Genetics in Parkinson's disease, state-of-the-art and future perspectives.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is clinically characterized by the presence of motor (bradykinesia, rigidity, rest tremor and postural instability) and non-motor symptoms (cognitive impairment, autonomic dysfunction, sleep disorders, depression and hyposmia). The aetiology of PD is unknown except for a small but significant contribution of monogenic forms. SOURCES OF DATA: No new data were generated or analyzed in support of this review. AREAS OF AGREEMENT: Up to 15% of PD patients carry pathogenic variants in PD-associated genes. Some of these genes are associated with mendelian inheritance, while others act as risk factors. Genetic background influences age of onset, disease course, prognosis and therapeutic response. AREAS OF CONTROVERSY: Genetic testing is not routinely offered in the clinical setting, but it may have relevant implications, especially in terms of prognosis, response to therapies and inclusion in clinical trials. Widely adopted clinical guidelines on genetic testing are still lacking and open to debate. Some new genetic associations are still awaiting confirmation, and selecting the appropriate genes to be included in diagnostic panels represents a difficult task. Finally, it is still under study whether (and to which degree) specific genetic forms may influence the outcome of PD therapies. GROWING POINTS: Polygenic Risk Scores (PRS) may represent a useful tool to genetically stratify the population in terms of disease risk, prognosis and therapeutic outcomes. AREAS TIMELY FOR DEVELOPING RESEARCH: The application of PRS and integrated multi-omics in PD promises to improve the personalized care of patients.

A gait-based paradigm to investigate central body representation in cervical dystonia patients.

BACKGROUND: Cervical dystonia (CD) is a common adult-onset idiopathic form of dystonia characterized by an abnormal head posture caused by an excessive activity of the neck muscles. The position of the head is important to direct viewpoint in the rounding environment, and the body orientation, during gait, must be coherent with the subjective straight ahead (SSA). An alteration of the SSA, as in the case of CD patients, could affect gait when visual input is not available. The aim of this study was to probe the behavior of patients with CD during blindfolded walking, investigating the ability to walk straight ahead based only on somatosensory and vestibular information. METHODS: In this observational cross-sectional study, patients with CD and healthy control subjects (HC) were compared. All participants were evaluated through a gait analysis during blindfolded walking on a GAITRite carpet, relying on their own sense of straightness. RESULTS: Patients with CD showed lower values of path length (p < 0.001), a lower number of steps on the carpet (p < 0.001). A higher number of CD patients deviated during the task, walking out of the carpet, (p < 0.005) compared to HS. No relation was found between the dystonic side and the gait trajectory deviation. A significant correlation was found between pain symptom and gait performance. CONCLUSIONS: CD patients showed dysfunctions in controlling dynamic body location during walking without visual afferences, while the dystonic side does not seem to be related to the lateral deviation of the trajectory. Our results would assume that a general proprioceptive impairment could lead to an improper body position awareness in patients with CD.

Spread of dystonia in patients with idiopathic adult-onset laryngeal dystonia.

BACKGROUND AND PURPOSE: Adult-onset laryngeal dystonia (LD) can be isolated or can be associated with dystonia in other body parts. Combined forms can be segmental at the onset or can result from dystonia spread to or from the larynx. The aim of this study was to identify the main clinical and demographic features of adult-onset idiopathic LD in an Italian population with special focus on dystonia spread. METHODS: Data were obtained from the Italian Dystonia Registry (IDR) produced by 37 Italian institutions. Clinical and demographic data of 71 patients with idiopathic adult-onset LD were extracted from a pool of 1131 subjects included in the IDR. RESULTS: Fifty of 71 patients presented a laryngeal focal onset; the remaining subjects had onset in other body regions and later laryngeal spread. The two groups did not show significant differences of demographic features. 32% of patients with laryngeal onset reported spread to contiguous body regions afterwards and in most cases (12 of 16 subjects) dystonia started to spread within 1 year from the onset. LD patients who remained focal and those who had dystonia spread did not show other differences. CONCLUSIONS: Data from IDR show that dystonic patients with focal laryngeal onset will present spread in almost one-third of cases. Spread from the larynx occurs early and is directed to contiguous body regions showing similarities with clinical progression of blepharospasm. This study gives a new accurate description of LD phenomenology that may contribute to improving the comprehension of dystonia pathophysiology.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings.

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

The Italian Dystonia Registry: rationale, design and preliminary findings.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

Correlation between Quality of Life and severity of Parkinson's Disease by assessing an optimal cut-off point on the Parkinson's Disease questionnaire (PDQ-39) as related to the Hoehn & Yahr (H&Y) scale.

Purpose: Strong evidence shows that symptoms in individuals with Parkinson's Disease (PD) restrict both their independence and social participation, leading to a low Quality of Life (QoL). Conversely, a reduced QoL has a negative impact on symptoms. The aim is to evaluate the correlation between QoL and severity of PD by assessing the presence of an optimal cut-off point on the Parkinson's disease questionnaire (PDQ-39) as related to the Hoehn &Yahr (H&Y) scale in a cohort of Italian adults with PD. Methods: A multicenter, cross-sectional study was performed. This study was conducted on a cohort of consecutive individuals. All participants were evaluated with the PDQ-39, and the severity of PD was recorded according to the H&Y scale by a neurologist. Receiver op-erating characteristic (ROC) curves and coordinates, visually inspected, were used to find cut-off points with optimal sensitivity and specificity. These were in turn used to determine the optimal PDQ-39 cut-off score for identifying disease severity according to H&Y stages. Results: 513 individuals were included in the study. The ROC curve analysis showed that QoL worsened with an increase in disease severity and age. Moreover, QoL was worse in females. Conclusions: The results of this study allowed for the correlation of QoL and disease severity in a cohort of individuals with PD. With this cut-off point, it is now possible to make a determination of QoL of an individual with PD at a certain stage of the disease, in a specific age range, and of a particular gender.

Quality of sleep in primary focal dystonia: a case-control study.

BACKGROUND: Sleep disturbances are common in patients with movement disorders. Evaluating quality of sleep is of primary importance because of the effect that nocturnal and daytime sleep abnormalities exert on general health status. However, quality of sleep has never been addressed in detail in patients with dystonia. The aim of this case-control study was to analyse quality of sleep in patients with the two most common forms of primary focal dystonia, blepharospasm (BSP) and cervical dystonia (CD). METHODS: We evaluated quality of sleep (Pittsburgh Sleep Quality Index, PSQI) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS) in 98 patients with focal adult-onset dystonia (52 with BSP; 46 with CD) and in a group of 56 age-and gender-matched healthy subjects. The Beck Depression Inventory (BDI) was used for the evaluation of depressive symptomatology. RESULTS: Quality of sleep was impaired (significantly higher PSQI scores) in both groups of patients. However, differences in PSQI scores between patients with CD and control subjects were partly confounded by BDI scores, whereas differences in PSQI scores between patients with BSP and control subjects were not influenced by BDI. Excessive daytime sleepiness was not significantly more frequent than in control subjects in either patients with BSP or patients with CD. CONCLUSIONS: This study suggests that the assessment and treatment of insomnia-related complaints should be considered in global management plans of patients with focal dystonia, particularly in those affected by BSP.

Familiarity with a Tool Influences Peripersonal Space and Primary Motor Cortex Excitability of Muscles Involved in Haptic Contact.

Long-term experience with a tool stably enlarges peripersonal space (PPS). Also, gained experience with a tool modulates internal models of action. The aim of this work was to understand whether the familiarity with a tool influences both PPS and motor representation. Toward this goal, we tested in 13 expert fencers through a multisensory integration paradigm the embodiment in their PPS of a personal (pE) or a common (cE) épée. Then, we evaluated the primary motor cortex excitability of proximal (ECR) and distal (APB) muscles during a motor imagery (MI) task of an athletic gesture when athletes handled these tools. Results showed that pE enlarges subjects' PPS, while cE does not. Moreover, during MI, handling tools increased cortical excitability of ECR muscle. Notably, APB's cortical excitability during MI only increased with pE as a function of its embodiment in PPS. These findings indicate that the familiarity with a tool specifically enlarges PPS and modulates the cortical motor representation of those muscles involved in the haptic contact with it.

External shock waves therapy in dystonia: preliminary results.

BACKGROUND AND PURPOSE: Extracorporeal shock wave therapy (ESWT) has been shown to reduce hypertonia in patients with upper motor neuron syndrome without any side effect. The aim of the present study is to investigate whether ESWT could be useful also in patients with dystonia. METHODS: We evaluated three patients with secondary dystonia and three patients with idiopathic writer's cramp. Placebo treatment was performed in each patient. ESWT was administered during four sessions (once weekly) to the target muscles of hand and forearm using an electromagnetic lithotripter (Modulith SLK--Storz Medical). Clinical evaluation was performed using the Unified Dystonia Rating Scale in patients with secondary dystonia and the Arm Dystonia Disability Scale in patients with writer's cramp. RESULTS: After treatment, the three patients with secondary dystonia showed a marked improvement which lasted at least until 1 month after the last session. In the patients with writer's cramp, the improvement after ESWT was less consistent being effective only in two subjects. There were no associated adverse effects. CONCLUSIONS: Extracorporeal shock wave therapy is probably an effective and safe treatment for upper limb dystonia, particularly for the secondary forms. Larger randomized studies are needed to confirm these preliminary results.

Long-term assessment of the risk of spread in primary late-onset focal dystonia.

BACKGROUND: Primary late-onset focal dystonias may spread over time to adjacent body regions, but differences in the risk of spread over time among the various focal forms and the influence of age at dystonia onset on the risk of spread are not well established. METHODS: Patients presenting with primary late-onset focal blepharospasm (BSP, n = 124), cervical dystonia (CD, n = 73) and focal hand dystonia (FHD, n = 24) with 10 years or more of disease duration (mean +/- SD, 15.3 (SD 4.9) years) were included in the study. The relationship between demographic/clinical variables and spread of dystonia was assessed by Kaplan-Meier survival curves and Cox proportional hazard regression models. RESULTS: Patients starting with BSP, CD and FHD had similar age, sex and disease duration. Age at dystonia onset, age at initial spread and the risk of initial spread were significantly higher, whereas time elapsing from onset to initial spread was significantly lower in the BSP group than in those with onset in the neck or in the upper extremities. Conversely, these parameters were similar in the CD and FHD groups. The greater risk of spread in the BSP group was mainly evident in the first 5 years of history; thereafter, it declined and became similar to that of patients with CD/FHD. The difference in the risk of initial spread by site of onset was partly confounded by age at dystonia onset. Site of and age at dystonia onset, and age at first spread, were not significant predictors of the risk of a second spread. CONCLUSION: This study adds new insights into the phenomenon of spread of primary late-onset focal dystonia and provides the framework for future studies aimed at an indepth investigation of the mechanism(s) of spread.

Intrafusal effects of botulinum toxin in post-stroke upper limb spasticity.

A previous study in subjects with focal dystonia suggested that the greater and longer-lasting effect induced by botulinum toxin type A (BoNT-A) on the tonic vibration reflex (TVR) than on the maximal M-wave (M-max) might be the physiological marker of the toxin's action at the level of intrafusal muscle fibres. With this approach, we investigated the possible effect of BoNT-A on fusimotor synapses in eight patients with post-stroke spasticity (four with no residual motor capacity before treatment and four with partially spared muscle strength and residual motor capacity). TVR and M-max were recorded from the wrist and finger flexor muscles before treatment and at 1, 4 and 7 months afterwards. The TVR reduction was greater than the M-max reduction and remained fairly constant over time only in the subjects with a residual motor capacity before the treatment. This pilot study suggests that some degree of strength and active movement is necessary for the action of BoNT-A on intrafusal fibres.

