Maria Stella Aniello

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects

There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.

Severity of neuropsychiatric symptoms and dopamine transporter levels in dementia with Lewy bodies: A 123I-FP-CIT SPECT study†

Neuropsychiatric symptoms are frequent in dementia with Lewy bodies (DLB). Dopamine transporter (DAT) imaging with 123I‐labeled ligand N‐δ‐(fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)tropene (123I‐FP‐CIT), which reliably measures midbrain dopaminergic dysfunction, has provided important evidence on the neurobiological substrate of some of these symptoms including apathy and depression. However, little is known on DAT levels and other distressing symptoms such as delusions and hallucinations. Therefore, 123I‐FP‐CIT imaging was performed in 18 well‐characterized patients with DLB, and striatal DAT levels were correlated with the frequency/severity ratings of several neuropsychiatric symptoms. A wide range of neuropsychiatric symptoms could be observed in the sample. Significant correlations were observed between decreased striatal DAT levels and visual hallucinations. Although there were no correlations between striatal DAT levels and other neuropsychiatric symptoms, when considering the putamen and the caudate nucleus separately, delusions, depression, and apathy were inversely correlated to decreased caudate DAT levels. Theseresults provide intriguing evidence on the involvement of the mesocortical dopaminergic pathways in neuropsychiatric symptoms in DLB.

A family study on primary blepharospasm

Background: Previous family studies provided evidence that blepharospasm (BSP) can aggregate in families but did not give accurate and reliable information on the characteristics and degree of familial clustering. Aim: To evaluate the proportion of familial and non-familial BSP cases, the clinical expression of dystonia within families, the inheritance pattern, and the extent of penetrance. Methods: The study was based on the examination of the first degree relatives of 56 probands with primary BSP. Results: The 56 families produced a potential population of 436 first degree relatives of whom 296 were alive and 233 were examined. The proportion of index patients with at least one first degree relative affected by BSP, or adult onset dystonia other than BSP, was 27%. There was a remarkable degree of phenotypic variability of dystonia within families. Similar segregation ratios were calculated for probands’ siblings and children. Under the assumption of autosomal dominant transmission of adult onset dystonia, penetrance was about 20%. Conclusions: The findings of this family study are relevant for accurately counselling the families of patients with BSP and may help identify the most appropriate study design to explore genetic susceptibility in BSP.

Midbrain SERT in degenerative parkinsonisms: a 123I-FP-CIT SPECT study.

SPECT imaging is widely used for the differential diagnosis of degenerative parkinsonisms by exploiting the high affinitiy of the radiotracer 123I‐FP‐CIT for the dopamine transporter. Reduced levels of DAT are found in Parkinson Disease (PD), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) compared to in Essential Tremor (ET) and Healthy Controls (HC). However, the extent of the neurodegenerative process may extend beyond nigrostriatal system. We have exploited the affinity of the same radiotracer 123I‐FP‐CIT for the serotonin transporter to investigate SERT levels in the midbrain of patients with PD, DLB, PSP, and ET compared to HC. Using MRI images as anatomical templates for midbrain uptake quantification, we found a mild decrease in SERT levels in PD compared to ET and HC, with marked inter‐individual variability; on the other side, PSP and DLB patients displayed markedly reduced to undetectable levels of SERT, respectively. These findings show that the neurodegenerative process affects serotoninergic neurons in parkinsonisms, with much more severe involvement in DLB than in PD patients, despite the comparable loss of striatal DAT. SERT‐dependent 123I‐FP‐CIT uptake may allow a more comprehensive assessment of neurochemical disturbances in degenerative parkinsonisms and may have a value for differential diagnosis.

Treatment of essential tremor: A systematic review of evidence and recommendations from the Italian Movement Disorders Association

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as “low” or “very low” for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.

The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia

The geste antagoniste (GA), a relatively common feature of adult‐onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult‐onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test‐retest reliability (κ = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP‐related and five CD‐related types of GA were recorded, and a “forcible” type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult‐onset dystonia.

Frequency of apraxia of eyelid opening in the general population and in patients with extrapyramidal disorders.

Abstract. We ascertained the prevalence of apraxia of eyelid opening (AEO) in a community located in Puglia, a region of southern Italy. The crude prevalence rate was 59 per million (95% confidence interval, 24–173). AEO coexisted with adult onset blepharospasm in 75% of cases, with atypical parkinsonism in 25% of cases. Among the overall patient population seen at our movement disorders clinic from 1987 to 1997, AEO was isolated in 10 otherwise healthy individuals, associated with adult-onset dystonia in 13 cases, and associated with a parkinsonian syndrome in 9 cases. The frequency of AEO was 10.8% in the dystonia group, and 2.1% in the overall parkinsonian group (Parkinsons disease, 0.7%; progressive supranuclear palsy, 33.3%). In two patients with possible progressive supranuclear palsy, AEO worsened after increasing levodopa dosage or acute apomorphine challenge and disappeared following levodopa discontinuation. AEO developing in the setting of a parkinsonian syndrome may be either disease- or drug-related.

Environmental risk factors and clinical phenotype in familial and sporadic primary blepharospasm

Background: Although environmental and genetic factors may contribute to the etiology of blepharospasm, their relative contribution in causing familial and sporadic blepharospasm is unknown. Methods: First-degree relatives of 122 patients with primary blepharospasm were examined with a validated 2-step diagnostic procedure, including a screening questionnaire and examination of some relatives. Examiners were blinded to the questionnaire data for family history of probands. Data for demographic and clinical features, prior ophthalmologic complaints, and nondecaffeinated coffee intake were collected from probands before family investigation. Results: Dystonia was diagnosed in 27 relatives from 23 families (20% rate of family history for dystonia). No significant differences were found between familial and sporadic cases in the frequency of coffee drinking and eye diseases or in sex, age at onset, or tendency to spread. Multivariable conditional logistic analysis testing of 67 case patients and 127 family-matched unaffected siblings yielded a significant positive association between blepharospasm and prior eye diseases (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.1–6.1; p = 0.03) and a significant inverse association between case status and ever coffee drinking (adjusted OR 0.23; 95% CI 0.1–0.8; p = 0.02). Conclusions: The new information from this large family-based study on primary blepharospasm strongly supports eye diseases and coffee as risk factors for blepharospasm. The finding that the 2 environmental exposures exerted a similar influence on familial and sporadic blepharospasm, together with the convergent phenotypic expression in familial and sporadic cases, implies that familial and sporadic blepharospasm probably share a common etiologic background.

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).

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.