Esteban Muñoz

Patterned ballistic movements triggered by a startle in healthy humans

1 The reaction time to a visual stimulus shortens significantly when an unexpected acoustic startle is delivered together with the ‘go’ signal in healthy human subjects. In this paper we have investigated the physiological mechanisms underlying this effect. If the commands for the startle and the voluntary reaction were superimposed at some level in the CNS, then we would expect to see alterations in the configuration of the voluntary response. Conversely, if the circuit activated by the startling stimulus is somehow involved in the execution of voluntary movements, then reaction time would be sped up but the configuration of the motor programme would be preserved. 2 Fourteen healthy male and female volunteers were instructed to react as fast as possible to a visual ‘go’ signal by flexing or extending their wrist, or rising onto tiptoe from a standing position. These movements generated consistent and characteristic patterns of EMG activation. In random trials, the ‘go’ signal was accompanied by a very loud acoustic stimulus. This stimulus was sufficient to produce a startle reflex when given unexpectedly on its own. 3 The startling stimulus almost halved the latency of the voluntary response but did not change the configuration of the EMG pattern in either the arm or the leg. In some subjects the reaction times were shorter than the calculated minimum time for processing of sensory information at the cerebral cortex. Most subjects reported that the very rapid responses were produced by something other than their own will. 4 We conclude that the very short reaction times were not produced by an early startle reflex adding on to a later voluntary response. This would have changed the form of the EMG pattern associated with the voluntary response. Instead, we suggest that such rapid reactions were triggered entirely by activity at subcortical levels, probably involving the startle circuit. 5 The implication is that instructions for voluntary movement can in some circumstances be stored and released from subcortical structures.

Cerebrospinal tau, phospho‐tau, and beta‐amyloid and neuropsychological functions in Parkinson's disease

Alzheimers disease (AD)‐pathology may play a role in Parkinsons disease (PD)‐related dementia (PDD). The aim of this study was to assess cerebrospinal fluid (CSF) levels of tau, phospho‐tau, and beta‐amyloid, proposed AD biomarkers, and their relationship with cognitive function in PD. Forty PD patients [20 nondemented (PDND); 20 PDD] and 30 controls underwent CSF tau, phospho‐tau, and beta‐amyloid analysis using specific ELISA techniques. All PD patients and 15 controls underwent neuropsychological testing of fronto‐subcortical (attention, fluency) and neocortical (memory, naming, visuoperceptive) functions. CSF markers levels were compared between groups, and compared and correlated with neuropsychological measures in PDND and PDD separately and as a continuum (PD). CSF tau and phospho‐tau were higher in PDD than in PDND and controls (P < 0.05). CSF beta‐amyloid ranged from high (controls) to intermediate (PDND) and low (PDD) levels (P < 0.001). In all PD and PDD patients, high CSF tau and phospho‐tau were associated with impaired memory and naming. In PDND, CSF beta‐amyloid was related with phonetic fluency. These findings suggest underlying AD‐pathology in PDD in association with cortical cognitive dysfunction, and that low CSF beta‐amyloid in PDND patients with impaired phonetic fluency can constitute an early marker of cognitive dysfunction.

Significant association between the tau gene A0/A0 genotype and Parkinson's disease

A significant association between the tau gene A0/A0 genotype and progressive supranuclear palsy has been reported recently. To determine if the presence of a tau polymorphism could constitute a risk factor for the development of sporadic and familial Parkinson’s disease, a dinucleotide repeat marker at intron 11 was genotyped in 152 patients with PD, 52 patients with Alzheimers disease, and 150 healthy controls. We detected a significant difference in A0 allelic frequency in the Parkinsons disease group (79.27%) compared with the control group (71%) and the Alzheimers disease group (73.07%). Individuals homozygous for the A0 allele were also detected significantly more frequently in the Parkinsons disease group (63.8%) compared with the control group (52.66%) and the Alzheimers disease group (48.07%). These results suggest a possible involvement of the tau gene in the pathogenesis of some cases of Parkinsons disease. Ann Neurol 2000;47:242–245

REM sleep behavior disorder and vocal cord paralysis in Machado‐Joseph disease

We evaluated the occurrence of REM sleep behaviour disorder (RBD) and vocal cord abductor paralysis (VCAP) in a group of 9 Machado‐Joseph disease (MJD) patients. RBD was diagnosed by clinical history plus audiovisual polysomnography in 4 men and 1 woman (55%). While dreaming, 4 fell out of the bed and the other injured his arms. Laryngoscopy detected bilateral VCAP in 1 patient with stridor who required emergency tracheotomy, and partial vocal cord abductor restriction in 2. RBD and VCAP are two potentially injurious conditions that should be considered part of the clinical spectrum of MJD.

Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson's disease dementia

Excessive daytime sleepiness is common in Parkinsons disease and has been associated with Parkinsons disease-related dementia. Narcoleptic features have been observed in Parkinsons disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinsons disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinsons disease have been inconclusive. Reports of sleep studies in Parkinsons disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinsons disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinsons disease patients without dementia and 20 Parkinsons disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinsons disease patients without dementia and seven Parkinsons disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinsons disease patients without dementia and Parkinsons disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinsons disease patients with dementia than in Parkinsons disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 +/- 47.15 pg/ml; without dementia = 300.99 +/- 58.68 pg/ml; with dementia = 309.94 +/- 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinsons disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinsons disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.

Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations

Rapid eye movement sleep behavior disorder (RBD) in the setting of parkinsonism or dementia often reflects an underlying synucleinopathy. Lewy bodies, intraneuronal aggregates containing abnormal α‐synuclein, are absent in most cases of parkinsonism with parkin mutations (Park2). We performed clinical history and video‐polysomnography in 10 Park2 patients (seven men; age, 51.2 ± 11.6 years; parkinsonism duration, 18.3 ± 11.2 years) and found RBD in 6. In all instances, RBD followed the onset of motor symptoms by several years. Our study shows that RBD is frequent in Park2, suggesting that mechanisms other than synuclein deposition can cause RBD in neurodegenerative disorders. Ann Neurol 2004;56:599–603

Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the α-synuclein gene in early onset patients

We initiated the present work in order to determine if the Ala53Thr mutation of the alpha-synuclein gene previously described by Polymeropoulos et al. [Science, 276 (1997) 2045-2047] could be detected in Spanish early onset Parkinsons disease (PD) patients. Thirty-four PD patients were evaluated. Of these, 13 were considered early onset patients (six familial and seven sporadic) and were included in the genetic study. We detected the presence of genetic anticipation in four kindreds with early onset PD members. The Ala53Thr mutation of the alpha-synuclein gene was absent in all patients. The results do not support a role for this mutation in our patients with early onset PD and, in agreement with the results previously reported, indicate that the Ala53Thr mutation of the alpha-synuclein gene is a rare cause of PD.

Further extension of the H1 haplotype associated with progressive supranuclear palsy

The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800‐D17S791), associated with some cases of familial frontotemporal dementia (FTDP‐17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice‐site region of the exon 10 and in the microtubule‐binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5′ or in the 3′ flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP.

Reflex excitability of facial motoneurons at onset of muscle reinnervation after facial nerve palsy

We studied 18 patients with complete unilateral denervation of the facial muscles after idiopathic facial nerve palsy to determine whether motoneuronal excitability is enhanced in the few motor units that are active at onset of muscle reinnervation. The study was carried out between 75 and 90 days after the facial nerve lesion. We used two needle electrodes to record simultaneously the spontaneous and voluntary activity of the orbicularis oris (OOris) and orbicularis oculi (OOculi) muscles, as well as the responses to ipsilateral and contralateral facial and supraorbital nerve stimuli. All patients showed involuntary firing of motor unit action potentials (MUAPs) in at least one of the muscles. Synkinetic activation of motor units in the OOris was induced by spontaneous blinking in all patients, and by inhalation and swallowing in some. Electrical stimulation of the ipsilateral facial nerve induced a direct M response in only 4 patients. In contrast, long‐latency reflex responses were induced in both muscles by electrical stimulation of ipsilateral and contralateral facial and supraorbital nerves in all patients, at latencies ranging between 44 and 132 ms. The shape of such MUAP reflex responses was the same as that of the MUAPs seen to fire at rest. These findings provide evidence of enhanced excitability of facial motoneurons in our patients. Such hyperexcitability may be partly responsible for the postparalytic motor dysfunction syndrome that occurs after facial palsy with severe axonal damage.

Lack of association of APOE and tau polymorphisms with dementia in Parkinson’s disease

Some APOE or tau gene polymorphisms have been associated with Alzheimers disease (AD), progressive supranuclear palsy (PSP) and Parkinsons disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan-Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD.