Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease.

All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.

Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis. Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93. It did not, however, alter the duration of the disease. Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice.

Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.

Engineered modeling and the secrets of Parkinson's disease.

The development of new methods for manipulating the animal genome by transgenic and gene-targeting technologies provides a unique means of studying the most intimate aspects of countless human diseases, including Parkinson's disease (PD). In this review, the contribution of such engineered models to our current understanding of the pathophysiology, etiology and pathogenesis of PD will be discussed.

Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis.

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.

Delaying caspase activation by Bcl-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis.

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant copper/zinc superoxide dismutase (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, herein we show that the spinal cord of transgenic mSOD1 mice is the site of the sequential activation of caspase-1 and caspase-3. Activated caspase-3 and its produced beta-actin cleavage fragments are found in apoptotic neurons in the anterior horn of the spinal cord of affected transgenic mSOD1 mice; although such neurons are few, their scarcity should not undermine the potential importance of apoptosis in the overall mSOD1-related neurodegeneration. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurodegeneration and delays activation of the caspases and fragmentation of beta-actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modulation of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase inhibition extending the survival of transgenic mSOD1 mice.

The metabolic topography of parkinsonism.

We used [18F]fluorodeoxyglucose/positron emission tomography (18F-FDG/PET) and a statistical model of regional covariation to study brain topographic organization in parkinsonism. We studied 22 patients with Parkinson's disease (PD), 20 age-matched normal volunteers, and 10 age- and severity-matched patients with presumed striatonigral degeneration (SND). We used FDG/PET to calculate global, regional, and normalized metabolic rates for glucose (GMR, rCMRglc, rCMRglc/GMR). Metabolic parameters in the three groups were compared using an analysis of variance, with a correction for multiple comparisons, and discriminant analysis. The scaled subprofile model (SSM) was applied to the combined rCMRglc dataset to identify topographic covariance profiles that distinguish PD patients from SND patients and normals. GMR, rCMRglc, and rCMRglc/GMR were normal in PD; caudate and lentiform rCMRglc/GMR was reduced in the SND group (p < 0.01). SSM analysis of the combined group of patients and normals revealed a significant topographic profile characterized by increased metabolic activity in the lentiform nucleus and thalamus associated with decreased activity in the lateral frontal, paracentral, inferior parietal, and parietooccipital areas. Individual subject scores for this profile were significantly elevated in PD patients compared with normals and SND patients (p < 0.001) and discriminated the three groups. In the PD group, subject scores for this factor correlated with individual subject Hoehn and Yahr (H & Y) scores (p < 0.02), and with quantitative rigidity (p < 0.01) and bradykinesia (p < 0.03) ratings, but not with tremor ratings. SSM analysis of right-left metabolic asymmetries yielded a topographic contrast profile that accurately discriminated mildly affected PD patients (H & Y Stage I) from normals. Our findings demonstrate that abnormal topographic covariance profiles exist in parkinsonism. These profiles have potential clinical application as neuroimaging markers in parkinsonism.

Developmental cell death in dopaminergic neurons of the substantia nigra of mice.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo natural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpc dopaminergic neurons in the developing mouse. Herein, by using an array of morphologic techniques, we show that many SNpc neurons fulfill the criteria for apoptosis and that the number of apoptotic neurons in the SNpc vary in a time-dependent manner from postnatal day 2 to 32. These dying neurons also show evidence of DNA fragmentation, of activated caspase-3, and of cleavage of beta-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine hydroxylase, confirming their dopaminergic nature. Consistent with the importance of target-derived trophic support in modulating developmental cell death, we demonstrate that destruction of intrinsic striatal neurons by a local injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpc dopaminergic neurons. Strengthening the apoptotic nature of the observed SNpc developmental cell death, we demonstrate that overexpression of the anti-apoptotic protein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The present study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this process plays a critical role in regulating the adult number of dopaminergic neurons in the SNpc.

Clinical presentation and pharmacological therapy in corticobasal degeneration.

BACKGROUND: To date, to our knowledge, there is no systematic presentation of treatment outcome in large series of patients clinically diagnosed as having corticobasal degeneration. OBJECTIVE: To evaluate the clinical presentation and treatment outcome of patients clinically diagnosed as having corticobasal degeneration. SUBJECTS: We gathered case patients seen in 8 major movement disorder clinics during the last 5 years who were diagnosed as having corticobasal ganglionic degeneration. METHODS: Using a chart review method, we recorded the clinical presentation, medications used, response to medications, and adverse effects. RESULTS: A total of 147 case patients were reviewed, 7 were autopsy proven. Parkinsonian features were present in all, other movement disorders in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). Other movement disorders were dystonia in 71% and myoclonus in 55%. Higher cortical dysfunction included dyspraxia (82%), alien limb (42%), cortical sensory loss (33%), and dementia (25%). Ninety-two percent of the case patients received dopaminergic drugs, which resulted in a beneficial effect for 24%. Parkinsonian signs were the elements improving the most and levodopa was the most effective drug. Benzodiazepines, primarily clonazepam, were administered to 47 case patients, which resulted in improvement of myoclonus in 23% and dystonia in 9%. The most frequent disabling adverse effects of drug trials in these case patients were somnolence (n = 24), gastrointestinal complaints (n = 23), confusion (n = 16), dizziness (n =12), hallucinations (n = 5), and dry mouth (n = 5). CONCLUSIONS: Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.

Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease.

We evaluated whether patients with young-onset Parkinson's disease (PD) (onset between 21 and 40 years) develop levodopa-induced dyskinesias and motor response fluctuations more frequently and earlier than patients with older-onset PD (onset after 40 years) by determining the period from levodopa introduction to development of dyskinesias or fluctuations in 25 young-onset (mean age at onset, 33.54 years) and in 25 matched older-onset PD patients (mean age at onset, 55.76 years). Young-onset PD patients had significantly higher frequency for both dyskinesias and fluctuations after both 3 and 5 years of levodopa. Young-onset PD patients also developed both levodopa-induced dyskinesias and fluctuations earlier than older-onset PD patients. We suggest that the introduction of levodopa therapy in patients with young onset PD should be postponed as long as possible.

Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients.

Levels of the potent pro-inflammatory prostaglandin E(2) (PGE(2)) are elevated in postmortem spinal cords from patients with ALS, and inhibition of a key PGE(2)-synthesizing enzyme, cylcooxygenase-2, is neuroprotective in an in vitro model of ALS. The authors report that 82% of the patients with ALS studied had 2 to 10 times higher PGE(2) levels in CSF compared with normal control subjects. That affected areas of the CNS are inflamed in ALS supports this. CSF PGE(2) measurement may be useful in monitoring treatment for ALS.

Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiologic features.

We evaluated 11 patients with hemiparkinson-hemiatrophy syndrome, 6 with body and contralateral cerebral hemispheric hemiatrophy, 4 with only body hemiatrophy, and 1 with just brain hemiatrophy. The mean age of symptom onset was 38.1 years (range, 18 to 54) with 5.2 +/- 3.1 (mean +/- SD) years of illness until the last follow-up visit. The presenting symptom was unilateral tremor in 6 patients, hand dystonia in 2, bradykinesia in 2, and abnormal gait in 1 patient. Three patients had a good response to levodopa, 4 had moderate response, and 2 patients had a poor response. During a mean follow-up period of 1.7 years (range, 4 months to 5 years), the Hoehn and Yahr score changed in only 3 patients: 2 gained 1.5 points and 1 gained 3 points over 2.5 years. We discuss the association between hemiparkinsonism-body hemiatrophy and contralateral hemispheric hemiatrophy, and raise the possibility of early childhood brain insult with delayed-onset parkinsonism.

Freezing of gait in PD: prospective assessment in the DATATOP cohort.

OBJECTIVE: To study the development of freezing of gait in PD. BACKGROUND: Freezing of gait is a common, disabling, and poorly understood symptom in PD. METHODS: The authors analyzed data from 800 patients with early PD from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial who were assigned either placebo, deprenyl, tocopherol, or the combination of deprenyl and tocopherol. The primary outcome measure was the time from randomization until the freezing of gait score on the Unified Parkinson's Disease Rating Scale (UPDRS) became positive. RESULTS: Fifty-seven patients (7.1%) had freezing of gait at study entry and 193 (26%) of the remaining patients experienced the symptom by the end of the follow-up period. Those with freezing of gait at baseline had significantly more advanced disease than those without the symptom, as measured by total UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing freezing of gait during the follow-up period were the onset of PD with a gait disorder; higher scores of rigidity, postural instability, bradykinesia and speech; and longer disease duration. In contrast, tremor was strongly associated with a decreased risk for freezing of gait. At the end of follow-up, the signs most strongly associated with the freezing phenomenon were gait, balance, and speech disorders, not rigidity or bradykinesia. Deprenyl treatment was strongly associated with a decreased risk for developing freezing of gait; tocopherol had no effect. CONCLUSIONS: Freezing of gait is directly related to duration of PD. Risk factors at onset of disease are the absence of tremor and PD beginning as a gait disorder. The development of freezing of gait in the course of the illness is strongly associated with the development of balance and speech problems, less so with the worsening of bradykinesia, and is not associated with the progression of rigidity. These results support the concept that the freezing phenomenon is distinct from bradykinesia. Deprenyl, in the absence of L-dopa, was found to be an effective prophylactic treatment and should be considered for patients with PD who have an onset of gait difficulty.

Motor blocks in Parkinson's disease.

Freezing episodes and related phenomena (as a general term, motor blocks [MBs]) are poorly understood, particularly disabling, and a therapeutically frustrating problem in Parkinson's disease (PD). Epidemiologic and clinical characteristics of MBs, as well as risk factors to develop MBs, have never been fully addressed. Herein, we report our database survey on 990 PD patients, of whom 318 (32%) had MBs. The majority of MBs were linked to gait. Start hesitation occurred in 86%, blocking on turning in 45%, and blocking in narrow spaces in 25% of patients. Initial parkinsonian symptoms in the upper body and tremor as the initial motor symptom were less likely to be associated with the presence of MBs (odds ratios [OR] 0.6 and 0.7, respectively), while initial symptoms affecting gait or trunk had higher association with MBs (OR = 1.58). Longer disease duration, higher Hoehn and Yahr stage, and longer duration of levodopa treatment are all significantly associated with the presence of MBs. We observed significant association between the existence of MBs and levodopa-induced dyskinesias to suggest similar pathophysiology. We propose that MBs in PD are abnormal retrieval or execution of complex motor tasks that can occur as a result of disease progression or as short- or long-term side effects of levodopa treatment.

The effect of acute hemiplegia on intercostal muscle activity.

We recorded the EMG of parasternal intercostal muscles in 25 patients with flaccid hemiplegia during quiet spontaneous breathing, voluntary hyperventilation, and CO2-induced hyperventilation. The respiratory drive was abnormal on the hemiplegic side and the function of the intercostal muscles was affected specifically during voluntary hyperventilation.

Early differential diagnosis of Parkinson's disease with 18F-fluorodeoxyglucose and positron emission tomography.

Early-stage Parkinson's disease (EPD) is often clinically asymmetric. We used 18F-fluorodeoxyglucose (FDG) and PET to assess whether EPD can be detected by a characteristic pattern of regional metabolic asymmetry. To identify this pattern, we studied 10 EPD (Hoehn and Yahr stage I) patients (mean age 61.1 +/- 11.1 years) using 18F-FDG and PET to calculate regional metabolic rates for glucose. The scaled subprofile model (SSM) was applied to metabolic asymmetry measurements for the combined group of EPD patients and normal subjects to identify a specific covariation pattern that discriminated EPD patients from normal subjects. To determine whether this pattern could be used diagnostically, we studied a subsequent group of five presumptive EPD patients (mean age 50.9 +/- 18.3), five normal subjects (mean age 44.6 +/- 15.3), and nine patients with atypical drug-resistant early-stage parkinsonism (APD) (mean age 44.6 +/- 14.0). In each member of this prospective cohort, we calculated the expression of the EPD-related covariation pattern (subject scores) on a case-by-case basis. We also studied 11 of the EPD patients, five patients with APD, and 10 normal subjects with 18F-fluorodopa (FDOPA) and PET to measure presynaptic nigrostriatal dopaminergic function, and we assessed the accuracy of differential diagnosis with both PET methods using discrimination analysis. SSM analysis disclosed a significant topographic contrast profile characterized by covariate basal ganglia and thalamic asymmetries. Subject scores for this profile accurately discriminated EPD patients from normal subjects and APD patients (p < 0.0001). Group assignments into the normal or parkinsonian categories with FDG/PET were comparable to those achieved with FDOPA/PET, although APD and EPD patients were not differentiable by the latter method. Metabolic brain imaging with FDG/PET may be useful in the differential diagnosis of EPD.

Metabolic correlates of levodopa response in Parkinson's disease.

OBJECTIVE: To assess the effects of levodopa on resting-state brain metabolism in PD. BACKGROUND: In previous studies the authors used [18F] fluorodeoxyglucose (FDG) and PET to quantify regional metabolic abnormalities in PD. They found that this disease is characterized reproducibly by a specific abnormal PD-related pattern (PDRP). In this study the authors used IV levodopa infusion to quantify the effects of dopamine replacement on regional metabolism and PDRP network activity. They tested the hypothesis that clinical response to dopaminergic therapy correlates with these metabolic changes. METHODS: The authors used FDG/PET to measure resting-state regional brain metabolism in seven patients with PD (age, 59.4 +/- 4.2 years; Hoehn and Yahr stage, 1.9 +/- 0.7, mean +/- SD); subjects were scanned both off levodopa and during an individually titrated constant-rate IV levodopa infusion. The authors used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. They also quantified levodopa-induced changes in PDRP expression. Metabolic changes with levodopa correlated with clinical improvement as measured by changes in Unified PD Rating Scale (UPDRS) motor scores. RESULTS: Levodopa infusion improved UPDRS motor ratings (30.6% +/- 12.0%, p < 0.002) and significantly decreased regional glucose metabolism in the left putamen, right thalamus, bilateral cerebellum, and left primary motor cortex (p < 0.001). Changes in pallidal metabolism correlated significantly with clinical improvement in UPDRS motor ratings (p < 0.01). Levodopa infusion also resulted in a significant (p = 0.01) decline in PDRP expression. The changes in PDRP activity mediated by levodopa correlated significantly with clinical improvement in UPDRS motor ratings (r = -0.78, p < 0.04). CONCLUSION: Levodopa reduces brain metabolism in the putamen, thalamus, and cerebellum in patients with PD. Additionally, levodopa reduces PD-related pattern activity, and the degree of network suppression correlates with clinical improvement. The response to dopaminergic therapy in Patients with PD may be determined by the modulation of cortico-striato-pallido-thalamocortical pathways.