortical silent period (CSP). Furthermore, we selected and compared 27 patients with a disease duration of less than 3 years.
Results –  CMCT, MT, L and CSP were different among the three groups. Post hoc analyses revealed that CMCT and CSP were the shortest in PD, and that MT was significantly lower in PD than in MSA. In patients whose disease duration was less than 3 years, CMCT and CSP were different among the three groups. Post hoc analyses showed significantly shorter CMCT in PD.
Conclusions –  TMS can detect the pathophysiological difference among the groups in the early stages of the disease.     

The in vivo distribution of brain tissue loss in Richardson’s syndrome and PSP‐parkinsonism: a VBM‐DARTEL study

In this study, we wished to test, using magnetic resonance imaging and voxel‐based morphometry (VBM), whether specific cortical and subcortical patterns of brain grey (GM) and white matter (WM) tissue loss can be detected in patients with Richardson’s syndrome (PSP‐RS) and progressive supranuclear palsy‐parkinsonism (PSP‐P), and possibly account for their clinical heterogeneity. Twenty patients with PSP, classified as PSP‐RS (10 patients) or PSP‐P (10 patients), and 24 healthy controls were studied. The Statistical Parametric Mapping (SPM5) and the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra method were used to perform a VBM analysis. Compared with controls, both patient groups showed GM loss in the central midbrain, cerebellar lobes, caudate nuclei, frontotemporal cortices and right hippocampus. WM loss was detected in both conditions in the midbrain, left superior cerebellar peduncle, internal capsulae, and left premotor and bilateral prefrontal regions. Compared with PSP‐P, patients with PSP‐RS showed additional regions of GM loss in the midbrain, left cerebellar lobe and dentate nuclei. PSP‐RS was also associated with a more severe WM loss in the midbrain, internal capsulae, and orbitofrontal, prefrontal and precentral/premotor regions, bilaterally. Patients with PSP‐P showed a more pronounced GM loss only in the frontal cortex, bilaterally. This study shows that, albeit the overall pattern of brain atrophy associated with PSP appears remarkably consistent across the spectrum of clinical features recorded in life, major anatomical differences between these two conditions do exist. Such a different topographical distribution of tissue damage may account for the clinical differences between PSP‐RS and PSP‐P.     

Incidence of Parkinson's disease and atypical parkinsonism: Russian population‐based study

Data on the incidence of Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) in East European countries and Asia are limited. The objective of this prospective population‐based study was to determine the incidence of PD and APS in the Russian population. The study area was a large district of Moscow with a population of 1,237,900 inhabitants. Multiple sources of case ascertainment were used to identify incident cases of PD and APS between July 2006 and December 2008. All incident cases were examined by a specialist and followed up prospectively to confirm the diagnosis. The age‐standardized incidence rates per 100,000/year were 9.03 [95% confidence interval (CI) 8.01–10.15] for PD, 0.11 (95% CI 0.03–0.23) for multiple system atrophy, 0.14 (95% CI 0.08–0.21) for progressive supranuclear palsy, and 0.02 (95% CI 0.01–0.12) for corticobasal degeneration. The age‐standardized male‐to‐female ratio of PD was 0.87 for all ages and 1.46 for those aged 60 and older. A high proportion of new cases with PD (34%) and APS (50%) had comorbid depressive symptoms. Given the rapid growth of the elderly population in Eastern Europe and Asia, the epidemiology of PD and APS in these regions should be investigated in greater depth. The incidence of PD in our study was slightly lower than in studies of Western populations and the male‐to‐female ratio was closer to those reported in studies from Asia. The clinical implication of our study is that it highlights the need for better diagnosis and treatment of depression in early stages of PD. © 2010 Movement Disorder Society     

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The “hummingbird” and “morning glory” signs were highly specific for PSP, and “the middle cerebellar peduncle sign” and “hot cross bun” for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy. © 2012 Movement Disorder Society     

Quantitative magnetic resonance spectroscopic imaging in Parkinson’s disease,progressive supranuclear palsy and multiple system atrophy