DRD3 Ser9Gly variant is not associated with essential tremor in a series of Italian patients.

BACKGROUND: Essential tremor (ET) is the most common movement disorder worldwide. Three susceptibility loci on chromosomes 3q13, 2p24.1, and 6p23 have been reported, but no causative genes were found. The Ser9Gly variant of dopamine D3 receptor (DRD3) receptor was found associated to ET in a French and US population. METHODS: A case-control study to evaluate the association between the Ser9Gly variant and ET was performed in a cohort of 116 Italian patients with familial ET and in 158 normal controls. RESULTS: No significant difference in allele and genotype frequencies was found between the two groups. CONCLUSIONS: These results do not support an association between DRD3 Ser9Gly and susceptibility to ET in Italian patients.

Influence of coffee drinking and cigarette smoking on the risk of primary late onset blepharospasm: evidence from a multicentre case control study.

Prior coffee and smoking habits were investigated in a multicentre case control study involving 166 patients presenting with primary late onset blepharospasm (BSP), 228 hospital control patients with primary hemifacial spasm and 187 population control subjects from five Italian centres. Information on age at disease onset, smoking and coffee drinking status at the reference age and average number of cups of coffee drunk/cigarettes smoked per day reached high and similar test-retest reproducibility in case and control patients. Unadjusted logistic regression analysis yielded a significant inverse association of prior coffee drinking and cigarette smoking with case status for the control groups. After adjustment for age, sex, referral centre, disease duration, years of schooling and ever coffee drinking/cigarette smoking, as appropriate, the smoking estimate lacked significance whereas the association of coffee intake and BSP did not (cases vs hospital control patients: OR 0.37 (95% CI 0.20 to 0.67); cases vs population control subjects: OR 0.44 (95% CI 0.23 to 0.85)). The strength of the inverse association between BSP and coffee intake tended to increase with the average number of cups drunk per day. There was a significant correlation between age of BSP onset and number of cups per day (adjusted regression coefficient 1.73; p = 0.001) whereas no correlation was found with number of packs of cigarettes per day. Coffee drinking may be inversely associated with the development of primary BSP and this association may partly depend on the amount consumed.

Abnormal lateralization of fine motor actions in Tourette syndrome persists into adulthood.

Youth with Tourette syndrome (TS) exhibit, compared to healthy, abnormal ability to lateralize digital sequential tasks. It is unknown whether this trait is related to inter-hemispheric connections, and whether it is preserved or lost in patients with TS persisting through adult life. We studied 13 adult TS patients and 15 age-matched healthy volunteers. All participants undertook: 1) a finger opposition task, performed with the right hand (RH) only or with both hands, using a sensor-engineered glove in synchrony with a metronome at 2 Hz; we calculated a lateralization index [(single RH-bimanual RH)/single RH X 100) for percentage of correct movements (%CORR); 2) MRI-based diffusion tensor imaging and probabilistic tractography of inter-hemispheric corpus callosum (CC) connections between supplementary motor areas (SMA) and primary motor cortices (M1). We confirmed a significant increase in the %CORR in RH in the bimanual vs. single task in TS patients (p<0.001), coupled to an abnormal ability to lateralize finger movements (significantly lower lateralization index for %CORR in TS patients, p = 0.04). The %CORR lateralization index correlated positively with tic severity measured with the Yale Global Tic Severity Scale (R = 0.55;p = 0.04). We detected a significantly higher fractional anisotropy (FA) in both the M1-M1 (p = 0.036) and the SMA-SMA (p = 0.018) callosal fibre tracts in TS patients. In healthy subjects, the %CORR lateralization index correlated positively with fractional anisotropy of SMA-SMA fibre tracts (R = 0.63, p = 0.02); this correlation was not significant in TS patients. TS patients exhibited an abnormal ability to lateralize finger movements in sequential tasks, which increased in accuracy when the task was performed bimanually. This abnormality persists throughout different age periods and appears dissociated from the transcallosal connectivity of motor cortical regions. The altered interhemispheric transfer of motor abilities in TS may be the result of compensatory processes linked to self-regulation of motor control.

Relaxation in distal and proximal arm muscles: a reaction time study.

OBJECTIVE: To investigate whether the same mechanisms underlie muscle relaxation in proximal and distal arm muscles of normal subjects. METHODS: Fourteen healthy subjects were studied using a simple visual reaction time paradigm. Relaxation reaction time (R-RT) and contraction reaction time (C-RT) were compared across different tasks involving distal (first dorsal interosseus, FDI, flexor carpi radialis, FCR) and proximal (biceps brachii, BB, triceps brachii, TR) arm muscles. Changes of FCR H-reflex before and during voluntary relaxation were investigated in two subjects. RESULTS: No significant difference was observed between R-RT and C-RT in the distal muscles. The R-RT was significantly shorter than C-RT in both the BB and TR muscles. The relaxation latency (R-RT) was significantly correlated to the subjects' age in all the muscles except the FDI. No inhibition of the FCR H-reflex could be observed in the 20 ms preceding muscle relaxation. CONCLUSIONS: Our findings suggest that neural mechanisms contribute differently to the relaxation of muscles with a different functional role. Voluntary relaxation in distal arm muscles is mainly related to the reduction of motor cortical output, while in proximal muscles a spinal disfacilitation is also present and possibly sustained by the modulation of presynaptic inhibition.

The tool as the last piece of the athlete's gesture imagery puzzle.

The present study tested whether and how motor experience with a specific tool affects motor representation of a specific movement. To this aim, we considered a group of expert tennis players and a control group of athletic individuals without tennis experience. Participants were asked to execute 20 single forehands into the wall with a tennis racket (movement execution - ME) and, afterward, to produce a kinesthetic image of themselves while executing the same movements (motor imagery - MI). During MI participants handled one of the following tools: a tennis racket, a tennis-like racket and an umbrella. Results showed that the duration of the real and the imagined movements were almost similar when participants of both groups held the tennis rackets. In contrast, when tennis players handled the tools not specific for tennis the duration of the imagined movements increased significantly compared to the MI duration with a tennis racket. On the opposite, the handled tool did not modulate MI performances of the control group. In conclusion, this study showed that motor representation of subjects who developed motor skills associated to tool-use is reliant on the object used to practice movements. This finding suggests that, although MI mainly relies on the activity of cortical motor regions, non-motor information - as the use of the tool to practice movement - strongly affects the MI performance.

Associative cortico-cortical plasticity may affect ipsilateral finger opposition movements.

We have recently demonstrated that cortico-cortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Here we further explored the after effects of cc-PAS on fine hand movements. Ten healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. We studied the after effects of cc-PAS on the performance of repetitive finger opposition movements of different complexity on both hands using a sensor-engineered glove. A quantitative evaluation of the following parameters was performed: Touch Duration (TD), Inter Tapping Interval (ITI) and Number of Errors (NE). We confirmed previous data by showing that left-to-right and right-to-left cc-PAS attenuated IHI. The new finding is that both left-to-right and right-to-left cc-PAS were able to influence the performance of a simple finger opposition movement changing the duration of TD and ITI. Interestingly the effect on the two hands was opposite in direction. These results provide further insight that cc-PAS can induce associative plasticity in connections between the targeted cortical areas influencing motor hand performances. These results may be relevant for future rehabilitative applications.

Recovery of motor performance deterioration induced by a demanding finger motor task does not follow cortical excitability dynamics.

The performance of a demanding exercise can result in motor performance deterioration and depression of primary motor cortex excitability. In the present work we defined a motor task that requires measurable skilled performance to unveil motor performance changes during the execution of a demanding task and to investigate the dynamics of motor performance and cortical excitability changes in absence of overt peripheral fatigue. Twenty-one normal subjects, divided into three groups were asked to perform a sequence of finger opposition movements (SEQ) paced at 2 Hz for 5 min, quantitatively evaluated by means of a sensor-engineered glove able to perform a spatio-temporal analysis of motor performance. Maximal voluntary contraction (MVC) was evaluated before and after the motor task in group 1 while motor evoked potentials (MEP) were evaluated before and after the motor task in group 2 and 3. Group 1 and 2 performed the 5 min-SEQ while group 3 was asked to perform the 5 min-SEQ twice to assess the dynamics of motor performance and cortical excitability. As a result, we found that the execution of 5 min-SEQ induced motor performance deterioration associated with no change in MVC but a decrease in cortical excitability. We further found that the dynamics of cortical excitability and motor performance were different. In fact, a short rest period (i.e., period necessary to collect MEP) between the execution of two 5 min-SEQs was able to recover the motor performance but not the cortical excitability. Finally, no change in spinal excitability was observed. These findings suggest that although primary motor cortex seems to be mainly involved in motor performance deterioration during the execution of a demanding finger motor task, the recovery of motor performance does not follow cortical excitability dynamics.

Intracortical circuits modulate transcallosal inhibition in humans.

Previous results using paired-pulse transcranial magnetic stimulation (TMS) have suggested that the excitability of transcallosal (TC) connections between the hand areas of the two motor cortices is modulated by intracortical inhibitory circuits in the same way as corticospinal tract (CTS) projections to spinal motoneurons. Here we describe two further similarities in TC and CTS control using (1) an I-wave facilitation protocol and (2) preconditioning with rTMS. In experiment 1, excitability of TC pathways was measured using interhemispheric inhibition (IHI) and the ipsilateral silent period (iSP), whilst excitability of CTS pathways was measured by recording the EMG response evoked in the first dorsal interosseous muscle contralateral to the conditioning stimulus (cMEP). The intensity of the conditioning stimulus was first adjusted to threshold for evoking IHI and iSP, then pairs of conditioning stimuli were applied randomly at interstimulus intervals (ISIs) from 1.3 to 4.3 ms. IHI and iSP were facilitated at ISI=1.5 ms and 3.0 ms, respectively, as was the MEP evoked by the conditioning stimuli in the contralateral hand. We suggest that TC projections receive I-wave-like facilitation similar to that seen in CTS projections. In experiment 2, short interval inhibition of the iSP (SICIiSP), and short interval intracortical inhibition of the cMEP (SICIcMEP) were examined before and after 600 pulses of 5 Hz rTMS at 90% resting motor threshold. Both SICIiSP and SICIcMEP were reduced, as was the iSP; the cMEP was unchanged. This shows that the population of inhibitory interneurons that control TC neurons respond in the same way to 5 Hz rTMS as those that control CTS neurons. Taken together, the data from the two experiments suggest that the layer III and layer V pyramidal neurons that give rise to TC and CTS pathways, respectively, are controlled by neuronal circuitry with similar properties.

Creutzfeldt-Jakob disease presenting as corticobasal degeneration: a neurophysiological study.

Creutzfeldt-Jakob disease (CJD) can occasionally present with a clinical picture resembling a corticobasal degeneration (CBD). Transcallosal inhibition, as tested by focal transcranial magnetic stimulation, is frequently absent or highly disrupted in CBD patients. We report a case of CJD presenting at the beginning of the disease as a CBD in which the ipsilateral silent period (iSP) was present and well detectable. This brief report shows that study of the iSP may be a useful diagnostic tool in order to differentiate CBD from syndromes presenting with similar clinical features.