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The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

The N30 component of the somatosensory evoked responses (SEP) was reported as absent or abnormally low in various basal ganglia disorders, including Parkinson's disease (PD), but its relationship to the more affected side in asymmetric disease has not been assessed systematically. In 14 patients with unilateral PD and 10 controls, SEP were performed by stimulating each upper limb and recording from the parietal and frontal contralateral cortex. N30 was symmetric in 4 patients and 4 controls; it was asymmetric in 2 controls and in 8 patients (in 4 the responses were of lower amplitude over the affected hemisphere); no response was elicited in 2 patients and 4 controls. In all patients SEP were recorded off medication; in 9 of them the test was repeated following administration of L-dopa and did not show any significant changes. In conclusion, the N30 was asymmetric in a similar proportion of PD patients and controls. No correlation was found between the affected side and N30 latencies or amplitudes; no change was seen following L-dopa administration as well. The motor deficits and SEP abnormalities in PD probably reflect pathologies in different anatomical structures or functional circuits.

James Parkinson in 1817 in his famous Essay on the Shaking Palsy described the “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured” (Parkinson, 1817). Indeed the possibility that PD is associated with dementia has been negated by neurologists for several decades. It should be mentioned that antedating levodopa therapy patients could not be formally cognitively tested because of their motor disability, bradyphrenia and speech impairment. There was also a tendency to attribute dementia in old age (and the great majority of PD patients are aged) to concurrent “senility” or “cerebral aterosclerosis” Once levodopa and dopa-agonist therapy was instituted this situation, surprisingly, did not change and the impression emerged that dementia is common in PD, more so in patients with advanced PD (Korczyn et al., 1986). Since then, overwhelming proof has accumulated that PD is accompanied by dementia in at least 20% of the cases. The debate over the issue of coincidental AD in demented PD patients is still not entirely resolved since some of the clinical and pathological features of the two dementias are similar.

Motor fluctuations constitute a severe complication of chronic levodopa therapy. The addition of dopamine agonists may partially alleviate these responses; however, due to the short half-life of these drugs, several daily doses are required. Cabergoline is a new dopamine agonist with a long half-life and can be given in a single daily dose. Seventeen patients with severe fluctuations were treated with cabergoline, seven of them for > 1 year (up to 39 months). The motor status ameliorated and the percentage of "off" hours significantly decreased in the first year and did not increase significantly later during long-term follow-up. Cabergoline is a promising treatment for parkinsonian patients with motor fluctuations.

Using the technique of transcranial magnetic stimulation over the motor areas of cortex and recording electromyographic (EMG) responses from the first dorsal interosseous muscle, we measured the excitability of corticocortical inhibitory circuits at rest using a double pulse paradigm, in 11 patients with Parkinson's disease (PD) studied both on (ON) and off (OFF) (after overnight withdrawal) their normal medication and in 10 age-matched control subjects. There was a significant decrease in the amount of corticocortical inhibition at short (1-5 msec) interstimulus intervals in patients relative to their controls, which improved after L-dopa intake. For comparison with previous reports using transcranial magnetic stimulation we also measured the duration of the EMG silent period when stimuli were given to voluntarily active muscle, and the threshold for evoking an EMG response in both the active and relaxed states, There was no change in the threshold for evoking EMG responses whether muscles were active or relaxed. However, the silent period was significantly prolonged when ON compared with OFF, although in neither state was the duration significantly different from that seen in normals. We suggest that there may be abnormalities of motor cortical inhibitory mechanisms in patients with Parkinson's disease that are not readily detected using threshold or silent period measurements alone.

The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic amyloid β (Aβ) peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1—a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8309 AD cases and 7366 cognitively normal elders using individual single nucleotide polymorphism (SNP)- and gene-based tests. We obtained significant evidence of association with KIAA1033 (VEGAS p = 0.025), SNX1 (VEGAS p = 0.035), SNX3 (p = 0.0057), and RAB7A (VEGAS p = 0.018). Ten KIAA1033 SNPs were also significantly associated with AD in a group of African Americans (513 AD cases, 504 control subjects). Findings with four significant SNX3 SNPs in the discovery sample were replicated in a community-based sample of Israeli-Arabs (124 AD cases, 142 control subjects). We show that Snx3 and Rab7A proteins interact with the cargo-selective retromer complex through independent mechanisms to regulate the membrane association of retromer and thereby are key mediators of retromer function. These data implicate additional AD risk genes in the retromer pathway and formally demonstrate a direct link between the activity of the retromer complex and the pathogenesis of AD.

