Vincenzo Moschella

Treatment of the Symptoms of Huntington's Disease : Preliminary Results Comparing Aripiprazole and Tetrabenazine

Aripiprazole (AP), a dopamine (DA) D2 receptor partial agonist, has recently been used to reduce schizophrenic symptoms, while tetrabenazine (TBZ), a DA depletor, has been used to treat hyperkinesias in Huntingtons disease (HD). The aim of this study is to define the role of AP on chorea, motor performance, and functional disability, and to compare the effects of AP vs. TBZ in a small study of six patients with HD. Both AP and TBZ increased the Unified Huntingtons Disease Rating Scale (UHDRS) chorea score in a similar way. However, AP caused less sedation and sleepiness than TBZ and was better tolerated by the patients on the trial. Moreover, AP showed a slight but not significant improvement of depression in the patients as compared to TBZ. A larger group of patients and a longer period of observation are an important prerequisite for further evaluations of APs therapeutic use.

Multi-target strategy for Parkinsonian patients : The role of deep brain stimulation in the centromedian-parafascicularis complex

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinsons disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.

Acute vs chronic effects of L-dopa on bladder function in patients with mild Parkinson disease

Objective: To compare acute and chronic effects of l-dopa on bladder function in levodopa-naive Parkinson disease (PD) patients who had urinary urgency. Methods: We evaluated 26 l-dopa–naive PD patients at a university-based PD center with a first urodynamic session with a double examination: in the off treatment condition and 1 hour after acute challenge with carbidopa/l-dopa 50/200 mg; then, a chronic l-dopa monotherapy was administered (mean dose 300 ± 150 mg). Two months later, patients underwent a second urodynamic session with a single evaluation 1 hour after the acute carbidopa/l-dopa challenge. Results: The first acute l-dopa challenge significantly worsened bladder overactivity (neurogenic overactive detrusor contractions threshold [NDOC-t; 32% of worsening] and bladder capacity [BC; 22% of worsening]); on the contrary, l-dopa challenge during chronic administration ameliorated the first sensation of bladder filling (FS; 120% of improvement), NDOCT-t (93% improvement), and BC (33% of improvement) vs the values obtained with acute administration. An 86% significant improvement of FS in comparison with the basal value was observed. Conclusions: The acute and chronic l-dopa effects may be due to the different synaptic concentrations or to the activation of postsynaptic mechanisms obtained by chronic administration.

Pedunculopontine nucleus stimulation influences REM sleep in Parkinson’s disease

OBJECTIVE: To investigate the sleep-wake cycle and the effects of cabergoline monotherapy in a homogenous group of de novo Parkinsons Disease (PD) patients without confounding comorbid factors. DESIGN AND PARTICIPANTS: Twelve de novo patients affected by idiopathic PD underwent two ambulatory polysomnographic (APSG)monitoring sessions. The first was performed at baseline, and the second recording one-month after stable treatment with cabergoline monotherapy. Subjective daytime sleepiness was evaluated by means of the Epworth Sleepiness Scale.Data obtained in PD patients at baseline were compared with those obtained in 12 age- and sex-matched healthy subjects. RESULTS: Diurnal sleep parameters did not show significant differences between controls and PD patients at baseline. In PD patients, no significant changes in diurnal sleep were observed between baseline and cabergoline treatment. Regarding nocturnal sleep, patients at baseline showed a significantly lower sleep efficiency and a significantly higher Wakefulness After Sleep Onset than controls. With respect to baseline, a significant increase in REM latency and a significant reduction in REM sleep were observed during cabergoline treatment. CONCLUSIONS: In the early stage of PD, the neurodegenerative process does not seem to be directly responsible for daytime somnolence, but it may be directly involved in the alteration of nocturnal sleep. Cabergoline monotherapy does not affect daytime sleep propensity and, despite clinical improvement, it may have negative effects on REM sleep.

Central acute D2 stimulation worsens bladder function in patients with mild Parkinson's disease.

PURPOSE The different roles of D1 and D2 dopamine receptors in LUT behavior have been demonstrated in animal studies. In particular D2 selective agonists and D1 selective antagonists seem to produce a reduction of the bladder capacity in conscious rats. This finding has never been confirmed in human studies. Thus, in this study we investigated the role of D1 and D2 agonists/antagonists on LUT behavior in patients with PD. MATERIALS AND METHODS A total of 87 patients with mild PD were evaluated. Patients were evaluated with urodynamic studies (cystometry followed by a pressure flow study with perineal floor electromyography) performed in off status and after oral administration of 250 mg of LD. In 70 patients a third urodynamic evaluation was conducted in one of the following conditions: after simultaneous administration of 250 mg oral LD and 60 or 120 mg oral domperidone (D2 peripheral antagonist); after simultaneous administration of 250 mg oral LD and 25, 50 or 150 mg intramuscular L-sulpiride (D2 central and peripheral antagonist). Several urodynamic parameters were evaluated and results obtained in different conditions compared. RESULTS LD alone worsened detrusor overactivity: in particular, a reduction of first urinary sensation, involuntary detrusor contraction threshold (reflex volume) and bladder capacity was observed. L-sulpiride (central and peripheral D2 antagonist) coadministration counteracted the worsening in a dose dependent manner. Domperidone (peripheral D2 antagonist) coadministration failed to determine the same counteraction. CONCLUSIONS According to our results, a central acute D2 stimulation seems to be responsible of a reduction of bladder capacity with worsening of detrusor overactivity in patients with mild PD.

Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson's disease patients

A correct balance between endocannabinoid and dopamine‐dependent systems is believed to underlie physiological motor control. We measured the levels of the endocannabinoid anandamide in the cerebrospinal fluid of Parkinsons disease (PD) patients. Subjects were divided into three groups: newly diagnosed de novo patients, subjects undergoing drug withdrawal, and patients under pharmacological therapy. These groups were compared to age‐matched control subjects. Anandamide levels in untreated patients were more than doubled as compared to controls. However, chronic dopaminergic replacement restored control anandamide levels. Abnormal anandamide increase might reflect a compensatory mechanism occurring in course of PD, aimed at normalizing dopamine depletion.

Correlation between changes in CSF dopamine turnover and development of dyskinesia in Parkinson's disease

To assess possible differences in dopamine metabolism that could parallel disease progression in Parkinsons disease (PD), we measured dopamine (DA) and its metabolites in the cerebrospinal fluid (CSF) in PD patients at different stages of disease: de novo (DEN), advanced not showing dyskinesias (ADV), and advanced with dyskinesias (DYS). DA, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly higher in DEN patients compared with other groups. A negative exponential correlation related DA level and disease duration. The HVA/DA ratio was significantly higher in the ADV and DYS group than that found in DEN group. Our data show that disease progression produces an early large decay of DA levels, followed by a stabilization. On the contrary, a late change in DA turnover (increased HVA/DA ratio) is documented in patients with longer disease duration. Our results suggest that the appearance of dyskinesia may not be related to a further loss of DA terminals but to a different, abnormal, DA turnover.

Grammar improvement following deep brain stimulation of the subthalamic and the pedunculopontine nuclei in advanced Parkinson's disease: A pilot study

Combined deep brain stimulation of the subthalamic (STN) and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced Parkinsons disease. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. We studied five advanced Parkinsons disease patients who underwent combined deep brain stimulation (STN + PPN). Overall cognitive profile did not change. On the contrary, an interesting trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) was found when stimulating the STN, and also the PPN, when the STN was switched off. These findings replicate previous observations on the STN, and provide the rationale for further investigation of the role of the PPN in processing linguistic grammar.

Silver syndrome variant of hereditary spastic paraplegia A locus to 4p and allelism with SPG4

Objective: To perform a clinical and genetic study of two large Italian families (RM-36 and RM-51) showing the cardinal clinical features of Silver syndrome (SS), a rare dominantly inherited form of hereditary spastic paraplegia (HSP) complicated by amyotrophy of the small hand muscles. Methods: Clinical assessment including neurophysiologic, neuropsychological, and neuroimaging evaluations. Genetic studies included linkage and sequence analyses. Results: Using a genome-wide survey in the RM-36 family, a novel locus (SPG38) has been identified and mapped within the 13.1-cM region on chromosome 4p16-p15 between markers D4S432 and D4S1599. The RM-51 family was linked to the SPG4 locus at 2p21-p24 and sequence analysis of SPG4 showed a novel frameshift mutation p.Asp321GlyfsX6. Clinical examination of the affected members carrying the mutation showed high frequency of additional clinical features including decreased vibration sense, pes cavus, temporal lobe epilepsy, and cognitive impairment. Conclusions: This study demonstrates evidence of a novel locus SPG38 for Silver syndrome (SS) and suggests that genetic defects in SPG4 might lead to broad clinical features overlapped with those of SS.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

Background and purpose:  To evaluate the effects of 25‐Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity.