Lori McGee-Minnich

Welding-related parkinsonism Clinical features, treatment, and pathophysiology

Objective: To determine whether welding-related parkinsonism differs from idiopathic PD. Background: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. Methods: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex- and age-matched to compare the frequency of motor fluctuations. Results: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p < 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. Conclusions: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD

Objective: To assess whether subthalamic nuclei (STN) stimulation’s primary mechanism of action is to drive or inhibit output neurons. Methods: Cerebral blood flow responses to STN stimulation were measured using PET in 13 patients with Parkinson disease. Patients were scanned with stimulators off and on (six scans each condition). Clinical ratings, EMG, and videotaping of movements were obtained at each scan. Scans with observable tremor or movement were eliminated from analysis. Brain regions where STN stimulation significantly altered blood flow were identified. Results: STN stimulation increased blood flow in midbrain (including STN), globus pallidus, and thalamus, primarily on the left side, but reduced blood flow bilaterally in frontal, parietal, and temporal cortex. Conclusions: These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntingtons disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ± 1.6 vs. 5.1 ± 0.9, P = 0.04). CMRO2 was not different from controls (126 ± 37 vs. 134 ± 31 μmol 100 g−1 min−1, P = 0.49), whereas CMRglc was decreased (21.6 ± 6.1 vs. 26.4 ± 4.6 μmol 100 g−1 min−1, P = 0.01). Striatal volume was decreased as well (13.9 ± 3.5 vs. 17.6 ± 2.0 ml, P = 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.

[18F]FDOPA PET and clinical features in parkinsonism due to manganism

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinsons disease (PD). We describe the clinical features and results of positron emission tomography with 6‐[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1‐weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese‐associated parkinsonism may overlap with that of PD.

Diminished regional cerebral blood flow response to vibration in patients with blepharospasm

Objective: To determine whether patients with blepharospasm have abnormal sensorimotor processing similar to patients with writer’s cramp. Background: Blepharospasm is a focal dystonia manifest by involuntary, excessive blinking and squeezing of the eyes. Altered sensorimotor processing may contribute to the development of dystonic movements. Previously the authors demonstrated decreased vibration-induced cortical blood flow responses in hand primary sensorimotor area (PSA) in patients with hand dystonia. Methods: In this prospective, case–control study, seven patients with blepharospasm were compared with seven normal subjects. PET measurements of regional blood flow were obtained using bolus administration of H215O at rest or during sequential vibration of either the left or the right hand or side of the mouth. Results: PSA activation decreased significantly in the patients with blepharospasm both ipsilateral (−68%; p= 0.0004) and contralateral to the side of facial stimulation (−56%; p = 0.0009). Patients had a 31% lower mean contralateral PSA response to hand vibration and a 51% smaller right supplementary motor area response to left-hand vibration than normal subjects, but these differences did not reach statistical significance. Conclusions: Patients with blepharospasm have abnormal sensorimotor processing in response to lower face vibration. They may also have abnormal brain responses to stimulation of clinically uninvolved parts of the body, but this requires confirmation.

Long term treatment and disease severity change brain responses to levodopa in Parkinson’s disease

Objectives: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain’s response to levodopa in the absence of these altered clinical responses to levodopa. Methods: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. Results: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. Conclusions: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.

Effect of stimulation frequency on tremor suppression in essential tremor

We sought to determine the effect of deep brain stimulation (DBS) frequency on tremor suppression in essential tremor (ET) patients with deep brain stimulators implanted in the ventral intermediate nucleus (VIM) of the thalamus. A uniaxial accelerometer was used to measure tremor in the right upper extremity of subjects with a diagnosis of ET who had DBS electrodes implanted in the left VIM. The root‐mean‐square acceleration was used as the index of tremor magnitude and normalized to the OFF DBS condition. There was a highly significant inverse sigmoidal relationship between stimulation frequency and normalized tremor acceleration (X2/DoF = 0.42, r2 = 0.997). Tremor acceleration had a nearly linear response to stimulation frequencies between 45 and 100 Hz with little additional benefit above 100 Hz. These findings have two important implications. Clinically, frequency of thalamic stimulation is an important variable for optimal tremor control with maximal benefit achieved with 100 to 130 Hz in most patients. Second, thalamic DBS provides tremor benefit in a graded manner and is not an all‐or‐nothing phenomenon.

Pramipexole in levodopa-treated Parkinson disease patients of African, Asian, and Hispanic heritage

Background: Little is known regarding the effects of antiparkinsonian drugs in US racial or ethnic minorities. Objective: To evaluate the safety, tolerability, and efficacy of adjunctive pramipexole in Parkinson disease (PD) patients of African, Asian, or Hispanic heritage stably treated with levodopa. Design: Multicenter, parallel-group, double-blind, randomized, placebo-controlled trial. Setting: Seventeen Parkinson Study Group sites in the United States and Puerto Rico. Patients: One hundred forty-four PD patients of African, Asian, or Hispanic heritage enrolled from January 1997 to August 1998 and observed until October 1998. Intervention: Subjects received pramipexole or placebo (3:1 ratio), 0.375 mg/d to a maximum tolerated dose (≤4.5 mg/d) over a 6-week period, achieving optimum levels (0.375, 1.5, 3.0, or 4.5 mg/d) in the 4-week maintenance period. Main Outcome Measure: Change in the sum of the Unified Parkinsons Disease Rating Scale parts 2 (activities of daily living) and 3 (motor) from baseline to week 10. Results: Parkinsonism improved (mean [SD] reduction in Unified Parkinsons Disease Rating Scale activities of daily living + motor score at 10 weeks, 10.27 [11.96] pramipexole vs 6.54 [13.58] placebo, P = 0.012) and was similar in each group. Adverse events occurred in 85.3% on pramipexole and 68.6% on placebo. Hallucinations and insomnia were more common on pramipexole than placebo (18 vs 0, P = 0.023, and 15 vs 0, P = 0.045, respectively). Conclusions: Pramipexole is an effective adjunctive antiparkinsonian therapy in PD patients of African, Asian, and Hispanic heritage. Tolerability and safety overall were similar among the groups, but differences in profiles of adverse effects and tolerability were suggested.

[18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Parkinson disease (PD) is a late onset disorder with age‐dependent penetrance that may confound genetic studies, since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at‐risk subjects. Positron emission tomography (PET) measurements of 6‐[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi‐incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than 3 standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD.” The remainder had normal PETs. The average maximum LOD score with the pre‐PET was 6.14 ± 0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36 ± 1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi‐incident PD families and may increase LOD score accuracy and power of an informative pedigree.