Extradural motor cortex stimulation in Parkinson's disease.

Extradural motor cortex stimulation (EMCS) is a surgical procedure proposed for patients with advanced Parkinson's disease (PD) who cannot undergo deep brain stimulation (DBS). Five PD patients with motor fluctuations and dyskinesia underwent EMCS of the left hemisphere. All fulfilled CAPSIT criteria for DBS, with the exception of age > 70 years. Patients were assessed preoperatively and 6 months after surgery on and off medications, with stimulator on, and 2 weeks later with stimulator off. Outcome measures included changes in mean medication dosage (levodopa and dopamine agonists), Unified Parkinson's Disease Rating Scale (UPDRS Parts II-III and Item 39), and dyskinesias (Abnormal Involuntary Movements Scale [AIMS]). We found no significant mean changes following EMCS. However, there was a trend for a reduction of mean daily medication intake (-30%) and AIMS (-19%). There were 3 patients who reported reduced OFF time (UPDRS Item 39) and 4 of 5 who felt a subjective benefit in stability and gait. In our PD cohort, EMCS induced no objective benefit, although some subjective improvement was reported mostly on axial symptoms.     

Decreased noradrenaline transporter density in the motor cortex of Parkinson's disease patients

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical ¹¹C‐MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with ¹¹C‐MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced ¹¹C‐MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced ¹¹C‐MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society     

Longitudinal study of the motor response to levodopa in Parkinson's disease.

In this prospective study of 34 patients with Parkinson's disease, measurements of the short duration levodopa motor response have been performed in defined off states at 3 yearly intervals over a mean period of 11.4 years from the point of commencement of levodopa treatment. Twenty-two patients were still available for study; 10 had died and 2 were lost to follow-up. The levodopa motor response amplitude increases over the first 5 years of treatment, and thereafter, on and off scores worsen in parallel with conservation of the response. Patients who developed motor fluctuations within the first 5 years of treatment had, on average, a stronger response to levodopa with significantly better on phase motor function (P = 0.003). Although the proportion of "midline" motor disability (affecting gait, balance, and cranial motor function) increases with time, these deficits do not actually become unresponsive to levodopa. Patients who developed dementia had a significantly more rapid decline in motor function. The latest graph of serial scores for the whole cohort shows an upward curving or exponential increase in motor disability after the first decade of treatment. Applying a notional untreated disability line to this graph--an estimate of the disability that would have accrued if drugs had never been given--we suggest that the long-duration response to levodopa eventually runs down with disease progression.     

Statins,plasma cholesterol,and risk of Parkinson's disease: A prospective study

Previous findings on the association of statins, plasma lipids, and Parkinson's disease (PD) are confounded by the fact that statins also affect lipid profiles. We prospectively examined plasma lipids and statin use in relation to PD in the Atherosclerosis Risk in Communities (ARIC) Study. Statin use and plasma lipids were assessed at baseline (visit 1, 1987‐89) and at three triennial visits thereafter (visits 2‐4) until 1998. Potential PD cases were identified from multiple sources and validated where possible. The primary analysis was limited to incident PD cases diagnosed between 1998 and 2008. Odds ratios and 95% confidence intervals were derived from multivariate logistic regression models. Statin use was rare at baseline (0.57%) but increased to 11.2% at visit 4. During this time frame, total‐cholesterol levels decreased, particularly among statin users. Fifty‐six PD cases were identified after 1998. Statin use before 1998 was associated with significantly higher PD risk after 1998 (odds ratio = 2.39, 95% confidence interval 1.11‐5.13) after adjusting for total cholesterol and other confounders. Conversely, higher total cholesterol was associated with lower risk for PD after adjustment for statin usage and confounders. Compared with the lowest tertile of average total cholesterol, the odds ratios for PD were 0.56 (0.30‐1.04) for the second and 0.43 (0.22‐0.87) for the third tertile (P_trend = 0.02). Statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk. These data are inconsistent with the hypothesis that statins are protective against PD. © 2015 International Parkinson and Movement Disorder Society     

Dietary fat intake and risk for Parkinson's disease

Previous epidemiological studies have generated inconsistent results regarding the associations between dietary fat intakes and risk for Parkinson's disease (PD). We therefore prospectively examined these associations in the National Institutes of Health–American Association of Retired Persons (NIH‐AARP) Diet and Health Study. A 124‐item food frequency questionnaire was administered at baseline in1995 to 1996, and PD diagnosis was self‐reported at the follow‐up survey in 2004 to 2006. A total of 1,087 cases with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the analyses. Overall, intakes of fats and other macronutrients were not associated with PD risk. However, we found a weak positive association between n‐6 polyunsaturated fatty acids (PUFA) and the risk for PD. After adjusting for potential confounders, the odds ratio (OR) and 95% confidence interval (CI) between extreme quintiles of n‐6 PUFA intake was 1.23 (95% CI = 1.02‐1.49, P for trend = 0.02). A similar association was observed for the intake of linoleic acid. Results were similar among men and among women. Our study suggests that fat intake in general is not related to the risk for PD. The weak positive association between intake of n‐6 PUFA and PD risk needs further investigation. © 2014 International Parkinson and Movement Disorder Society     

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and ¹⁸F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.     

Ambulatory motor assessment in Parkinson's disease.

We developed an algorithm that distinguishes between on and off states in patients with Parkinson's disease during daily life activities. Twenty-three patients were monitored continuously in a home-like situation for approximately 3 hours while they carried out normal daily-life activities. Behavior and comments of patients during the experiment were used to determine the on and off periods by a trained observer. Behavior of the patients was measured using triaxial accelerometers, which were placed at six different positions on the body. Parameters related to hypokinesia (percentage movement), bradykinesia (mean velocity), and tremor (percentage peak frequencies above 4 Hz) were used to distinguish between on and off states. The on-off detection was evaluated using sensitivity and specificity. The performance for each patient was defined as the average of the sensitivity and specificity. The best performance to classify on and off states was obtained by analysis of movements in the frequency domain with a sensitivity of 0.97 and a specificity of 0.97. We conclude that our algorithm can distinguish between on and off states with a sensitivity and specificity near 0.97. This method, together with our previously published method to detect levodopa-induced dyskinesia, can automatically assess the motor state of Parkinson's disease patients and can operate successfully in unsupervised ambulatory conditions.     

Premorbid exercise engagement and motor reserve in Parkinson's disease

BackgroundLife-long experiences of cognitive activity could enhance cognitive reserve, which may lead individuals to show less cognitive deficits in Alzheimer's disease, despite similar pathological changes. We performed this study to test whether premorbid physical activity may enhance motor reserve in Parkinson's disease (PD) (i.e., less motor deficits despite similar degrees of dopamine depletion).MethodsWe assessed engagement in premorbid leisure-time exercise among 102 drug naive PD patients who had been initially diagnosed at our hospital by dopamine transporter scanning. Patients were classified into tertile groups based on the frequency, duration, and intensity of the exercises in which they participated.ResultsAmong patients with mild to moderate reductions in striatal dopaminergic activity (above the median dopaminergic activity), the exercise group of the highest tertile showed significantly lower motor scores (i.e., fewer motor deficits, 15.53 ± 6.25), despite similar degrees of dopamine reduction, compared to the combined group of the middle and the lowest tertiles (21.57 ± 8.34, p = 0.01). Nonetheless, the highest tertile group showed a more rapid decline in motor function related to reductions in striatal dopaminergic activity than the other two groups (p = 0.002 with the middle tertile group and p = 0.001 with the lowest tertile group).ConclusionsThese results suggest that engagement in premorbid exercise acts as a proxy for an active reserve in the motor domain (i.e., motor reserve) in patients with PD.     

Intact presupplementary motor area function in early,untreated Parkinson's disease

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre‐SMA) in PD. Our objective was to determine whether pre‐SMA abnormalities are present in untreated patients with early disease. We measured N‐acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre‐SMA in 26 untreated patients with early PD (disease duration 3.0 ± 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre‐SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre‐SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression. © 2008 Movement Disorder Society     

Non motor off in Parkinson's disease.

Besides the classic motor swings, many non motor fluctuations may occur in Parkinson's disease, but the clinical spectrum and the frequency of these symptoms are not well recognized. A total of 47 parkinsonian outpatients were questioned about any symptoms associated with off state. Nine patients had no fluctuations, 16 referred only to motor fluctuations and 22 to motor fluctuations associated with non motor symptoms. Overall, these patients referred to 54 symptoms (average 2.3/patients, range 1-6). These symptoms were classified as: autonomic (3 difficulty in swallowing, 7 hot, 11 sweat, 2 cold, 1 pallor, 1 abdominal bloating, 1 abdominal pain, 1 abdominal and genital pain, 5 bladder dysfunction, 2 feet oedema); sensory (7 sensory dyspnoea, 1 pain in lower limbs, 1 internal tremor); cognitive (3 depression, 4 anxiety, 2 panic, 1 drowsiness, 1 confusion). In patients without off periods, the length, severity and the average dosages of levodopa were fewer than in patients with fluctuations. No significant differences were found between patients with motor off and patients with associated non motor off regarding age (71.2+/-9.6 years vs 71.6+/-10.7 years), length of the disease (83.2+/-38.5 months vs 95.9+/-58.1 months), the Hoehn-Yahr (3.06+/-0.96 vs 3.02+/-0.96) and Webster (15.5+/-6.99 vs 15.1+/-5.9) scale, the dosages of levodopa (680.9+/-238.9 mg/die vs 679.7+/-289.6 mg/die), the number (2.3+/-1.7 vs 2.8+/-1.5) and length (6.8+/-5.2 h vs 7.2+/-7.1 h) of motor off. The non motor fluctuations were recognized in about 60% of patients with motor fluctuations: usually they were mild and less important than motor off, but sometimes these problems were disabling and led to unnecessary tests and therapies.     

Timed motor tests can detect subtle motor dysfunction in early Parkinson's disease

Early diagnosis of Parkinson's disease (PD) is important for putative neuroprotective therapies to be initiated in the earliest stage of the disease. We investigated whether a previously validated timed motor test (TMT) battery could detect subtle motor dysfunction in early PD patients and even in clinically unaffected limbs of strictly hemiparkinsonian patients. We assessed 107 PD patients (symptom duration ≤2 years; dopa‐naive) and 100 healthy, age‐matched controls with eight simple TMTs based on aspects of (a) walking, (b) writing, (c) single and double‐handed pegboard performance, (d) finger tapping, and (e) diadochokinesis. We evaluated the ability of individual and combined TMTs to discriminate patients from controls using ROC curves. Second, we investigated whether these TMTs could identify motor dysfunction of the clinically unaffected limb in 42 strictly hemiparkinsonian patients. The pegboard dexterity test had the best ROC curve (AUC 0.97; 95% sensitivity, 89% specificity) for patients versus controls. It retained reasonable accuracy when testing the clinically unaffected limb of hemiparkinsonian patients versus the mean of right and left‐hand scores in controls (AUC 0.73). The pegboard dexterity test is a sensitive and inexpensive instrument to detect motor dysfunction in early PD. Therefore, it may be worth evaluating as a diagnostic tool in everyday clinical practice to assess patients with early symptomatic PD, or as part of a more elaborate screening battery in a defined population at risk. © 2010 Movement Disorder Society     

The influence of age and gender on motor and non-motor features of early Parkinson's disease: Initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort

BackgroundIdentifying factors influencing phenotypic heterogeneity in Parkinson's Disease is crucial for understanding variability in disease severity and progression. Age and gender are two most basic epidemiological characteristics, yet their effect on expression of PD symptoms is not fully defined. We aimed to delineate effects of age and gender on the phenotype in an incident cohort of PD patients and healthy controls from the Oxford Parkinson Disease Centre (OPDC).MethodsClinical features, including demographic and medical characteristics and non-motor and motor symptoms, were analyzed in a group of PD patients within 3 years of diagnosis and a group of healthy controls from the OPDC cohort. Disease features were stratified according to age and compared between genders, controlling for effects of common covariates.Results490 PD patients and 176 healthy controls were analyzed. Stratification by age showed increased disease severity with age on motor scales. Some non-motor features showed similar trend, including cognition and autonomic features. Comparison across genders highlighted a pattern of increased severity and greater symptom symmetricality in the face, neck and arms in men with women having more postural problems. Amongst the non-motor symptoms, men had more cognitive impairment, greater rate of REM behavior disorder (RBD), more orthostatic hypotension and sexual dysfunction.ConclusionsAge in PD is a strong factor contributing to disease severity even after controlling for the effect of disease duration. Gender-related motor phenotype can be defined by a vertical split into more symmetrical upper-body disease in men and disease dominated by postural symptoms in women.     

Functional (psychogenic) symptoms in Parkinson's disease

It has been reported that patients who have Parkinson's disease have a high prevalence of somatisation (functional neurological symptoms) compared with patients who have other neurodegenerative conditions. Numerous explanations have been advanced for this phenomenon. Here, with illustrative cases, we discuss this topic, including its clinical importance, and suggest a link between the pathophysiology of Parkinson's disease and the proposed propensity to develop functional symptoms. © 2013 International Parkinson and Movement Disorder Society     

Controlled trial on the effect of 10 days low‐frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease

We evaluated the effect of low‐frequency rTMS on motor signs in Parkinson's disease (PD), under a double‐blind placebo‐controlled trial design. PD patients were randomly assigned to received either real (n = 9) or sham (n = 9) rTMS for 10 days. Each session comprises two trains of 50 stimuli each delivered at 1 Hz and at 90% of daily rest motor threshold using a large circular coil over the vertex. The effect of the stimulation, delivered during the ON‐period, was evaluated during both ON and OFF periods. Tests were carried out before and after the stimulation period, and again 1 week after. The effect of the stimulation was evaluated through several gait variables (cadence, step amplitude, velocity, the CV_{stride‐time}, and the turn time), hand dexterity, and also the total and motor sections of the UPDRS. Only the total and motor section of the UPDRS and the turn time during gait were affected by the stimulation, the effect appearing during either ON or OFF evaluation, and most importantly, equally displayed in both real and sham group. The rest of the variables were not influenced. We conclude the protocol of stimulation used, different from most protocols that apply larger amount of stimuli, but very similar to some previously reported to have excellent results, has no therapeutic value and should be abandoned. This contrasts with the positive reported effects using higher frequency and focal coils. Our work also reinforces the need for sham stimulation when evaluating the therapeutic effect of rTMS. © 2010 Movement Disorder Society     

Clinical measures of progression in Parkinson's disease

Despite all recent advances in symptomatic therapy Parkinson's disease (PD) continues to be a relentlessly progressive neurodegenerative disorder. Therefore therapies that will slow or hold disease progression are a major medical unmet need in PD. Clinical measures of disease progression that have been used in disease modification trials so far have focused on indices of progression of cardinal motor features like bradykinesia, rigidity, and tremor as captured by the UPDRS and the emerging need for effective dopaminergic symptomatic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites in the brain or peripheral autonomic nervous system contribute to poorly levodopa responsive motor symptoms like postural instability, freezing and falls or nonmotor symptoms. In addition treatment‐induced motor complications also impact on PD disability. Although it is widely accepted that clinical progression of PD is multidimensional and in addition includes effects of aging, there is no consensus how to best implement more clinically meaningful endpoints for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers for disease progression that would faithfully reflect advancing neurodegeneration and resulted clinical disability in PD and that could be used in shorter term clinical trials testing putative disease modifying agents. © 2009 Movement Disorder Society