Background and purpose: Magnetic resonance spectroscopy (MRS) allows the measurement of a number of brain tissue metabolites in vivo, including N‐acetylaspartate (NAA), a putative marker of neuronal integrity. Unlike single voxel MRS, magnetic resonance spectroscopic imaging (MRSI) enables quantification of these metabolites simultaneously from multiple anatomically localized voxels. Both single voxel MRS and MRSI allow the absolute quantification of these metabolites and, when combined with tissue segmentation, can give accurate metabolite concentrations even in the presence of partial volume effects from nearby cerebrospinal fluid. Methods: Using MRSI with cubic voxels with a nominal volume of 1.0 cm³, we tested the hypothesis that concentrations of NAA in the basal ganglia in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) would show differences compared to Parkinson’s disease (IPD). NAA values (in mM) from MRSI voxels centred to the putamen, pallidum and thalamus were obtained from 11 patients with IPD, 11 with MSA‐P, six with MSA‐C, 13 with PSP and 18 controls. The mean concentrations of NAA and its bulk grey and white matter values were also estimated over the whole brain slab. Results: N‐acetylaspartate concentrations in the pallidum, putamen and lentiform nucleus were significantly lower in patients with MSA‐P and PSP compared to IPD and controls. The putaminal values were also significantly reduced in PSP compared to MSA‐P. There were no significant differences between groups in the thalamus and over the whole brain slab. Conclusion: Our findings support the notion that MRSI can potentially quantify basal ganglia cellular pathology in MSA and PSP.     

Differential pattern of brain‐specific CSF proteins tau and amyloid‐beta in Parkinsonian syndromes

To evaluate cerebrospinal fluid (CSF) proteins reflecting processes of neurodegeneration and glial activation in progressive supranuclear palsy (PSP; Richardson's syndrome, n = 20; PSP‐Parkinsonism, n = 7) and multiple system atrophy (MSA, n = 25), we analyzed tau, phosphorylated tau, amyloid‐beta_1–42 (Aβ1–42), Aβ1–40, glial fibrillary acidic protein (GFAP), and CSF routine variables. Individuals with PSP‐Parkinsonism and MSA had elevated tau levels when compared with Richardson's syndrome, Parkinson's disease (PD), and age‐matched controls (P ≤ 0.001). Ratios of P‐tau/T‐tau were significantly different in Parkinsonian syndromes. CSF Aβ1–42 was decreased only in patients with Richardson's syndrome. In a subset of Parkinsonian syndromes, we found elevated GFAP concentrations and increased CSF/serum albumin ratios. There were no correlations between biomarker concentrations and clinical scores in any of the diseases. In conclusion, this preliminary data show that changes in CSF tau and Aβ1–42 may indicate different protein processing in PSP patients and might, therefore, be relevant in the differentiation of PSP subtypes. © 2010 Movement Disorder Society     

Lack of autonomic nervous dysfunction in progressive supranuclear palsy, a study of blood pressure variability

Blood pressure and heart rate variability were analyzed in eight patients with progressive supranuclear palsy in comparison with two control groups (10 healthy patients and 10 patients with multiple system atrophy). Blood pressure and heart rate were recorded using digital photoplethysmography with the patient in supine position and during a head-up-tilt test (70° for 10 minutes). Spectral analysis was performed using fast Fourier transformation for 512 consecutive systolic blood pressure and heart rate values. The head-up-tilt test induced a significant increase in systolic blood pressure in patients with progressive supranuclear palsy and in healthy patients and a significant systolic blood pressure decrease in patients with multiple system atrophy. During the head-up-tilt test, low-frequency energy of systolic blood pressure (70–130 mHz) that reflected baroreflex-dependent sympathetic tone also increased in patients with progressive supranuclear palsy and in healthy patients. By contrast, in patients with multiple system atrophy, the low-frequency energy of systolic blood pressure decreased significantly. The changes observed in the low-frequency band and the high-frequency band of heart rate (reflecting parasym-pathetic drive to the heart) were not different among the three groups. These data show the lack of impairment in autonomic nervous system activity in patients with progressive supranuclear palsy.     

