Pietro Balbi

Effectiveness of Intensive Inpatient Rehabilitation Treatment on Disease Progression in Parkinsonian Patients: A Randomized Controlled Trial With 1-Year Follow-up

Background. Rehabilitation treatments have acute beneficial effects in Parkinson’s disease (PD) patients, but whether the effects persist over time is unclear. Objective. To assess whether an intensive rehabilitation treatment (IRT) is effective in improving motor performance compared with a control group in a 12-month follow-up, to investigate whether a second cycle administered after 1 year has the same efficacy as the first treatment, and to determine whether IRT reduces the need for increasing levodopa dosage. Methods. A total of 50 PD patients were randomly assigned to 2 groups; 25 participants had 4 weeks of inpatient physical therapy that included treadmill and stabilometric platform training. At discharge, these patients were invited to continue doing the learned exercises. After 12 months, the same treatment was repeated. The control group of 25 patients received only pharmacological treatment and was invited to practice generic physical exercise at home. The rating scales used for the clinical evaluation were the Unified Parkinson’s Disease Rating Scale Sections II and III (UPDRS II and III) and total (UPDRS tot). Results. The authors found that the beneficial effects of IRT persisted over time. A second rehabilitation cycle administered after 1 year was as effective as the first treatment. At the end of the study, daily medication dosage was reduced in treated patients, whereas it was significantly increased in control patients. Conclusion. These findings suggest that the natural worsening of symptoms associated with PD can be effectively counteracted by a properly designed IRT.

The Beneficial Role of Intensive Exercise on Parkinson Disease Progression

ABSTRACTIn the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease.

Postexercise facilitation of motor evoked potentials following transcranial magnetic stimulation: A study in normal subjects

The size of the motor evoked potential (MEP) elicited by transcranial magnetic stimulation increases soon after a nonexhaustive voluntary contraction of the target muscle (postexercise facilitation). Our aim was to determine whether the duration or intensity of voluntary muscle contraction influenced postexercise facilitation in normal subjects. We recorded the MEP from the thenar muscles following contractions of different durations (5, 15, and 30 s) and intensities (10%, 25%, and 50% of maximal voluntary contraction). We found that every combination of the tested intensities and durations of physical effort could induce postexercise MEP facilitation. Although the degree of postexercise MEP facilitation was comparable across the different durations and intensities, the maximal facilitation was observed with the shortest and strongest muscle contraction. Our study thus defines the optimal setting to study postexercise facilitation for clinical purposes.

The clinical spectrum of late-onset Alexander disease: a systematic literature review

Following the discovery of glial fibrillary acidic protein (GFAP) mutations as the causative factor of Alexander disease (AxD), new case reports have recently increased, prompting a more detailed comprehension of the clinical features of the three disease subtypes (infantile, juvenile and adult). While the clinical pattern of the infantile form has been substantially confirmed, the late-onset subtypes (i.e., juvenile and adult), once considered rare manifestations of AxD, have displayed a wider clinical spectrum. Our aim was to evaluate the clinical phenotype of the adult and juvenile forms by reviewing the previously reported cases. Data were collected from previously published reports on 112 subjects affected by neuropathologically or genetically proven adult and juvenile Alexander disease. Although the late-onset forms of AxD show a wide clinical variability, a common pattern emerges from comparing previously reported cases, characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Late-onset AxD cases can no longer be considered as rare manifestations of the disease. The clinical pattern usually reflects the topographic localization of the lesions, with adult cases displaying a predominant infratentorial localization of the lesions. Juvenile cases show clinical and radiological features which are intermediate between adult and infantile forms.

In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation

Alexander disease is a rare, untreatable and usually fatal neurodegenerative disorder caused by heterozygous mutations of the glial fibrillary acidic protein (GFAP) gene which ultimately lead to formation of aggregates, containing also alphaB-Crystallin, HSP27, ubiquitin and proteasome components. Recent findings indicate that up-regulation of alphaB-Crystallin in mice carrying GFAP mutations may temper the pathogenesis of the disease. Neuroprotective effects of ceftriaxone have been reported in various animal models and, noteworthy, we have recently shown that the chronic use of ceftriaxone in a patient affected by an adult form of Alexander disease could halt its progression and ameliorate some of the symptoms. Here we show that ceftriaxone is able to reduce the intracytoplasmic aggregates of mutant GFAP in a cellular model of Alexander disease. Underlying mechanisms include mutant GFAP elimination, concurrent with up-regulation of HSP27 and alphaB-Crystallin, polyubiquitination and autophagy. Ceftriaxone has also been shown to modulate the proteasome system, thus decreasing NF-kappaB activation and GFAP promoter transcriptional regulation, which further accounts for the down-modulation of GFAP protein levels. These mechanisms provide previously unknown neuroprotective targets of ceftriaxone and confirm its potential therapeutic role in patients with Alexander disease and other neurodegenerative disorders with astrocyte involvement.

Patterns of motor control reorganization in a patient with mirror movements

OBJECTIVE To explore motor control reorganization in a 40-year-old, left-handed patient with perinatally acquired mirror movements. METHODS We performed simultaneous bilateral recordings of motor evoked potentials (MEPs) following focal transcranial magnetic stimulation (fTMS) and of central silent period (cSP) during unilateral voluntary contraction in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. RESULTS For both muscles the MEP study showed bilateral fast-conducting corticospinal projections from the right undamaged hemisphere, and residual contralateral projections from the left hemisphere. The cSP findings differed in the two muscles: the mirror phenomenon was bilateral in the ADM, but present only on the right side in the APB muscles; the mirror activity of right ADM and APB muscles was inhibited only by fTMS of the ipsilateral right motor cortex; the mirror phenomenon in the left ADM muscle was inhibited only by fTMS of the contralateral right motor cortex. CONCLUSIONS Mirror movements of right APB and ADM muscles were sustained by the ipsilateral connections from the undamaged motor cortex, while the mirror phenomenon in the left ADM muscle could be explained by hypothesizing a bilateral activation of motor cortices. This previously unreported electrophysiological picture demonstrates that different patterns of motor control may realize after perinatal cerebral lesions, even in different distal muscles of the same patient.

Adult-onset Alexander disease : report on a family.

AbstractPathogenic, dominant, de novo missense mutations in the glial fibrillary acidic protein (GFAP) have been found in the three subtypes of infantile, juvenile and adult Alexander disease.Here we describe four members of an Italian family (32 to 66-yearsold, 2 women and 2 men) affected by adult Alexander disease, the least common and the most clinically variable form.Direct sequencing of all coding regions of the GFAP gene, neurological examination and brain MRI were performed.Two novel missense mutations were found involving two very close codons, c.[988C > G, 994G > A], leading to p.[Arg330Gly, Glu332Lys]. Clinically, two members exhibited pseudo-bulbar signs, gait ataxia and spasticity, one showed a severe cranial sensory symptomatology, and one subject was asymptomatic.Medulla and cervical cord atrophy was present in all of them on MRI.Although adult Alexander disease shows a wide clinical variability, a more frequent pattern can be identified characterized by bulbar or pseudo-bulbar signs, gait ataxia, and spasticity, and including on MRI medulla and cervical cord atrophy. Our findings also confirm that the clinical spectrum of adult Alexander disease includes cases without overt neurological involvement and with minimal brain MRI alterations.

Rehabilitation improves dyskinesias in Parkinsonian patients: a pilot study comparing two different rehabilitative treatments.

