Ali H. Rajput

Accuracy of clinical diagnosis in Parkinsonism―A prospective study

Clinical diagnosis of Parkinsons syndrome (PS) is reasonably easy in most cases but the distinction between different variants of PS may be difficult in early cases. The correct diagnosis is not only important for counselling and management of patients but also in conducting pharmacological and epidemiological studies. There is very little critical literature on the pathological verification of the clinical diagnosis in PS. We report our 22 years experience to address that issue. Between 1968 and 1990, 65 PS patients came to autopsy. Complete data are available in 59 (M-50, F-19) cases. The initial diagnosis made by a qualified neurologist was idiopathic Parkinsons disease (IPD) in 43 cases. Of those 28 (65%) had Lewy body pathology. After a mean duration of 12 years the final diagnosis was IPD in 41 cases which was confirmed in 31 (76%). The IPD could not be clinically distinguished from cases with severe substantia nigra neuronal loss without inclusions or from those with neurofibrillary tangle inclusions and neuronal loss at the anatomical sites typically involved in IPD. All progressive supra-nuclear palsy, olivopontocerebellar atrophy, Jakob-Creutzfeldts disease and the majority of the multiple system atrophy cases were diagnosed correctly during life. The correct clinical diagnosis in most non-IPD variants of PS was possible within 5 years of onset (range: 2 months to 18 years). We recommend that studies aimed at including only the IPD cases restrict the enrollment to those cases that have had PS motor manifestations for five years or longer duration.

VPS35 Mutations in Parkinson Disease

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.

Brain Cytochrome Oxidase in Alzheimer's Disease

Abstract: A recent demonstration of markedly reduced (‐50%) activity of cytochrome oxidase (CO; complex 4), the terminal enzyme of the mitochondrial enzyme transport chain, in platelets of patients with Alzheimers disease (AD) suggested the possibility of a systemic and etiologically fundamental CO defect in AD. To determine whether a CO deficiency occurs in AD brain, we measured the activity of CO in homogenates of autopsied brain regions of 19 patients with AD and 30 controls matched with respect to age, postmortem time, sex, and, as indices of agonal status, brain pH and lactic acid concentration. Mean CO activity in AD brain was reduced in frontal (‐26%; p < 0.01), temporal (‐17%; p < 0.05), and parietal (‐16%; not significant, p= 0.055) cortices. In occipital cortex and putamen, mean CO levels were normal, whereas in hippocampus, CO activity, on average, was nonsignificantly elevated (20%). The reduction of CO activity, which is tightly coupled to neuronal metabolic activity, could be explained by hypofunction of neurons, neuronal or mitochondrial loss, or possibly by a more primary, but region‐specific, defect in the enzyme itself. The absence of a CO activity reduction in all of the examined brain areas does not support the notion of a generalized brain CO abnormality. Although the functional significance of a 16‐26% cerebral cortical CO deficit in human brain is not known, a deficiency of this key energy‐metabolizing enzyme could reduce energy stores and thereby contribute to the brain dysfunction and neurodegenerative processes in AD.

Levodopa in the treatment of Parkinson's disease: Current controversies

Levodopa is the most effective symptomatic agent in the treatment of Parkinsons disease (PD) and the “gold standard” against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half‐life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease.

Alpha‐synuclein plays a central role in the pathophysiology of Parkinsons disease. Three missense mutations in SNCA, the gene encoding alpha‐synuclein, as well as genomic multiplications have been identified as causes for autosomal‐dominantly inherited Parkinsonism.

