Training dual tasks together or apart in Parkinson's disease: Results from the DUALITY trial.

BACKGROUND AND OBJECTIVES: Many controversies surround the usefulness of dual-task training in Parkinson's disease (PD). This study (1) compared the efficacy of two different dual-task training programs for improving dual-task gait and (2) assessed the possible fall risk of such training. METHODS: Patients (N = 121) with a diagnosis of PD (aged 65.93 [±9.22] years, Hoehn and Yahr stage II-III on-medication) were randomized to (1) a consecutive group in which gait and cognitive tasks were trained separately or (2) an integrated group in which gait and cognitive tasks were trained simultaneously. Both interventions involved 6 weeks of at-home physiotherapist-led training. Two baseline tests were performed as a 6-week control period before training. Posttests were performed immediately after training and at 12-week follow-up. Dual-task gait was assessed during trained and untrained secondary tasks to assess consolidation of learning. Fall risk was determined by a weekly telephone call for 24 weeks. RESULTS: No significant time by group interactions were found, suggesting that both training modes had a similar effect on dual-task gait. Immediately after training, and not after the control period, significant improvements (P < .001) in dual-task gait velocity were found in all trained and untrained dual tasks. Improvements ranged between 7.75% and 13.44% when compared with baseline values and were retained at 12-week follow-up. No significant change in fall risk occurred in both study arms (P = .84). CONCLUSIONS: Consecutive and integrated dual-task training led to similar and sustained improvements in dual-task gait velocity without increasing fall risk. These novel findings support adoption of dual-task training in clinical practice. © 2017 International Parkinson and Movement Disorder Society.

A case of mental nerve paresthesia due to dynamic compression of alveolar inferior nerve along an elongated styloid process.

Spontaneous paresthesia of the mental nerve is considered an ominous clinical sign. Mental nerve paresthesia has also been referred to as numb chin syndrome. Several potentially different factors have been investigated for their role in interfering with the inferior alveolar nerve (IAN) and causing mental nerve neuropathy. In the present case, the patient had an elongated calcified styloid process that we hypothesized had caused IAN irritation during mandibular movement. This eventually resulted in progressive loss of sensation in the mental nerve region. To our knowledge, this dynamic irritation, with complete recovery after resection of the styloid process, has not been previously reported.

The clinical features of pathologically confirmed vascular parkinsonism.

OBJECTIVE: To evaluate in detail the clinical features in a large series of pathologically confirmed cases of vascular Parkinsonism (VP). BACKGROUND: In the absence of widely accepted diagnostic criteria for VP pathological confirmation of diagnosis is necessary to ensure diagnostic reliability, and has only been reported in a few small series. DESIGN/METHODS: The archival records of the Queen Square Brain Bank (QSBB) have been used to identify cases of Parkinsonism where cerebrovascular disease was the only pathological finding. Clinical notes were scrutinised and milestones of disease progression were compared with other atypical Parkinsonian syndromes from previous QSBB studies. RESULTS: Twenty-eight cases were included. Mean age of onset and disease duration were 70.6 (SD± 6.42) and 10.5 (SD± 66.1) years respectively. Bradykinesia was present in all cases, rigidity in 96%, falls in 76%, pyramidal signs in 54%, urinary incontinence in 50% and dementia in 39%.Visual hallucinations in 0%. Two-thirds had an insidious onset and a relentless rather than stepwise progression of disability. When compared with other Parkinsonian syndromes, VP had an older age of onset. CONCLUSIONS: In comparison with other Parkinsonian syndromes the patients were older and had an extremely low frequency of visual hallucinations compared with Parkinson's disease.

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations.

Early-onset Parkinson's disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin.

Dopaminergic modulation of striato-frontal connectivity during motor timing in Parkinson's disease.

