SPG11: clinical and genetic features of seven Czech patients and literature review.

SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.

Functional imaging of the cerebellum and basal ganglia during predictive motor timing in early Parkinson's disease.

BACKGROUND AND PURPOSE: The basal ganglia and the cerebellum have both emerged as important structures involved in the processing of temporal information. METHODS: We examined the roles of the cerebellum and striatum in predictive motor timing during a target interception task in healthy individuals (HC group; n = 21) and in patients with early Parkinson's disease (early stage PD group; n = 20) using functional magnetic resonance imaging. RESULTS: Despite having similar hit ratios, the PD failed more often than the HC to postpone their actions until the right moment and to adapt their behavior from one trial to the next. We found more activation in the right cerebellar lobule VI in HC than in early stage PD during successful trials. Successful trial-by-trial adjustments were associated with higher activity in the right putamen and lobule VI of the cerebellum in HC. CONCLUSIONS: We conclude that both the cerebellum and striatum are involved in predictive motor timing tasks. The cerebellar activity is associated exclusively with the postponement of action until the right moment, whereas both the cerebellum and striatum are needed for successful adaptation of motor actions from one trial to the next. We found a general ''hypoactivation'' of basal ganglia and cerebellum in early stage PD relative to HC, indicating that even in early stages of the PD there could be functional perturbations in the motor system beyond striatum.

Functional anatomy of outcome evaluation during Iowa Gambling Task performance in patients with Parkinson's disease: an fMRI study.

The aim of this study was to investigate the functional anatomy of decision-making during the Iowa Gambling Task in patients with Parkinson's disease. We used event-related functional magnetic resonance imaging (fMRI) during a computerized version of IGT to compare 18 PD patients on dopaminergic medication in the ON state and 18 healthy control subjects. Our analyses focused on outcome evaluation following card selection, because we expected this aspect of decision-making to be impaired in PD patients. The PD patients exhibited lower activation of the left putamen than the control group as a reaction to penalty. Using psychophysiological interaction analysis, we identified decreased functional connectivity between the right globus pallidus internus and the left anterior cingulate gyrus in the PD group. In contrast, increased connectivity between these structures was observed after penalty in the control group. Our results suggest altered functioning of the basal ganglia and their connections with the cortical structures involved in the limbic loop (e.g., the limbic fronto-striatal circuit of the basal ganglia) during decision-making in PD patients. Differences in the response to loss could be associated with insufficient negative reinforcement after a loss in PD patients in the ON state in comparison to a healthy population.

Iowa Gambling Task in patients with early-onset Parkinson's disease: strategy analysis.

The aim of our study was to analyse decision making in early-onset Parkinson's disease (PD) patients performing the Iowa Gambling Task (IGT). We compared 19 patients with early-onset PD (≤ 45 years) on dopaminergic medication (no evidence of depression, dementia, executive dysfunction according to the Tower of London test and the Stroop test, or pathological gambling) with 20 age-matched controls. A computer version of the IGT was employed. The PD patients achieved slightly lower IGT scores than the control group. A detailed analysis based on 'shift frequencies' between the individual decks showed that the patients tended to change their preferences for the decks more frequently, with a higher preference for the 'disadvantageous' deck B. Control subjects seemed to develop a more effective strategy. These differences could be caused by the poorer ability of the patients to develop any strategy at all. We observed changes in decision making during IGT performance in patients with early-onset PD, although they had no executive dysfunction as measured by established neuropsychological tests. The more detailed analysis employed in the present study could lead to a more accurate study of IGT performance and application of IGT in clinical practice.

Impulse control disorders in patients with Parkinson's disease.

In patients with Parkinson's disease with higher prevalence than in current population there appear pathological behaviours characterized by compulsion, repetitiveness and impulsivity, which are connected with material profit or pleasurable experience. They are, in particular, pathological gambling, hypersexuality, compulsive shopping and compulsive eating (in the literature they are collectively referred to as impulse control disorders). Pathological preoccupation with repeated mechanical activities (so-called punding) and excessive compulsive intake of dopaminergic medication (so-called dopamine dysregulation syndrome or also syndrome of hedonistic homeostatic dysregulation) are of similar nature. The paper treats briefly the risk factors and prevalence of these pathological behaviours. In current clinical practice, these psychiatric complications frequently escape doctors' attention, they are underdiagnosed. Although no generally valid recommendations for their therapy are currently available, they can be influenced medically. Of advantage can be modified dopaminergic medication (usually dose reduction ofdopaminergic agonists); multidisciplinary approach to the problem is appropriate. The pathological behaviours given above can frequently lead to considerable material losses and markedly aggravate patients' handicap in the social sphere; it can be expected that in the future they can become a problem also from the ethical and legal points of view.

Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson's disease.

There is evidence that both the basal ganglia and the cerebellum play a role in the neural representation of time in a variety of behaviours, but whether one of them is more important is not yet clear. To address this question in the context of predictive motor timing, we tested patients with various movement disorders implicating these two structures in a motor-timing task. Specifically, we investigated four different groups: (1) patients with early Parkinson's disease (PD); (2) patients with sporadic spinocerebellar ataxia (SCA); (3) patients with familial essential tremor (ET); and (4) matched healthy controls. We used a predictive motor-timing task that involved mediated interception of a moving target, and we assessed the effect of movement type (acceleration, deceleration and constant), speed (slow, medium and fast) and angle (0 degrees , 15 degrees and 30 degrees) on performance (hit, early error and late error). The main results showed that PD group and arm ET subgroup did not significantly differ from the control group. SCA and head ET subjects (severe and mild cerebellar damage, respectively) were significantly worse at interception than the other two groups. Our findings support the idea that the basal ganglia play a less significant role in predictive motor timing than the cerebellum. The fact that SCA and ET subjects seemed to have a fundamental problem with predictive motor timing suggests that the cerebellum plays an essential role in integrating incoming visual information with the motor output in a timely manner, and that ET is a heterogeneous entity that deserves increased attention from clinicians.