Abnormal metabolic networks in atypical parkinsonism

Spatial covariance analysis has been used with ¹⁸F‐fluorodeoxyglucose (FDG) PET to detect and quantify specific metabolic patterns associated with Parkinson's disease (PD). However, PD‐related patterns cannot necessarily serve as biomarkers of the processes that underlie the atypical parkinsonian syndromes. In this FDG PET study, we used strictly defined statistical criteria to identify disease‐related metabolic patterns in the imaging data from patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the two most common of these atypical conditions. We found that MSA and PSP were each associated with a specific, highly stable metabolic brain network (P < 0.0001, bootstrap estimation). The MSA‐related pattern was characterized by decreased metabolism in the putamen and cerebellum. The PSP‐related pattern was characterized by metabolic decreases in the brainstem and medial frontal cortex. For both conditions, pattern expression was significantly elevated in patients relative to age‐matched healthy control subjects (P < 0.001). For each condition, we validated the associated disease‐related metabolic pattern by computing its expression on an individual scan basis in two independent patient cohorts, and in one subsequent healthy volunteer cohort. We found that for both MSA and PSP, prospective assessments of pattern expression accurately discriminated patients from controls (P < 0.001). These findings suggest that the major atypical parkinsonian syndromes are associated with distinct patterns of abnormal regional metabolic activity. These disease‐related networks can potentially be used in conjunction with functional brain imaging as quantifiable biomarkers for the assessment of these pathological conditions. © 2008 Movement Disorder Society     

Olfactory function in atypical parkinsonian syndromes

Introduction – Olfaction is markedly impaired in patients with idiopathic Parkinson's disease (IPD). This deficit contrasts with reports of preserved or only mildly reduced olfaction in patients with atypical parkinsonism. However, the sensitivity and specificity of olfactory function testing in the differential diagnosis of parkinsonian syndromes has not been studied. In addition, olfactory function in patients with corticobasal degeneration (CBD) is unknown. Material and methods — Using the University of Pennsylvania Smell Identification Test (UPSIT) with a test score ranging from 0 to 40 we studied olfactory function in patients with IPD as well as other parkinsonian syndromes including CBD and progressive supranuclear palsy (PSP). Results — UPSIT scores in 118 patients with IPD, 29 with MSA, 15 with PSP, and 7 patients with CBD, as well as in 123 healthy control subjects revealed a marked impairment in the IPD group in contrast to mild impairment in MSA patients and normal olfaction in PSP and CBD patients. An UPSIT score of 25/40 was associated with a sensitivity of 77% and a specificity of 85% in differentiating IPD from atypical parkinsonism. Conclusions — These results indicate that olfactory function is differentially impaired or preserved in distinct parkinsonian syndromes and that it might also have some value as a diagnostic pointer. Thus, preserved or mildly impaired olfactory function in a parkinsonian patient is more likely to be related to atypical parkinsonism such as MSA, PSP or CBD, whereas markedly reduced olfaction is more suggestive of IPD.     

Assessment of midbrain atrophy in patients with progressive supranuclear palsy with routine magnetic resonance imaging

OBJECTIVES: To assess midbrain atrophy through morphometric (linear, surface and volumetric) measurements in patients with clinically diagnosed progressive supranuclear palsy (PSP) and to establish the most accurate measure to be implemented in routine magnetic resonance (MR) protocol in distinguishing PSP from healthy subjects and MSA-p (multiple system atrophy, parkinsonian form) patients. MATERIALS AND METHODS: We studied 15 patients with the diagnosis of probable PSP, seven patients with the diagnosis of probable MSA-p and 14 age-matched healthy volunteers. MR protocol includes a sagittal SE T1-weighted sequence for cross-sectional area and linear brainstem measurements and a 3D-FSPGR sequence for brainstem volume measurements. RESULTS: A highly significant difference in the antero-posterior midbrain diameter, area and volume in PSP compared with control subjects was found. Only a measurement of the midbrain area and pons area enabled one to distinguish between PSP and MSA-p. Receiver operating characteristic analysis revealed that the midbrain area has the highest diagnostic accuracy in distinguishing between PSP and other conditions, with a sensitivity of 100% and specificity of 90.5%. The addition of the midbrain area/pons area ratio (A(ms)/A(pn) ratio) measurement improves the specificity in distinguishing between PSP and MSA. CONCLUSIONS: Morphological indexes indicate midbrain atrophy in PSP patients The combination of the A(ms) and A(ms)/A(pn) ratio measurements allows to discriminate between PSP and other conditions.     