Patients with Parkinson's disease experience motor and perceptual timing difficulties, which are ameliorated by dopaminergic medication. We investigated the neural correlates of motor timing in Parkinson's disease, including the effects of dopaminergic medication on patterns of brain activation. Eight patients with Parkinson's disease and eight healthy controls were scanned with H(15)(2)O positron emission tomography while engaged in three tasks: synchronization (right index finger tapping in synchrony with a tone presented at 1 Hz), continuation (tapping at 1 Hz in the absence of a tone), and a control simple reaction time task. During the first 6 scans, the patients were assessed after overnight withdrawal of medication. Scans 7-12 were completed with the patients in the 'ON' state, after injections of apomorphine, a dopamine receptor agonist. For the healthy controls, relative to the control reaction time task, motor timing (synchronization + continuation) was associated with significantly greater activation in left medial prefrontal cortex (Brodmann area 10, 32), right hippocampus, bilateral angular gyrus (Brodmann area 39), left posterior cingulate (Brodmann area 31) and left nucleus accumbens/caudate. This pattern of brain activation during motor timing was not observed for patients, who showed significantly greater activation in bilateral cerebellum, right thalamus and left midbrain/substantia nigra compared to the control participants. Relative to the externally-paced synchronization task, the internally controlled continuation task was associated with greater activation in the dorsolateral prefrontal cortex (Brodmann area 46/9) in both the control and Parkinson's disease groups. Analysis of medication-related effects indicated that cortical activation was significantly more predominant during motor timing when the patients were 'ON' medication, whereas pallidal and cerebellar activations were evident 'OFF' medication. Effective connectivity analysis established that activity in the left caudate nucleus was associated with increased activity in the right lentiform nucleus and cerebellum 'OFF' medication, and with increased activity in the prefrontal cortex 'ON' medication. These results suggest that in Parkinson's disease, in the 'OFF' medication state, excessive inhibitory pallidal outflow is associated with a lack of adequate frontal activation and reliance on the cerebellum for motor timing. In contrast, our results establish for the first time that administration of dopaminergic medication increases striatal-frontal connectivity between the caudate nucleus and prefrontal cortex during motor timing.

[123I] FP-CIT spect study in vascular parkinsonism and Parkinson's disease.

There is substantial evidence to support a role for small vessel disease (SVD) as a cause for vascular parkinsonism (VP). Using [(123)I] FP-CIT SPECT (single photon emission computed tomography), we have tried to determine whether VP patients have pre-synaptic dopaminergic function similar to PD patients, and whether the severity of parkinsonian symptoms as well as the levodopa response in VP patients are correlated with pre-synaptic dopaminergic dysfunction. Thirteen patients fulfilling operational clinical criteria for VP had [(123)I] FP-CIT scans. Mean [(123)I] FP-CIT uptake in the basal ganglia was significantly lower in VP patients than in healthy controls, and the asymmetry index was not significantly different between these groups. In contrast, compared with the PD group, only the mean asymmetry index was significantly lower in VP patients. None of the parameters measured was significantly different between VP patients who had an insidious onset of parkinsonism (VPi) and those who had an acute onset (VPa). There was a significant correlation between the bilateral basal ganglia FP-CIT uptake reduction in the VP patients and UPDRS motor scores, but not with the mean % reduction in motor UPDRS after levodopa. We suggest that in the majority of VP patients, pre-synaptic dopaminergic function is reduced. The presence of a rather symmetrical FP-CIT uptake in the basal ganglia may help to distinguish VP from PD and could therefore be used as a criterion for the clinical diagnosis of VP.

Risk of Disabling Response Fluctuations and Dyskinesias for Dopamine Agonists Versus Levodopa in Parkinson's Disease.

BACKGROUND: Response fluctuations and dyskinesias develop during the use of both levodopa (LD) and dopamine agonists (DA), but may not be equally disabling. OBJECTIVE: To compare the risk and time of onset of disabling response fluctuations and dyskinesias (DRFD) among patients with Parkinson's disease (PD) who were initially treated with either LD or DA. METHODS: Open cohort study of all consecutive de-novo PD patients in routine clinical practice, included over a period of 15 years (median follow-up: 8.1 years, range 1.1-17.7), since embarking on LD or DA. Older patients and patients with more severe PD were started on LD (n = 77), younger patients on a DA (n = 50). Therapy was adjusted according to generally accepted guidelines. The primary endpoints were: the onset of response fluctuations, dyskinesias, and the moment when these complications became disabling (DRFD). RESULTS: LD-starters developed response fluctuations 0.8 years earlier than DA-starters (p = 0.07), while dyskinesias appeared around 2.5 years earlier (p = 0.003). However, the risk and time of onset of DRFD did not differ statistically between the groups (LD-starters: 60% , median interval 7.3 years, DA-starters: 52% , 6.1 years, p = 0.63). DA-starters displayed a 0.19 points lower adjusted mean improvement in motor scores than LD-starters (p = 0.002). Adjustments for age and severity of PD at start of dopaminergic therapy did not change these results. CONCLUSIONS: In routine clinical practice, the risk and time of onset of DRFD is comparable for LD-starters versus DA-starters, but motor functioning is worse in DA-starters. These results support the use of LD as initial therapy for PD.

Vascular chorea in adults and children.

Chorea may occur as part of the symptomatology of acute stroke; it occasionally also may be delayed or progressive. Patients with vascular-related chorea typically present with an acute or subacute onset of chorea of one side of the body (hemichorea), contralateral to the lesion. Cerebrovascular disease is the most common cause of sporadic chorea. Lesions are most frequently found in the thalamus and lentiform nucleus, and less often in subthalamic nucleus. The differential diagnosis of choreic syndromes relies not so much on differences in the phenomenology of the hyperkinesia but the age at onset, mode of onset, time course, family history, drug use, distribution of chorea in the body, and presence of accompanying neurological findings. Magnetic resonance imaging is preferred to demonstrate the presence of strategic small lesions in regions that are difficult to image with computed tomography, such as the globus pallidus, thalamus, and subthalamic nucleus. Although the prognosis of hemichorea can be benign, the long-term prognosis is not specifically determined by the hemichorea but by the long-term prognosis of stroke patients. Symptomatic treatment with antichoreic drugs may be necessary in the acute phase. Surgery is rarely indicated to treat vascular chorea.

The role of imaging in the diagnosis of vascular parkinsonism.

Parkinsonism is a syndrome that features bradykinesia (slowness of the initiation of voluntary movement) and at least 1 of the following conditions: rest tremor, muscular rigidity, or postural instability. Criteria for the clinical diagnosis of vascular parkinsonism (VP) have been proposed, which are derived from a postmortem examination study. Computed tomography and magnetic resonance imaging can support this clinical diagnosis with positive imaging findings. Dopamine transporter single-photon emission computed tomography may also be of help to distinguish VP from Parkinson disease and other parkinsonisms.

Levodopa in the treatment of Parkinson's disease: an old drug still going strong.

After more than 40 years of clinical use, levodopa (LD) remains the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Compared with other available dopaminergic therapies, dopamine replacement with LD is associated with the greatest improvement in motor function. Long-term treatment with LD is, however, often complicated by the development of various types of motor response oscillations over the day, as well as drug-induced dyskinesias. Motor fluctuations can be improved by the addition of drugs such as entacapone or monoamine oxidase inhibitors, which extend the half-life of levodopa or dopamine, respectively. However, dyskinesia control still represents a major challenge. As a result, many neurologists have become cautious when prescribing therapy with LD. This review summarizes the available evidence regarding the use of LD to treat PD and will also address the issue of LD delivery as a critical factor for the drug's propensity to induce motor complications.

Parkinson disease and comorbid cerebrovascular disease.

Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop-either acutely or chronically-prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD.

Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson's disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study.

We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

Posttraumatic tremor without parkinsonism in a patient with complete contralateral loss of the nigrostriatal pathway.

We present a patient with posttraumatic tremor who did not show any [(123)I]FP-CIT uptake in the contralateral putamen and caudate. The absence of hypokinesia and rigidity is surprising in the presence of a striatal dopaminergic denervation that is even more severe than in Parkinson's disease. An explanation, therefore, could be that the lesion in the subthalamic nucleus in our patient prevented the onset of a Parkinson syndrome.

Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis.

Vascular parkinsonism (VP) is difficult to diagnose with any degree of clinical certainty. We investigated the importance of macroscopic cerebral infarcts and pathological findings associated with microscopic "small vessel disease" (SVD) in the aetiology of VP. The severity of microscopic SVD pathology (perivascular pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces) and the presence of macroscopically visible infarcts were assessed in 17 patients with parkinsonism and no pathological evidence of either Parkinson's disease or any histopathological condition known to be associated with a parkinsonian syndrome, and compared with age-matched controls. Microscopic SVD pathology was significantly more severe in the parkinsonian brains. Most patients presented with bilateral bradykinesia and rigidity together with a gait disorder characterised predominantly by a shuffling gait. Four patients presented acutely with hemiparesis and then progressed to develop a parkinsonian syndrome. They could be distinguished from the remaining VP patients by the presence at autopsy of macroscopically visible lacunar infarcts in regions where contralateral thalamocortical drive might be reduced. The clinical features at presentation varied according to the speed of onset and the underlying vascular pathological state. New clinical criteria for a diagnosis of VP are proposed based on the clinicopathological findings of this study.

[123I]beta-CIT SPECT distinguishes vascular parkinsonism from Parkinson's disease.

We investigated whether [(123)I]-beta-CIT and single-photon emission computed tomography (SPECT) imaging distinguishes patients with clinically suspected vascular parkinsonism (VP) from patients with idiopathic Parkinson's disease (PD). [(123)I]beta-CIT SPECT is a sensitive marker of dopaminergic degeneration, and the degree of striatal binding reduction in PD correlates with disease severity. Thirteen patients who fulfilled rigid clinical criteria for VP (mean +/- S.D.: age, 76.5 +/- 5.3 years; disease duration, 3.6 +/- 2.8 years), 20 PD patients (age, 66.2 +/- 9.5 years; disease duration, 4.3 +/- 2.7 years), and 30 healthy persons (age, 44.6 +/- 19.2 years) underwent [(123)I]beta-CIT SPECT imaging. Age-corrected striatal beta-CIT binding was reduced on average by 40.8% in PD but was near normal in the VP group (mean reduction, 1.2%). This difference was statistically significant (Z = 4.68; P < 0.001). The left-right asymmetry of striatal beta-CIT binding was significantly increased in the PD group compared with normal controls and the VP group (F(2) = 17.4, P <0.001). Moreover, putamen-caudate nucleus ratios were significantly reduced in PD compared with both VP patients and healthy controls (F(2) = 65.5, P < 0.001). Whole striatal beta-CIT binding was more than one standard deviation above the mean PD values in all but one of the individual VP patients. Our findings suggest that the presynaptic dopaminergic deficits seen in PD are absent in most patients with VP. [(123)I]beta-CIT SPECT imaging may be useful to help distinguish between PD and VP patients during life.

[123I]-FP-CIT-SPECT demonstrates dopaminergic deficit in orthostatic tremor.

There is increasing evidence of a potential role of the dopaminergic system in orthostatic tremor (OT): Association with parkinsonism and treatment effects of L-dopa and dopamine agonists have been reported. Eleven patients with isolated OT had single-photon emission computed tomography (SPECT) using (123)I-FP-CIT ([(123)I]-2 beta-carbomethoxy-3beta-(-4-iodophenyl)-N-(3-fluoropropyl)-nortropane) as dopamine transporter tracer. Results were compared with 12 age-matched normal controls and 12 patients with Parkinson's disease (PD). A marked reduction in striatal tracer binding was found in OT compared to normal controls (p < 0.001). Tracer uptake was significantly higher and more symmetrical than in PD, and caudate and putamen were equally affected. L-dopa challenges, performed in seven patients, showed a small but non-significant improvement on EMG and a small but significant improvement in clinical parameters on blinded video rating. Two-month open-label L-dopa treatment (600 mg/day) led to a small improvement in two of five patients but no significant overall change. Olfactory function on University of Pennsylvania Smell Identification Test was normal. Our finding of a marked tracer uptake reduction on dopamine transporter SPECT supports a role of the dopaminergic system in OT. Lack of evidence of a clinically relevant therapeutic response to L-dopa suggests that other mechanisms must also be involved in the pathogenesis.