Biomedical subjects
Publications and source records attributed to E Broussolle.
A 71-year-old woman was treated by botulinum toxin (BTX) type A injections for cervical dystonia related to a multiple system atrophy (MSA). A few days later and persisting for the next 4 months, she developed a severe dysphagia, requiring nasogastric feeding. This implicates cautious use of BTX in a case of MSA.
The objective of this study was to investigate whether eye-hand coupling was preserved or not in PD. We studied predictive saccade performance during hand pointing in six Parkinson's disease (PD) patients with asymmetrical motor signs compared to nine age-matched healthy subjects. The motor responses (saccades and hand pointing) were elicited under open loop conditions (without vision of the hand), by a visual target stepping at a predictable location (10 degrees right and left from the centre) and time. The subjects had to simultaneously move the eyes and point with the finger to the visual target alternating at one of three fixed frequencies (0.25, 0.5 and 1 Hz), for 30 cycles. This task was performed in two sessions balanced over the subjects: one session of ocular saccades only and another session of combined ocular saccades and manual pointing. In the PD group, motor performance was perturbed particularly in terms of increased latencies of hand movements. Interestingly, during pointing, associated predictive saccade disorders were tightly related to the defects of the pointing hand. Indeed, with respect to the latency of predictive saccades alone, the predictive saccade latency during hand pointing significantly decreased in the control group and in the PD group when using the non-affected hand. In contrast, for the PD group when using the affected hand, the saccade latency was increased from the latency values of predictive saccades induced without pointing. Moreover, in the control and in the PD groups, the correlation between eye and hand latencies was highly significant, suggesting an intact eye-hand coupling. No saccadic amplitude disorders were found in either condition. These results demonstrate that eye-hand coupling is preserved in PD, as revealed by the possible beneficial or adverse effects on the ocular saccades, respectively, of the less- or more-affected hand motor responses. This eye-hand coupling mechanism likely involves regions other than the nigro-striatal pathways affected in PD.
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OBJECTIVE: To investigate, using PET and H2(15)O, brain activation abnormalities of patients with PD during motor imagery. To determine whether motor imagery activation patterns depend on the hand used to complete the task. BACKGROUND: Previous work in PD has shown that bradykinesia is associated with slowness of motor imagery. METHODS: The PET study was performed in eight patients with PD with predominantly right-sided akinesia, and in eight age-matched control subjects, all right-handed. Regional cerebral blood flow was measured by PET and H2(15)O while subjects imagined a predetermined unimanual externally cued sequential movement with a joystick with either the left or the right hand, and during a rest condition. RESULTS: In normal subjects, the prefrontal cortex, supplementary motor area (SMA), superior parietal lobe, inferior frontal gyrus, and cerebellum were activated during motor imagery with either the left or the right hand. Contralateral primary motor cortex activation was noted only when the task was imagined with the right (dominant) hand, whereas activation of the dorsolateral prefrontal cortex was observed only during imagery with the left hand. In patients with PD, motor imagery with the right ("akinetic") hand was characterized by lack of activation of the contralateral primary sensorimotor cortex and the cerebellum, persistent activation of the SMA, and bilateral activation of the superior parietal cortex. Motor imagery with the left ("non-akinetic") hand was also abnormal, with lack of activation of the SMA compared with controls. CONCLUSIONS: In patients with PD with predominantly right-sided akinesia, brain activation during motor imagery is abnormal and may appear even with the less affected hand. In normal subjects, brain activation during motor imagery depends on the hand used in the imagined movement.
+Parkin gene mutations cause a form of early-onset autosomal recessive PD with neuronal loss in the substantia nigra and no Lewy bodies. The authors present a PET [18F]-dopa study of one familial and two sporadic cases with juvenile-onset PD resulting from parkin gene mutations. They found a profound decrease of [18F]-dopa uptake, representing 28% of putamen and 44% of caudate nucleus control subject values. PD caused by parkin gene mutations is distinct from idiopathic PD on molecular grounds but has similar clinical and PET findings.