GOAL AND OBJECTIVES The present study was devised: (a) to test whether an intensive (60 hours in 4 weeks) multidisciplinary rehabilitation treatment (involving physiotherapy, exercises to improve gait and balance using treadmill and stabilometric platform, occupational therapy) for Parkinsonian patients is effective in improving dyskinesia and motor performance compared to a control group undergoing a non-intensive non multidisciplinary rehabilitation treatment (30 hours in 4 weeks involving physiotherapy only); and (b) to verify whether rehabilitation may lead to a reduction in levodopa dosage. MATERIAL AND METHODS Forty Parkinsonian patients suffering from dyskinesias were admitted to study: 20 for an intensive multidisciplinary (Group1) and 20 for a non-intensive non multidisciplinary rehabilitation treatment (Group2). The rating scales used for the clinical evaluation were: Unified Parkinsons Disease Rating Scales (UPDRS) II, III, IV, Parkinsons disease disability scale (PDDS), Abnormal Involuntary Movement Scale (AIMS). RESULTS All outcome measurements improved in both groups of patients, but patients Group1 presented better results: UPDRS II was reduced by 33% in Group1 and by 22% in Group2, UPDRS III 29% vs. 22%, UPDRS IV 74% vs. 10%, PDDS 18% vs. 12%, and AIMS 71% vs. 8%. A different behaviour was observed for levodopa dosage at baseline and after treatment: dosage decreased by an average value of 210 mg (p< 0.0001) in Group1 and was virtually unchanged (30 mg reduction, p=0.08) in Group2. CONCLUSION Our findings suggest that a rehabilitation protocol should be considered as a valid non-invasive therapeutic support for patients who show dyskinesias and that there are better results when the treatment is intensive.

Ceftriaxone has a therapeutic role in Alexander disease

Alexander disease (AD) (MIM 203450) is a rare, usually fatal neurodegenerative disorder, involving primarily astroglial cells in the CNS, caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP) (Brenner et al., 2001). It is characterized by dystrophic astrocytes containing intermediate filament aggregates (Rosenthal fibers) (RFs), in combination with myelin abnormalities (Li et al., 2005). Pathogenetic determinants include a toxic gain-of-function of mutated GFAP which causes aggregates and RFs accumulation in astrocytes and an excitotoxicity related to impairment of the buffering capacity of dystrophic astrocytes and of their ability to metabolize extracellular glutamate ([Mignot et al., 2004] and [Sullivan et al., 2007]). AD remains an untreatable genetic disease that severely limits life expectancy in affected individuals. Here we studied the tolerability and therapeutic effects of the chronic use of cycles of ceftriaxone, a beta-lactam antibiotic with neuroprotective effects (Rothstein et al., 2005), in a patient affected by adult AD with a rapidly progressive clinical course. Because AD is rare and its presentation varies it is difficult to evaluate treatments in controlled trials, thus prolonged, longitudinal single-patient studies may be a useful approach to identify the new utilization of drugs in this pathology. The successful clinical outcome related to ceftriaxone reported here in a patient with adult AD highlights the possibility that this β-lactam antibiotic may be useful for other AD patients and, possibly, for other neurodegenerative disorders with astrocyte involvement.

Mild functional effects of a novel GFAP mutant allele identified in a familial case of adult-onset Alexander disease

Alexander disease is a neurological genetic disorder characterized by progressive white-matter degeneration, with astrocytes containing cytoplasmic aggregates, called Rosenthal fibers, including the intermediate filament glial fibrillary acidic protein (GFAP). The age of onset of the disease defines three different forms, infantile, juvenile and adult, all due to heterozygous GFAP mutations and characterized by a progressive less severe phenotype from infantile to adult forms. In an Italian family with a recurrent mild adult onset of Alexander disease, we have identified two GFAP mutations, coupled on a same allele, leading to p.[R330G; E332K]. Functional studies on this complex allele revealed less severe aggregation patterns compared to those observed with p.R239C GFAP mutant, associated with a severe Alexander disease phenotype. Moreover, in addition to confirming the involvement of the ubiquitin–proteasome system in cleaning cells from aggregates and a dominant effect of the novel mutant protein, in cells expressing the mild p.[R330G; E332K] mutant we have observed that indirect αB-crystallin overexpression, induced by high extracellular potassium concentration, could completely rescue the correct filament organization while, under the same experimental conditions, in cells expressing the severe p.R239C mutant only a partial rescue effect could be achieved.