Pallidal gap junctions‐triggers of synchrony in Parkinson's disease?

Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin‐36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin‐36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin‐36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin‐36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia. © 2014 International Parkinson and Movement Disorder Society     

l‐DOPA‐induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

Inflammation in Parkinson's disease (PD) is a new concept that has gained ground due to the potential of mitigating dopaminergic neuron death by decreasing inflammation. The solution to this question is likely to be complex. We propose here that the significance of inflammation in PD may go beyond the nigral cell death. The pathological process that underlies PD requires years to reach its full extent. A growing body of evidence has been accumulated on the presence of multiple inflammatory signs in the brain of PD patients even in very late stages of the disease. Because neuron‐microglia‐astrocyte interactions play a major role in the plasticity of neuronal response to l ‐DOPA in post‐synaptic neurons, we focused this review on our recent results of l ‐DOPA‐induced dyskinesia in rodents correlating it to significant findings regarding glial cells and neuroinflammation. We showed that in the rat model of PD/l ‐DOPA‐induced dyskinesia there was an increased expression of inflammatory markers, such as the enzymes COX2 in neurons and iNOS in glial cells, in the dopamine‐denervated striatum. The gliosis commonly seem in PD was associated with modifications in astrocytes and microglia that occur after chronic treatment with l ‐DOPA. Either as a cause, consequence, or promoter of progression of neuronal degeneration, inflammation plays a role in PD. The key aims of current PD research ought to be to elucidate (a) the time sequence in which the inflammatory factors act in PD patient brain and (b) the mechanisms by which neuroinflammatory response contributes to the collateral effects of l ‐DOPA treatment.     

Prevalence of headache in patients with Parkinson’s disease and its association with the side of motor symptom onset

We compared the lifetime prevalence and the prevalence of headache during the previous year in patients with Parkinson’s disease (PD) and control subjects. We also investigated the association between the side of PD symptom onset and the side of the headache. We interviewed 98 consecutive patients with an established diagnosis of PD between December 2010 and January 2012. The control group consisted of the 98 oldest sex-matched individuals from the nationwide Brazilian headache database. PD patients showed a significantly lower prevalence (40.8 %) of headache in the previous year than controls (69.4 %) (adjusted OR 0.5, CI 95 % 0.2–0.9, p = 0.03). PD patients also showed a lower prevalence of headache throughout life (74.5 %) than controls (93.9 %) (adjusted OR 0.2, CI 95 % 0.1–0.6, p = 0.01). Considering only patients who presented headache during the previous year, PD patients showed a higher association with occurrence of migraine than tension-type headache compared with controls (adjusted OR 3.3, CI 95 % 1.2–8.9, p = 0.02). The headache side was ipsilateral to the side of PD onset in 21 patients (84 %), with a concordance of 85.7 % on the left side and 81.8 % on the right side (p < 0.01). The prevalence of primary headache was significantly lower in patients with PD than controls. The predominant side of headache was ipsilateral to the side of initial motor signs of PD.     

Are the EEG microstates correlated with motor and non-motor parameters in patients with Parkinson's disease?

ObjectivesThis study compared electroencephalography microstates (EEG-MS) of patients with Parkinson's disease (PD) to healthy controls and correlated EEG-MS with motor and non-motor aspects of PD.MethodsThis cross-sectional exploratory study was conducted with patients with PD (n = 10) and healthy controls (n = 10) matched by sex and age. We recorded EEG-MS using 32 channels during eyes‐closed and eyes‐open conditions and analyzed the four classic EEG-MS maps (A, B, C, D). Clinical information (e.g., disease duration, medications, levodopa equivalent daily dose), motor (Movement Disorder Society - Unified Parkinson Disease Rating Scale II and III, Timed Up and Go simple and dual-task, and Mini-Balance Evaluation Systems Test) and non-motor aspects (Mini-Mental State Exam [MMSE], verbal fluency, Hospital Anxiety and Depression Scale, and Parkinson's Disease Questionnaire-39 [PDQ-39]) were assessed in the PD group. Mann-Whitney U test was used to compare groups, and Spearman's correlation coefficient to analyze the correlations between coverage of EEG-MS and clinical aspects of PD.ResultsThe PD group showed a shorter duration of EEG-MS C in the eyes-closed condition than the control group. We observed correlations (rho = 0.64 to 0.82) between EEG-MS B, C, and D and non-motor aspects of PD (MMSE, verbal fluency, PDQ-39, and levodopa equivalent daily dose).ConclusionAlterations in EEG-MS and correlations between topographies and cognitive aspects, quality of life, and medication dose indicate that EEG could be used as a PD biomarker. Future studies should investigate these associations using a longitudinal design.     

Are dementia and depression in Parkinson's disease related?

INTRODUCTION: Depression and dementia are common problems in PD. As the depression and dementia of PD share many symptoms such as apathy, anhedonia, anergia, and agitation, it is reasonable to ask if they are related. METHODS: 106 consecutive PD patients, unselected for depression or dementia were evaluated for depression using the Hamilton Depression Scale (Ham-D21). They were also evaluated using a modified neuropsychiatric inventory (NPI). Following the above, 100 consecutive PD patients were evaluated for dementia using Folstein's Mini Mental Status Examination (MMSE). They were also evaluated using the modified NPI. RESULTS: 29 of the first series of patients, 27%, were depressed, score of > or =14 on the Ham-D21. 8 of the second series of consecutive patients, 18%, were demented, score < or =24 on the MMSE. Depressed and demented patients were significantly more likely to suffer from apathy, anhedonia, mood lability, daytime drowsiness, paranoia, and hallucinations. Demented patients were significantly older, had PD longer, were more disabled and more likely to be depressed. COMMENT: The commonality of certain symptoms in demented and depressed patients suggests that dementia and depression in PD may be related and that, in PD depression may be a fore-runner of dementia. Five year follow-up of these patients supports this suggestion.     

Is freezing of gait in Parkinson's disease related to asymmetric motor function?

Freezing of gait (FOG) is a disabling phenomenon common in patients with advanced Parkinson's disease (PD). The cause of FOG is unclear. The objective of this study was to explore a novel hypothesis stating that FOG is related to asymmetric motor performance. We compared PD patients that experience FOG episodes (PD+FOG) with PD patients that do not (PD-FOG) and studied the relationship of FOG to asymmetry in gait and in rhythmic hand movement performance to determine whether potential FOG-related gait asymmetry is unique to walking or whether it is systemic. Subjects were tested in an "off" (unmedicated) and again in an "on" (medicated) state. Gait was more asymmetric in PD+FOG than in PD-FOG during "off" state (p = 0.005) and during "on" (p = 0.016). Rhythmicity of foot swing in one leg was correlated with the other leg in PD-FOG but not in PD+FOG. There was no difference in asymmetry in performance of rhythmic hand movements between the two groups. No correlation was found between asymmetry of clinical symptoms and gait asymmetry. Taken together, the results of this study suggest that bilateral uncoordinated gait and marked gait asymmetry, but not asymmetry in motor performance in general, are associated with FOG.     

Impaired motor speech performance in Huntington’s disease

Dysarthria is a common symptom of Huntington’s disease and has been reported, besides other features, to be characterized by alterations of speech rate and regularity. However, data on the specific pattern of motor speech impairment and their relationship to other motor and neuropsychological symptoms are sparse. Therefore, the aim of the present study was to describe and objectively analyse different speech parameters with special emphasis on the aspect of speech timing of connected speech and non-speech verbal utterances. 21 patients with manifest Huntington’s disease and 21 age- and gender-matched healthy controls had to perform a reading task and several syllable repetition tasks. Computerized acoustic analysis of different variables for the measurement of speech rate and regularity generated a typical pattern of impaired motor speech performance with a reduction of speech rate, an increase of pauses and a marked disability to steadily repeat single syllables. Abnormalities of speech parameters were more pronounced in the subgroup of patients with Huntington’s disease receiving antidopaminergic medication, but were also present in the drug-naïve patients. Speech rate related to connected speech and parameters of syllable repetition showed correlations to overall motor impairment, capacity of tapping in a quantitative motor assessment and some score of cognitive function. After these preliminary data, further investigations on patients in different stages of disease are warranted to survey if the analysis of speech and non-speech verbal utterances might be a helpful additional tool for the monitoring of functional disability in Huntington’s disease.     

REM sleep behavior disorder and motor dysfunction in Parkinson's disease – A longitudinal study

ObjectivesLongitudinal assessment of a Parkinson's disease (PD) cohort, to investigate the evolution or REM sleep behavior symptoms (RBD) over time and to test the relation between RBD at onset and motor dysfunction progression.MethodsAn early stage PD cohort (n = 61) was assessed at two time points, separated by a two years interval. Diagnostic criteria for RBD were: violent behavior during sleep and body movements or vocalization indicative of dream enacting and at least six affirmative answers in the REM sleep behavior disorder screening questionnaire. Motor function assessment was performed with the Unified Parkinson's Disease Scale part II and III (total and partial scores for tremor, bradykinesia, rigidity, gait/postural instability and dysarthria).Results25 Patients had RBD at baseline, vs. 35 at follow-up. Three RBD changed to non-RBD at follow-up, while 10 non-RBD patients developed RBD at follow-up (annual incidence of 12.5%). RBD and non-RBD patients did not differ significantly at baseline or follow-up. The presence of RBD at baseline was significantly related to an increase in UPDRS total and bradykinesia scores over time.DiscussionRBD symptoms can vary over time and have a tendency to increase during the early stages of disease. The presence of RBD symptoms could be a risk factor for motor function deterioration and particularly for bradykinesia worsening.     

FMR1 gray‐zone alleles: Association with Parkinson's disease in women?

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG‐repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray‐zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2–8.7). Gray‐zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray‐zone alleles may be associated with Parkinson's disease in women. © 2011 Movement Disorder Society