Regional cerebral blood flow (rCBF) was measured using PET and H2(15)O in Parkinson's disease (PD) patients with predominantly right-sided akinetic-rigid symptoms and in control subjects during the execution of an externally cued motor task either with the left or the right hand. During the execution of the task with the left, non-akinetic, hand, cerebral activation in PD patients appeared similar to that of controls. Activated areas were the primary motor cortex, premotor cortex, parietal cortex and cerebellum. When the task was executed with the right, akinetic, hand cerebral activation in PD patients differed from that of controls subjects. The most important change was a bilateral activation of the primary motor cortex. We conclude that overactivation of primary motor cortex is asymmetrical in hemiparkinsonian patients.
Neurologic manifestations are rarely described in hereditary hemochromatosis (HH). We describe three patients with HH and movement disorders. Patient 1, a 69-year-old man, had a 13-year history of disabling cerebellar syndrome, action tremor and myoclonus, and secondary dementia. Patient 2 was a 40-year-old man with a 9-year history of cerebellar syndrome, head and arm tremor, and cervical dystonia. Patient 3, a 75-year-old woman, had a 5-year history of rapidly disabling parkinsonian syndrome unresponsive to levodopa. The diagnosis of HH was established in the three patients by iron tests, evidence of a C282Y mutation, and, in two patients, by liver biopsy. High-field T2-weighted magnetic resonance imaging showed hyperintense signals in hemispheric white matter in patient 1, cerebellar atrophy in patient 2, and cerebellar and cerebral atrophy in patient 3 and no significant hypointense signals in the three patients. Phlebotomies and symptomatic treatments did not change the course of the disease. Our cases are compared with the five previously reported observations of HH with movement disorders. This rare association is one cause of the chronic acquired non-Wilsonian hepatocerebral degeneration syndromes and represents a separate entity from aceruloplasminemia. The pathophysiologic mechanism of movement disorders in HH is unresolved. No hepatic insufficiency and portosystemic encephalopathy is evidenced in our cases, whereas the putative role of abnormal iron load remains to be ascertained. HH should be investigated more systematically in patients with movement disorders.
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The contribution of striatal (caudate nucleus-putamen) dopaminergic deficiency to the severity of motor signs is well established in Parkinson's disease (PD), while its role in the occurrence of cognitive and mood changes remains unresolved. We therefore measured in 27 non-demented PD patients and 10 age-matched controls striatal uptake of [18F]-6-fluoro-L-Dopa (F-Dopa) with PET, and mood (Beck depression), memory (Grober-Buschke), frontal executive functions (verbal fluency and Wisconsin card sorting), and attentional processing of sensory stimuli (N2-P3 auditory event-related potentials--ERPs). Locomotor disability of patients was assessed by Hoehn and Yahr score and Unified Parkinson's Disease Rating Scale (UPDRS). ANOVA showed that memory, but neither frontal lobe functions nor ERPs, was significantly altered in PD patients, whereas indices of depression were found only in advanced PD. The F-Dopa rate constant Ki was significantly reduced in the striatum, more in putamen than caudate nucleus, and inversely correlated with disease duration. A significant inverse correlation was found between both putamen and caudate nucleus Ki and Hoehn and Yahr score, and between putamen--but not caudate nucleus Ki --and UPDRS motor score. Principal components analysis (PCA) of PD patients Ki values and mood, cognitive and ERP parameters gave a three-factor solution. Variables contributing to factor 1 were memory score and N2-P3 ERP latencies, those to factor 2 were striatal Ki values, and those to factor 3 frontal executive performances. Depression did not segregate with any variable. Our findings suggest that unlike locomotor disability, cognitive abilities and mood state of non-demented PD patients are for the most part unrelated to striatal dopaminergic depletion and may result from dysfunction of extra-striatal dopaminergic or from non-dopaminergic systems.
Localized phosphorus (31P) and proton (1H) magnetic resonance spectroscopy was performed in the cerebellum and the occipital lobe of 6 patients with episodic ataxia type 2. From use of 31P magnetic resonance spectroscopy, untreated patients showed decreased high-energy phosphate ratios in the cerebrum, and increased pH in the cerebellum and cerebrum, which normalized under acetazolamide. 1H magnetic resonance spectra demonstrated high lactate peaks in 3 of the 6 patients. These metabolic alterations, probably induced by the calcium channelopathy, may characterize episodic ataxia type 2.
Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.
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Two missense mutations and a nine-nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single-strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1612, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de nova mutation in SCN5A associated with LQTS.
BACKGROUND: Native valve strands might be related to the acute stage of thrombosis or might suggest a long-term valvular change. We aimed to estimate changes in the strands in patients with stroke through a serial transesophageal echocardiographic (TEE) study. METHODS AND RESULTS: A study was conducted among patients who were referred for TEE for stroke or cardiac pathology. Patients had TEE examinations with a 5-MHz multiplane TEE probe. Echocardiography was repeated 3 months later in patients with stroke. TEE was performed in 180 patients admitted to cardiology units and in 160 patients referred to neurology units. Among 34 patients with valvular strands, 30 were referred to neurology for stroke, whereas 4 patients were admitted to cardiology (18.8% versus 2.2%, difference 16.5%, 95% confidence interval 10% to 22.9%, P =.001). Strands were located on the mitral valve in 16 patients, the aortic valve in 6 patients, and both left heart valves in 8 patients. Among the 38 valves with strands, 17 (44. 7%) were morphologically normal, 4 (10.5%) were thickened, 7 (18.4%) were redundant, and 10 (26.3%) had both abnormalities. TEE showed other abnormalities in 16 (53.3%) patients, whereas 14 patients had only strands. Twenty-six (86.6%) patients had a second TEE study 3 months later. Strands were not found in 4 (15.4%) patients (95% confidence interval 4.3% to 34.9%). CONCLUSIONS: Valvular thickening or redundancy may predispose valves to strand formation. Native valve strands usually persist and thus reflect a chronic valvular change.
The gene for autosomal recessive juvenile Parkinsonism (AR-JP) recently has been mapped to chromosome 6q25.2-27 in Japanese families. We have tested one Algerian and 10 European multiplex families with early-onset Parkinson disease for linkage to this locus, with marker D6S305. Homogeneity analysis provided a conditional probability in favor of linkage of >.9 in eight families, which were analyzed further with eight microsatellite markers spanning the 17-cM AR-JP region. Haplotype reconstruction for eight families and determination of the smallest region of homozygosity in two consanguineous families reduced the candidate interval to 11.3 cM. If the deletion of two microsatellite markers (D6S411 and D6S1550) that colocalize on the genetic map and that segregate with the disease in the Algerian family is taken into account, the candidate region would be reduced to <1 cM. These findings should facilitate identification of the corresponding gene. We have confirmed linkage of AR-JP, in European families and in an Algerian family, to the PARK2 locus. PARK2 appears to be an important locus for AR-JP in European patients. The clinical spectrum of the disease in our families, with age at onset <=58 years and the presence of painful dystonia in some patients, is broader than that reported previously.
Several studies of procedural learning in Parkinson's disease (PD) have demonstrated that these patients are impaired with respect to age-matched control subjects. In order to examine more closely the specific impairment, we considered three dimensions along which a procedural learning task could vary. These are: (1) implicit vs explicit learning, (2) instance vs rule learning, and (3) learning with internal vs external error correction. We consider two hypotheses that could explain the impairments observed in PD for different types of explicit motor learning: (H1) an impairment related to the acquisition of rules vs specific instances, and (H2) an impairment in learning when no explicit error feedback is provided. In order to examine the condition of rule learning with external error feedback, we developed a modified version of the serial reaction time (SRT) protocol that tests analogical transfer in sequence learning (ATSL). Reaction times are measured for responses to visual stimuli that appear in several different repeating sequences. While these isomorphic sequences are different, they share a common rule. Verbatim learning of a sequence would result in negative transfer from one sequence to a different one, while rule learning would result in positive transfer. Parkinson's patients and age-matched controls demonstrate significant acquisition and positive transfer of the rule between sequences. Our results demonstrate that PD patients are capable of learning and transferring rule or schema-based representations in an explicit learning format, and that this form of learning may be functionally distinct from learning mechanisms that rely on representations of the verbatim or statistical structure of sequences.