Cabergoline, a new ergoline derivative with potent and long-lasting dopaminergic activity, is a promising drug for overcoming the akinetic episodes in L-Dopa-treated Parkinson's disease patients with motor fluctuations. Its long plasma half-life (65 h) allows a single daily dose administration. Seventeen patients with Parkinson's disease (mean age 66 years; mean disease duration 8.8 years; median Hoehn and Yahr stage, III) were included in an open-label study. All had persistent motor fluctuations while treated with L-Dopa plus carbidopa (mean dose, 660 mg + 66 mg). Cabergoline was added until a maximal dose was achieved (5 mg daily), while L-Dopa was slightly diminished. Eight patients completed 1 year of treatment. They showed significant improvement in their motor performance (Unified Parkinson's Disease Rating Scale) (bradykinesia score decreased from 8.2 to 4.2, p < 0.005), and in the proportion of "off" time spent during waking hours (32-23%, p < 0.05). Three patients abandoned the trial because of increasing severity of dyskinesias, hallucinations, and depression (one each), six were withdrawn because of poor compliance and refusal to continue the treatment. This study suggests that cabergoline may play an important role in the treatment of Parkinson's disease with motor fluctuations.

The natural history of 51 idiopathic torsion dystonia cases identified in a nationwide survey in Israel was studied. In order to take advantage of all data regarding the evolution of the disease, independently of the length of follow-up, we have used a life table method of analysis. An estimate of the mean degree of generalization of the disease at different times from onset was calculated and a curve of the estimated temporal evolution was drawn. This analysis confirmed the heterogeneity of the disease course. The most rapid deterioration occurred in patients with juvenile onset in the lower limbs, particularly in the first 2 years following the onset. The rate of evolution was not influenced by gender or familiarity. The course of the disease seemed more deleterious in non-Ashkenazic Jews. The present statistical method of estimating the evolution in different patient groups should be useful especially for the evaluation of therapeutic interventions.

Idiopathic torsion dystonia (ITD) is a dominantly inherited disorder with incomplete penetrance. It is important to identify factors that may cause dystonia or prevent its occurrence in a genetically predisposed individual. Because dystonia may be precipitated by peripheral triggers, we have investigated whether the preferential use of a limb affects the development of dystonia. Analysis of the correlation between the side of motor dominance and the limbs in which dystonic symptoms first appeared was performed in 49 patients with ITD ascertained in a country-wide survey in Israel. The dominant motor side was determined in 45 cases (92%). Among 29 patients with lateralized limb onset, 24 showed right-side motor dominance, of whom 21 had dystonia onset in a right limb. The first sign was in a left limb for all five cases with left-side motor dominance (90% coincidence). The pattern of limb involvement was studied. Detection bias could be ruled out. The highly significant relationship between the motor dominance and the laterality of limb onset in ITD patients suggests that the preferred use of a limb may trigger the onset of dystonia.

The clinical picture of Creutzfeldt-Jakob disease (CJD) includes various movement disorders such as myoclonus, parkinsonism, hemiballism, and dystonia. We report on a patient with CJD who manifested the alien hand sign. We suggest that CJD should be included in the differential diagnosis of diseases which present with an alien hand. Creutztfeldt-Jakob disease, one of the human prion diseases, is characterised by rapidly progressive mental and motor deterioration.1 Involuntary movements occur in above 90% of the patients in the course of the disease, the most common being myoclonus.1 Other movement disorders range from tremor to chorea, athetosis, dystonia, and hemiballism.1 We report on a patient with CJD who presented with an alien hand. Alien hand is a rare and striking phenomenon defined as “a patient's failure to recognise the action of one of his hands as his own”.2 One of the patient's hands acts as a stranger to the body and is uncooperative. Thus, there is loss of feeling of ownership but not loss of sensation in the affected hand. Originally described in callosal tumours,3 the aetiology of alien hand also includes surgical callosotomy,4 infarction of the medial frontal cortex, occipitotemporal lobe, and thalamus,1 5 infection,6 and corticobasal degeneration.5 7 A 70 year old, right handed Jewish man born in Argentina, living in Israel for the past 20 years, was …

We read with interest the article by Khan et al.1 The authors studied asymptomatic parkin heterozygotes by 18F-dopa PET and found a significant reduction of uptake in putamen, caudate, dorsal and ventral midbrain. An interesting observation relates to the subtle extrapyramidal symptoms in four of these “asymptomatic” carriers. The authors recommended follow-up to verify whether they develop parkin disease. One of our patients with a single parkin mutation developed parkin disease 23 years after the manifestation of tremor …

Article abstract We report a Jewish family of Yemenite origin in which three brothers born from a consanguineous marriage had juvenile parkinsonism. The DNA samples from three affected brothers and one healthy brother were analyzed for the linkage to markers covering the autosomal-recessive juvenile parkinsonism (AR-JP) locus. A perfect homozygous cosegregation to the markers was found, giving a maximal lod score of 3.11 at D6S1579, D6S305, and D6S411, all of which are 0 cm apart from each other (nonparametric linkage score, 8.041; p = 0.000977). Exon 3 of the Parkin gene was homozygously deleted in all patients. The AR-JP gene also exists in the Jewish population.