Spinocerebellar degeneration: Discrepancies between clinical and pathological diagnoses

To improve the diagnostic accuracy of sporadic spinocerebellar degeneration (SCD), we assessed the clinical and pathological data of 1494 consecutive autopsy cases. The number of patients who received a diagnosis of sporadic SCD (including multiple system atrophy) either clinically or pathologically was 19 (1.3%). We identified six cases with clinical misdiagnoses of SCD that were confirmed pathologically as progressive supranuclear palsy (PSP, four cases), basilar artery thrombosis (one case) and unclassified tauopathy (one case). The total number of patients who received a clinical diagnosis of sporadic SCD was 93 and the positive predictive value was 93.5%. We also identified 13 autopsy cases that were pathologically confirmed as SCD, but had been clinically misdiagnosed as having other disorders. Their clinical diagnoses comprised progressive supranuclear palsy (five cases) and Parkinson's disease (PD, four cases), as well as parkinsonism with dementia, amyotrophic lateral sclerosis, paraneoplastic syndrome and multiple cerebral infarction (one case each). The results indicate that it is often difficult to distinguish PSP and PD from SCD, because of the atypical combination of symptoms or atypical timing of the appearance of symptoms, such as severe autonomic failure, cognitive impairment, poor L‐dopa responsiveness, early cerebellar signs and obvious vertical gaze palsy.     

具有帕金森病样症状相关疾病的诊断探讨

目的探讨具有帕金森病样症状(PLS)相关疾病的临床诊断。方法回顾性分析作者医院2008-01-2010-12住院的78例具有PLS患者的临床资料,包括病史、体格检查、临床表现、血液学检查〔包括血生化(肝功能、肾功能、心肌酶谱、电解质、血糖、血脂全套)、血甲状旁腺素、血铜蓝蛋白〕、左旋多巴(L-dopa)试验、头CT和头MRI检查等,并依据PLS相关疾病诊断标准进行临床诊断。结果本组78例患者中,有肌张力增高74例、震颤67例、运动迟缓65例、姿势反射异常56例、步态异常52例、直立性低血压5例、垂直性凝视麻痹4例、角膜K-F环阳性和视幻觉各2例、一侧肢体忽略并失用1例;有肝功能异常5例、血清铜蓝蛋白降低2例和血清甲状旁腺素降低1例;头CT检出基底节区低密度影59例,脑萎缩35例,脑叶软化灶10例,基底节区和小脑半球钙化灶2例;头MRI检出基底节区、脑干、大脑白质异常信号65例,脑桥和小脑萎缩5例,壳核裂隙征4例,脑桥十字征3例,双侧苍白球T2高信号2例,脑干蜂鸟征1例。L-dopa试验反应不良31例。临床诊断为帕金森病(PD)36例,帕金森综合征(PS)28例〔其中血管性16例、中毒后5例(一氧化碳中毒后3例,农药中毒后2例)、脑外伤后3例、感染后和药物性各2例〕,多系统萎缩(MSA)和进行性核上性麻痹(PSP)各4例,路易体痴呆(DLB)和Wilson病(WD)各2例,基底节钙化症(BGC)和皮质基底节变性(CBD)各1例。结论详细可靠的病史、特异性体征、特征性影像学改变、铜蓝蛋白和甲状旁腺素降低及L-dopa试验反应不良,对于PLS患者相关疾病的诊断和鉴别诊断具有重要意义。