Absence of age-related changes in nigral dopaminergic neurons of Asian Indians: relevance to lower incidence of Parkinson's disease.

Age-related loss of melanized nigral neurons reported in the British Caucasians is not observed in Asian Indian, American and French adults. In the Americans, loss of dopaminergic phenotype occurs from midlife, without frank neurodegeneration. Here, we investigated whether nigral dopaminergic neurons in Asian Indians are lost with age or undergo morphological or biochemical dysfunction. Using unbiased stereology we estimated volume, number of melanized, borderline/non-melanized (n=34, 28 gestational weeks to 80 years) and tyrosine hydroxylase (TH)-Nurr1 co-labeled neurons (n=32, 28 gestational weeks to 80 years) in substantia nigra pars compacta. We quantified Nurr1 and TH proteins by immunoblotting (n=18, 28 gestational weeks to 69 years) and apoptotic neurons by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Nuclear and soma size was estimated by morphometry. There was no age-related decline in volume, neuronal density, neuronal numbers and TH-Nurr1 co-labeled neurons. TH and Nurr1 protein expression remained stable. Lack of TUNEL-TH co-labeled cells confirmed absence of neuronal apoptosis. The neuronal size remained unaltered. Our findings of preserved nigral dopaminergic neurons suggest no age-related loss of nigral function in Asian Indians, unlike the Americans. This may explain the lower incidence of Parkinson's disease in Asian Indians.

High occurrence and low recognition of Parkinsonism (and possible PD) in old age homes in Bangalore, South India.

BACKGROUND: The elderly population in developing countries is likely to increase by 200-280%. Age related diseases like Parkinsonism are also likely to increase in ageing population. The prevalence and awareness of Parkinsonism (and possible PD) amongst them are unknown. METHODS AND MATERIAL: The objective was to know the awareness and occurrence of Parkinsonism (and possible PD) in Old Age Homes in Bangalore, South India. The study design was prospective, direct clinical evaluation, and it was old age homes in Bangalore, South India setting. There were six hundred and twelve residents of the old age homes in Bangalore. A movement disorder neurologist examined 612 elderly residents living in Old age Homes in Bangalore city, India. RESULTS: Parkinsonism was diagnosed in 109 (17.8%) of 612 residents. Possible PD was diagnosed in 9 (1.5% of 612) while in 100 (16.3% of 612) definite PD was diagnosed.94 (86.2%) had bilateral Parkinsonian signs (Stage > or = 2 of Hoehn & Yahr), only 4 (3.7%) of them or the caregivers knew they had PD. CONCLUSIONS: Knowledge about the disease was very low in the elderly residents although the occurrence of Parkinsonism was very high. Improving awareness of PD amongst the elderly and their caregivers might reduce their disability and improve their quality of life.

Epidemiology of Parkinson's disease and movement disorders in India: problems and possibilities.

Improving economy and health in developing countries like India, has increased the life span and changed the emphasis from communicable to noncommunicable diseases. This is likely to increase the prevalence of movement disorders and, age-related diseases like Parkinson's disease (PD). We review Indian epidemiological studies to describe: a) Prevalence of movement disorders, b) methodological issues and c) potential of epidemiological research in a country with multiple ethnic races and environmental risks for PD. Most Indian epidemiological studies do not specifically assess PD and figures are from studies evaluating all neurological diseases. Well-designed Indian studies on PD and essential tremors estimate prevalence rates in Parsis who are ethnically different from Indians. We compare Indian prevalence studies with other parts of the world to examine the role of ethnicity in PD. Lack of accurate epidemiological data on PD and movement disorders creates an urgent need for properly designed and conducted epidemiological studies in India. This will help find out their load, identify areas of focus, create public health policies for elderly Indians and, possibly, provide etiological clues to the pathogenesis of PD.

Molecular analysis of Huntington's disease and linked polymorphisms in the Indian population.

OBJECTIVES: To understand the population variation and haplotypes of Huntington's disease (HD) in India we have analysed CAG repeats at the HD locus together with closely linked polymorphisms in both HD patients and normal controls. MATERIALS AND METHODS: The CAG repeat and linked polymorphisms were analysed in 30 Indian HD families together with 250 ethnically matched controls using fluorescent polymerase chain reaction (PCR) based size estimation. RESULTS: CAG repeats at the HD locus in the normal population showed a mean size of 17.99 +/- 2.66 repeats (range nine to 33 repeats). The HD mutation in our families did not show any significant association with either the (CCG)7 or (CCG)10 allele while haplotype analysis suggested the over-representation of the 7-2-I (CCG-D4s127-Delta 2642 loci) haplotype in a subset of families. CONCLUSION: The distribution of CAG repeats in the normal population suggests a higher prevalence of HD, closer to that seen in Western Europe. Haplotype analysis suggests the presence of a founder mutation in a subset of families and provides evidence for multiple and geographically distinct origins for the HD mutation in India.

Botulinum toxins: pharmacology and its current therapeutic evidence for use.

Botulinum toxins are, as a group, among the most potent neuromuscular toxins known, yet they are clinically useful in the management of conditions associated with muscular and glandular over-activity. Botulinum toxins act by preventing release of acetylcholine into the neuromuscular junction. While botulinum toxin type A is commonly available, different manufacturers produce specific products, which are not directly interchangeable and should not be considered as generically equivalent formulations. Type B is also available in the market. Each formulation of botulinum toxin is unique with distinct dosing, efficacy and safety profiles for each use to which it is applied. Botulinum toxin type A is the treatment of choice based on its depth of evidence in dystonias and most other conditions. Botulinum toxin type A is established as useful in the management of spasticity, tremors, headache prophylaxis and several other neurological conditions. Active research is underway to determine the parameters for which the type B toxin can be used in these conditions, as covered in this review. Botulinum toxin use has spread to several fields of medicine.

A clinical study of patients with genetically confirmed Huntington's disease from India.

BACKGROUND: Clinical data across the globe especially in genetic diseases like Huntington's disease (HD) is most helpful when collected using standardized formats. This helps in proper comparison of clinical and genetic data. METHODS: Herein, we report clinical data on 26 genetically confirmed HD patients from 19 Indian families predominantly from South India. Clinical data and evaluation was performed using standardized formats used by the Huntington Disease Study Group. RESULTS: Adult onset HD was commonest while Juvenile HD (onset <20 years) was observed in approximately 15% of patients. Chorea was the commonest presenting symptom (n=23, 88.5%) while remaining presented with psychiatric symptoms (n=3, 11.5%). Impairment of saccades was observed in approximately 75% of patients. Mean (SD) CAG repeats in the abnormal allele was 48.4 (8.7). Total motor score but not the total behavioral score worsens with duration of symptoms. The functional checklist score correlates with total motor score rather than with duration of symptoms. CONCLUSIONS: We detail clinical characteristics in genetically confirmed HD patients from a predominantly South Indian cohort. We observed a slightly higher occurrence of Juvenile HD. Functional disabilities in our patients correlate with worsening of motor rather than behavioral symptoms.

Hunting genes in Parkinson's disease from the roots.

Parkinson's disease (PD), a common, neurodegenerative disorder, has a worldwide distribution. The genetic basis of PD is not well understood, although some recent leads have emerged. Epidemiological studies suggest that there is significant variation in the prevalence of PD between different populations and rates are highest in populations of European origin. Significant differences in molecular pathology in PD and control brain tissue have been observed between African, British and Indian populations. In view of this epidemiological and pathological evidence, it is proposed that allelic variations in genes that predispose to PD may account for the ethnic variation. Advances in our knowledge about the human genome will allow us to make detailed comparisons between affected and control subjects in different populations. This may help us to understand the reasons for the variation, and a better understanding of the genetic processes underlying the disease process.

Persistent movement disorders following Japanese encephalitis.

The authors report on movement disorders that persist for a long duration following Japanese encephalitis (JE). Fifteen patients with diagnosed JE were followed up after an interval of 3 to 5 years. Of the four patients with a movement disorder, two were children with severe generalized dystonia in whom MRI revealed bilateral thalamic lesions. The two adult patients had parkinsonism. MRI in both adult patients showed lesions confined to the substantia nigra. Viral antibody and antigen were absent in the CSF of all patients.

Palatal tremor, progressive multiple cranial nerve palsies, and cerebellar ataxia: a case report and review of literature of palatal tremors in neurodegenerative disease.