Aging Produces a Specific Pattern of Striatal Dopamine Loss: Implications for the Etiology of Idiopathic Parkinson's Disease

Abstract: To examine the possible causal contribution of normal or accelerated aging to the neurodegenerative process of Parkinsons disease, we measured the influence of aging on subregional striatal dopamine and homovanillic acid levels in postmortem brain of 23 neurologically and psychiatrically normal human subjects 14–92 years old. We observed a significant decline in striatal dopamine levels and increase in the homovanillic acid/dopamine molar ratios with increasing age. The dopamine loss, on average, was of the same magnitude in the caudate nucleus and the putamen (‐60% in the 84‐year‐old group as compared with the 22‐year‐old group), with the caudal component of both nuclei being more affected than the rostral subdivisions. The level of subregional dopamine metabolism, as measured by the homovanillic acid/dopamine ratio, in our young individuals (mean age, 22 years) was found to be inversely correlated to the degree of subregional dopamine loss suffered by the individuals in the older age groups. We conclude the following: (a) Striatal subdivisions with physiologically higher dopamine metabolism are not at a greater risk of suffering dopamine neuronal damage with advancing age, as would seem to be implied by the oxidative stress hypothesis; thus, formation of dopamine‐derived oxy radicals in the human striatum appears unlikely to be a primary factor responsible for the age‐related striatal dopamine loss. (b) The regional and subregional pattern of striatal dopamine loss in normal aging differs substantially from the pattern typically observed in idiopathic Parkinsons disease; therefore, the cause of idiopathic Parkinsons disease cannot be primarily an age‐dependent neurodegenerative process.

Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease

Objective: This multicenter, randomized, double-blind study was performed to compare the safety and efficacy of the once-daily dopamine agonist rotigotine, in a continuous-dosing transdermal-patch formulation, vs placebo in patients with early-stage Parkinson disease (PD). Methods: Patients were randomized to receive placebo (n = 96) or rotigotine (n = 181), starting at 2 mg/24 h (10-cm2 patch size; 4.5-mg total drug content), titrated weekly up to 6 mg/24 h (30-cm2 patch size; 13.5-mg total drug content), and then maintained for 6 months. The primary efficacy measures were 1) the change in the Unified Parkinsons Disease Rating Scale (UPDRS) scores (parts II and III) from baseline to end of treatment and 2) responder rates (patients with ≥20% improvement). Results: Patients receiving rotigotine had a mean absolute difference of 5.28 (±1.18) points lower in UPDRS subtotal scores compared with those receiving placebo (p < 0.0001). The mean change in part III motor scores was −3.50 (±7.26) (n = 177) and was the greatest contributor to UPDRS improvement. The rotigotine group had more responders (48 vs 19%; p < 0.0001). The most commonly reported adverse events were application site reactions (44% rotigotine vs 12% placebo), nausea (41 vs17%), somnolence (33 vs 20%), and dizziness (19 vs 13%), and most were mild or moderate in intensity. Conclusions: Transdermal rotigotine, when titrated to a dosage of 6 mg/24 h, was effective for the treatment of early-stage Parkinson disease in this trial. Adverse events were similar to those found with other transdermal systems and dopamine agonists.

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease.

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinsons disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers.These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([sup 3 H]GBR 12,935 and [sup 3 H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [sup 3 H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [sup 3 H]WIN 35,428 > [sup 3 H]DTBZ > [sup 3 H]GBR 12,935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed. NEUROLOGY 1996;47: 718-726

Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease.

Glutamate receptors were studied in the brains of controls and Parkinsons disease (PD) patients, of which 10 of 14 developed motor complications (dyskinesias and/or wearing-off) following levodopa therapy. (125)I-RTI binding to the dopamine transporter and dopamine concentrations show comparable nigrostriatal denervation between the subgroups of PD patients. (3)H-Ro 25-6981 binding to the NR1/NR2B NMDA receptor was increased in the putamen of PD patients experiencing motor complications compared to those who did not (+53%) and compared to controls (+18%) whereas binding remained unchanged in the caudate nucleus. (3)H-AMPA binding was increased in the lateral putamen (+23%) of PD patients with motor complications compared to those without whereas it was decreased in the caudate nucleus of the PD patients (-16%) compared to controls. Caudate and putamen (3)H-CGP39653 binding to NR1/NR2A NMDA receptor and NR1 subunit mRNA levels measured by in situ hybridization were unchanged in subgroups of PD patients compared to controls. These findings suggest that glutamate receptor supersensitivity in the putamen plays a role in the development of motor complications (both wearing-Off and dyskinesias) following long-term levodopa therapy in PD.