The development of subdural hematoma in the course of hemodialysis treatment has been well documented in the literature. We report a case of a subdural hematoma in a patient on hemodialysis, in whom surgery was contraindicated, due to her concurrent use of anticoagulants. Good recovery was achieved by steroid treatment. Although surgical removal constitutes the essential therapeutic approach for subdural hematoma, we emphasize the importance of medical management in special cases where surgery is contraindicated.

In order to evaluate the relationship between brain atrophy and the motor and cognitive function in Parkinson's disease, we have evaluated CT changes in 132 consecutive patients and compared them to measures of physical and mental decline, using intercorrelations and variance analysis. The result demonstrated age as a most important factor relating to brain atrophy. After correction for this determinant, it became clear that the motor and cognitive parameters were interdependent but they affected similar CT parameters. The effect of motor decline was the stronger of the two and it was the only one which correlated with cortical atrophy. The results support the notion of subcortical changes underlying the dementia of Parkinson's disease.

— Lupus anticoagulant was found in the plasma of 4 patients who presented with late-onset epileptic seizures. Three of the patients had clinical or electroencephalographic evidence of focality. No significant cerebral pathological findings were detected by the computed tomogram except for an old infarction in one case. None of the patients fulfilled the diagnostic criteria for systemic lupus crythematosus. The relationship between late-onset seizures and the presence of lupus anticoagulant is discussed. The possible etiology of an ischemic episode due to hypercoagulability, expressed uniquely by seizures, is suggested.

The electroencephalograms (EEG) of patients with Parkinson's disease (PD) were evaluated in relation to age, mental status and motor disability. Abnormalities, particularly mild slowing, were observed in 34% of 128 patients and more frequently in the elderly. While a slowing in occipital background activity was more frequent in demented patients, a statistically significant association was also observed between the degree of motor disability and the frequency of slowing in occipital background activity in mentally intact patients. This correlation may suggest that subcortical structures (involved in motor control) influence occipital background activity.

Background The study of gait at self-selected speed is important. Traditional gait laboratories being relatively limited in space provide insufficient path length, while treadmill (TM) walking compromises natural gait by imposing speed variables. Self-paced (SP) walking can be realized on TM using feedback-controlled belt speed. We compared over ground walking vs. SP TM in two self-selected gait speed experiments: without visual flow, and while subjects were immersed in a virtual reality (VR) environment inducing natural visual flow. Methods Young healthy subjects walked 96 meters at self-selected comfortable speed, first over ground and then on the SP TM without (n=15), and with VR visual flow (n=11). Gait speed was compared across conditions for four 10 m long segments (7.5 – 17.5, 30.5 – 40.5, 55.5 – 65.5 and 78.5-88.5 m). Results During over ground walking mean (± SD) gait speed was equal for both experimental groups (1.50 ± 0.13 m/s). Without visual flow, gait speed over SP TM was smaller in the first and second epochs as compared to over ground (first: 1.15 ±0.18 vs. second: 1.53 ± 0.13 m/s; p0.3). With visual flow, gait speed became comparable to that of over ground performance already in the first epoch (1.43 ± 0.22 m/s; p>0.17). Curve fitting analyses estimated that steady state velocity in SP TM walking is reached after shorter distanced passed with visual flow (24.6 ± 14.7 m) versus without (36.5 ± 18.7 m, not statistically significant; p=0.097). Steady state velocity was estimated to be higher in the presence of visual flow (1.61 ± 0.17 m/s) versus its absence (1.42 ± 1.19 m/s; p

Whereas visual hallucinations are often found among patients with Parkinson's disease, the occurrence of auditory hallucinations has never been systematically documented. The occurrence, past and present, of auditory hallucinations has been studied in 121consecutive patients with Parkinson's disease attending a movement disorders clinic. The cognitive state was evaluated using the short mental test (SMT). Hallucinations were reported for 45patients (37%); 35 (29%) had only visual hallucinations and 10(8%) both visual and auditory hallucinations. No patient reported auditory hallucinations unaccompanied by visual hallucinations. The auditory hallucinations occurred repeatedly, consisting of human voices. They were non-imperative (n=9), non-paranoid (n=9), and often incomprehensible (n=5). They were not obviously influenced by the patients' age, duration of disease, or treatment with levodopa. Cognitive impairment was more common among hallucinating patients (64%, 50%, and 25% among patients with visual hallucinations, auditory hallucinations, and non-hallucinating parkinsonian patients respectively). Depression necessitating antidepressants was present in five of 10 and other psychotic features in six patients with auditory hallucinations. It is concluded that auditory hallucinations occur in Parkinson's disease, particularly in patients who also have visual hallucinations and are cognitively impaired.