We describe a patient with an unusual clinical presentation of progressive multiple cranial nerve palsies, cerebellar ataxia, and palatal tremor (PT) resulting from an unknown etiology. Magnetic resonance imaging showed evidence of hypertrophy of the inferior olivary nuclei, brain stem atrophy, and marked cerebellar atrophy. This combination of progressive multiple cranial nerve palsies, cerebellar ataxia, and PT has never been reported in the literature. We have also reviewed the literature of PT secondary to neurodegenerative causes. In a total of 23 patients, the common causes are sporadic olivopontocerebellar atrophy (OPCA; 22%), Alexander's disease (22%), unknown etiology (43.4%), and occasionally progressive supranuclear palsy (4.3%) and spinocerebellar degeneration (4.3%). Most patients present with progressive cerebellar ataxia and approximately two thirds of them have rhythmic tremors elsewhere. Ear clicks are observed in 13% and evidence of hypertrophy of the inferior olivary nucleus in 25% of the patients. The common neurodegenerative causes of PT are OPCA/multiple system atrophy, Alexander's disease, and, in most of them, the result of an unknown cause.

Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India.

The prevalence of Parkinson's disease (PD) is higher in whites than in nonwhites and it increases with advancing age. The pathological hallmarks of PD are loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and presence of Lewy bodies. With increasing age, a similar loss of pigmented neurons in the SNpc has been reported. Hence, age and race possibly play a role in the pathogenesis of PD. The objectives of this study were to count the number of melanized neurons in the SNpc in normal human brains from India and study the change in neuronal count with advancing age and to compare the neuronal counts from this Indian population with counts reported in normal brains from the United Kingdom. Melanized neurons in the SNpc were counted in 84 normal human brains (age range, 5-84 years) in a single 7-microm section at the level of emergence of the oculomotor nerve. In the brains from India, there was no loss of melanized nigral neurons with advancing age. The absolute number of these melanized neurons was about 40% lower than the brains from UK. Despite a low number of melanized nigral neurons in the brains from India, individuals function normally and have dopamine levels comparable with their Western counterparts, suggesting that it is not the absolute number of melanized nigral neurons but the percent loss of nigral neurons that results in dopaminergic deficiency in PD. There is no significant loss of pigmented nigral neurons with age, suggesting that the loss seen in PD is exclusively due to the disease process itself. Indians have a lower prevalence of PD despite having a low count of melanized nigral neurons, suggesting that better protective mechanisms may be present in the Indians to prevent the loss of nigral neurons.

Early onset Parkinson's disease: are juvenile- and young-onset different?

It is controversial if early onset Parkinson's disease (EOPD) (onset at < 41 years of age) is Parkinson's disease (PD) occurring at a younger age or a different disease. This controversy is due to some clinical and pathological differences between EOPD and PD. Within EOPD, there appear to be two groups namely: young onset Parkinson's disease (YOPD), with onset between 21 and 40 years, and juvenile parkinsonism (JP), with onset at < 20 years. The two major clinical differences between these groups are a higher familial occurrence of PD and dystonia in JP. In this study, we determine if the two groups have the classical features of PD, namely rest tremors, rigidity, bradykinesia, and postural instability, and have a meaningful response to levodopa. Furthermore, we compare their other clinical features, autonomic and cognitive functions, and levels of CSF monoamine metabolites to determine differences between these groups. We observe that all YOPD (100%) and JP (85%) patients had rest tremors. Most of these patients also had a meaningful response to levodopa (YOPD: 72%; JP: 100%). The prevalence of family history of PD was similar, whereas dystonia was more frequent in JP (43%) compared to YOPD (9%). Autonomic symptoms were twice as common in JP (42%) compared to YOPD (17%). However, bedside autonomic functions were abnormal in similar proportions and, like in PD, suggest involvement of parasympathetic nervous system. Cognitive dysfunction does occur but with no difference in severity between the two groups. The difference in number of patients between YOPD and JP groups makes statistical comparison of the occurrence of clinical features like dystonia and autonomic dysfunction difficult.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and electrophysiological study of intermediate syndrome in patients with organophosphorous poisoning.

Intermediate syndrome (IS) developed in 38 of 214 cases with organophosphorous compound poisoning (OPCP). Neck muscle weakness, motor cranial nerve palsy, respiratory muscle paralysis, proximal limb weakness were the chief neurological signs developed 16-120 hours after consumption of the insecticide. Two patients had pyramidal tract signs. Mean duration of IS was 9.26 (+/- 4.84) days. Electrophysiological study (EPS) was done in 21 patients. 18 patients showed decremental response to repetitive stimulation at 3Hz 5 pulses and absence of post tetanic facilitation. Motor conduction studies were abnormal in on (prolonged distal latency and reduced conduction velocity), 'F' responses were abnormal in, sensory nerve conduction was abnormal in two, and simple repetitive response were observed in 11 patients. 4 patients died. In IS neuromuscular junctional dysfunction is the predominant factor.

Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and CD-1 mice.

The present study demonstrates that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes significantly greater reductions in striatal dopamine levels in C57/bl mice than in CD-1 mice, thus confirming a greater sensitivity of the C57/bl mice to MPTP. To determine the possible reasons for this difference in MPTP sensitivity between these two mouse strains, we have compared both the organization and the number of substantia nigra (SN) neurons, the primary target of MPTP, in C57/bl and in CD-1 mice using immunostaining for tyrosine hydroxylase (TH) and calbindin-D28k (calbindin). In saline-injected animals, there is a significantly lower number of SN TH-positive and calbindin-positive neurons in C57/bl than CD-1 mice; no significant differences in the numbers of these neurons are found in the ventral tegmental area between the two strains. In MPTP-injected animals, the reductions in SN TH-positive neurons are significantly greater in C57/bl than in CD-1 mice. In contrast, MPTP does not cause any significant changes in the numbers of SN calbindin-positive neurons in either strain. The present study shows that C57/bl mice which have fewer SN TH-positive neurons are more sensitive to MPTP-induced toxicity than CD-1 mice. This observation suggests a possible inverse relationship between SN TH-positive neuron number and MPTP sensitivity. If correct, this hypothesis may be of major importance for Parkinson's disease since it is suggested that individuals at risk of developing this neurodegenerative disorder may have lower numbers of SN TH-positive neurons to start with. The present study also shows that SN calbindin-positive neurons are spared following MPTP administration. However, the observed difference in SN calbindin-positive neuron numbers does not account for the differential sensitivity to MPTP between these two mouse strains.

Porphyric neuropathy: prevention of progression using haeme-arginate.

We report on a patient with acute intermittent porphyria (AIP) who, during treatment with hypertonic glucose, developed peripheral neuropathy. Once haeme-arginate was started, the progression of the neuropathy was attenuated. This suggests that hypertonic glucose may be inadequate in preventing the development of neuropathy in a patient with porphyria. However, haeme-arginate, if started early, can attenuate the progression of porphyric neuropathy.

Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity.

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual and auditory evoked potentials in early onset Parkinson's disease and their relationship to cerebrospinal fluid monoamine metabolites.

We studied visual (VEP) and brainstem auditory (BAEP) evoked potential changes in 23 patients with early onset Parkinson's disease (EOPD) to establish the nature of the changes as well as their relationship to dopaminergic (DA) and serotonergic (5-HT) disturbances, as determined by cerebrospinal fluid levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). We also compared these parameters between the young onset (YOPD) and juvenile Parkinsonism (JP), the two subgroups of EOPD, to look for any possible differences between the two. In EOPD, the mean P100 latency of the VEP was significantly prolonged compared to controls (p < 0.001). However, within EOPD the evoked potential parameters were not significantly different between YOPD and the JP subgroups. P100 latency was abnormal in six patients (YOPD: 5, JP: 1) (26%). Six patients (YOPD: 3, JP:3) (26%) had abnormal BAEP. A significant negative correlation (r: -0.89, p < 1%) was observed between the P100 latency and CSF HVA levels. No correlation was observed between the BAEP interpeak latencies and either CSF HVA or 5-HIAA levels. This study suggests that VEP and BAEP abnormalities do occur in EOPD (in both YOPD and JP), and that the prolongation of P100 latency is secondary to DA deficiency as in PD. The cause of BAEP abnormalities is probably independent of DA and 5-HT disturbances. The only difference between EOPD and classical PD was the higher incidence of BAEP abnormalities in EOPD. There was no correlation between the VEP or BAEP changes to either the age at onset or duration of EOPD.

Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats.

Adenosine receptor antagonists, DMPX, PACPX and theophylline, produce contralateral rotations in unilateral 6-hydroxydopamine-lesioned rats. DMPX and theophylline markedly increase rotations produced by bromocriptine (a dopamine D2 receptor agonist) and/or SKF38393A (a dopamine D1 receptor agonist). All of these effects are inhibited by CGS21680C (an adenosine A2 receptor agonist). These findings suggest synergistic interactions among D1, D2 and A2 receptors that may be relevant to the treatment of Parkinson's disease.