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.

Charcot: Past and present.

Jean-Martin Charcot (1825-1893) was the preeminent neurologist of the nineteenth century. Several of his major contributions remain fully relevant to contemporary neurology, and this essay highlights three areas of particular importance to the modern neurologist: the anatomo-clinical method that Charcot developed as the anchor of neurological study; the integration of new scientific discoveries from other fields as a core strategy for neurological advancement; and the role of heredity as the fundamental etiological focus to the understanding of the pathogenesis of primary neurological disorders. Further, Charcot left a strong tradition of visual skills as the core requirement for accurate neurological diagnosis and emphasized scientific humility in the face of difficult diseases. In spite of vast advances in neuroscience over the 20th and 21st centuries, the challenges faced by Charcot remain largely the same for the contemporary neurologist, and the lessons provided by Charcot retain their power and significance today.

Charcot, hysteria, and simulated disorders.

Jean-Martin Charcot (1825-1893) was the 19th-century's premier international neurologist. One of his areas of focused interest was the neurologic disorder, hysteria, a condition with distinctive neurologic signs, but no established structural lesions identified at autopsy. Charcot considered hysteria as a physiologic disorder that affected specific neuroanatomic areas of the brain comparable to the same areas that were damaged by structural neurologic disorders provoking the same or similar signs. He considered hysteria primarily a hereditary disorder, but environmental factors including physical and emotional stress served as provoking factors. Charcot drew the strict distinction between hysteria and consciously simulated neurologic disorders, although he was keenly aware that the two disorders could occur in the same patients or be difficult to distinguish at times. He developed specific experimental techniques to separate hysteria from simulation. His studies of hysteria and simulation offer a basis for studies of functional neurologic disorders applicable to the 21st century.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

BACKGROUND AND PURPOSE: The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. METHODS: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. RESULTS: The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. CONCLUSIONS: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

Continuous in-home monitoring of essential tremor.

BACKGROUND: Essential tremor (ET) is typically measured in the clinic with subjective tremor rating scales which require the presence of a clinician for scoring and are not appropriate for measuring severity throughout the day. Motion sensors can accurately rate tremor severity during a set of predefined tasks in a laboratory. METHODS: We evaluated the ability of motion sensors to quantify tremor during unconstrained activities at home. 20 ET subjects wore a wireless sensor continuously for up to 10 h daily on two days and completed hourly standardized tremor assessments involving pre-defined tasks. Mathematical models were used to predict tremor rating scores from the sensor data. RESULTS: At home tremor scores from hourly standardized assessments correlated with at home tremor scores estimated during unconstrained activities immediately following the standardized assessments. The hourly standardized assessments did not significantly fluctuate throughout the day, while fluctuations in the continuous assessments tended to follow changes in voluntary activity level. Both types of tremor ratings (standardized and continuous) showed high day-to-day test-retest reliability with intraclass correlation coefficients ranging from 0.67 to 0.90 for continuous ratings and 0.77 to 0.95 for standardized ratings. CONCLUSIONS: Results demonstrate the feasibility of continuous monitoring of tremor severity at home, which should provide clinicians with a measure of the temporal pattern of tremor in the context of daily life and serve as a useful tool for the evaluation of novel anti-tremor medications in clinical trials.

Historical underpinnings of the term essential tremor in the late 19th century.

BACKGROUND: The term essential tremor has been in regular use since the second half of the 20th century. To modern neurologists, the word "essential" may seem cryptic. The historical underpinnings of this term have not been examined. OBJECTIVES: To bring to attention early medical reports using the term essential tremor and examine the characteristics of the disorder that contributed to the proposed use of the term. METHODS: Review of 19th and early 20th century medical literature on essential tremor. RESULTS: The term tremore semplice essenziale (simple essential tremor) was first used by Burresi (Italy, 1874) to describe an 18-year-old man with severe, isolated action tremor. Several years later, Maragliano (Italy, 1879), Nagy (Austria, 1890), and Raymond (France, 1892) described similar cases and proposed the terms tremore essenziale congenito (essential congenital tremor), essentieller Tremor (essential tremor), and tremblement essentiel héréditaire (hereditary essential tremor) to define the illness. Mirroring contemporaneous views of constitutional and inherited disease, the key ingredients of the disorder were viewed as the constant presence of tremor in the absence of other neurologic signs and its heritable nature. By the early 20th century, the term began to appear in the medical literature with greater frequency. CONCLUSIONS: Toward the end of the 19th century, several clinicians attempted to provide a nosologic separation for a tremor diathesis that was often familial and occurred in isolation of other neurologic signs. This disorder, which was termed essential tremor, was later recognized as one of the most common neurologic disorders.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged >or=50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers.

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

What's new? Clinical progression and staging of Parkinson's disease.

Several new advances facilitate current understanding of the progression of Parkinson's disease. The application of statistical modeling techniques has helped to estimate rates of clinical decline in the context of symptomatic interventions. These approaches may allow a new means for testing neuroprotection effects even when patients are on dopaminergic treatment. Further, the development of new rating scales, specifically the Movement Disorder Society-initiated revision of the Unified Parkinson's Disease Rating Scale has capitalized on a greater clinical appreciation of non-motor elements of Parkinson's disease. Finally, adaptations of new technologies that are computer-based and enable data transmission from at-home environments allow researchers to capture disease impairment and disability with potentially greater precision and much more frequently than permissible in a hospital clinic or practice setting.

Safety of rasagiline in elderly patients with Parkinson disease.

The authors examined age effects on adverse events from two randomized, controlled trials of rasagiline, comparing younger (younger than 70 years) and older (70 years and older) subjects. Older patients were more prone to serious adverse effects than younger patients, but there was no statistical interaction between age and rasagiline exposure. This absence of an age-rasagiline interaction suggests that rasagiline does not require special safety precautions for elderly subjects with Parkinson disease.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Altered cortical visual processing in PD with hallucinations: an fMRI study.

OBJECTIVE: To compare fMRI activation during two visual stimulation paradigms in Parkinson disease (PD) subjects with chronic visual hallucinations vs PD patients who had never hallucinated. METHODS: Twelve pairs of PD subjects, matched for age, PD duration, and dopaminergic drug exposure duration, participated in this study. The authors examined group differences in activation during stroboscopic (flashing) vs no visual stimulation and kinematic (apparent motion) vs stationary visual stimulation. RESULTS: During stroboscopic stimulation, non-hallucinating PD subjects showed significantly greater activation in the parietal lobe and cingulate gyrus compared to hallucinating PD subjects. In contrast, the hallucinating subjects showed significantly greater activation in the inferior frontal gyrus and the caudate nucleus. During kinematic stimulation, non-hallucinating PD subjects showed significantly greater activation in area V5/MT, parietal lobe, and cingulate gyrus compared to hallucinating PD subjects. Hallucinating PD subjects showed significantly greater activation in the superior frontal gyrus. CONCLUSIONS: PD patients with chronic visual hallucinations respond to visual stimuli with greater frontal and subcortical activation and less visual cortical activation than non-hallucinating PD subjects. Shifting visual circuitry from posterior to anterior regions associated primarily with attention processes suggests altered network organization may play a role in the pathophysiology of visual hallucinations in PD.

Apolipoprotein E controls the risk and age at onset of Parkinson disease.

BACKGROUND: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. OBJECTIVE: To investigate APOE's role in PD using family-based association analyses. METHODS: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. RESULTS: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a negative association of APOE-4 (p = 0.015) with age at onset in PD. CONCLUSIONS: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

Objective assessments of longitudinal outcome in Gilles de la Tourette's syndrome.

OBJECTIVE: To define the long-term outcome in Gilles de la Tourette syndrome (GTS) using objective rating measures. BACKGROUND: Previous historical studies suggest spontaneous improvement of tic symptoms after adolescence, but objective longitudinal data are limited. METHODS: The authors reviewed all videotapes in their database (1978 through 1991) of children with GTS (ages 8 to 14) who were seen in their tertiary care movement disorder center and underwent a standardized 5-minute filming protocol (n = 56). Through multiple contact methods, they successfully located 36 of these patients, who are now adults (age >20 years), and recruited 31 (28 men and 3 women) to volunteer for a second videotape and in-person assessment. A blinded rater evaluated the 62 tapes and rated five tic domains: body areas involved, motor and phonic tic frequency, and motor and phonic tic severity. Using standardized GTS videotape rating scale and Wilcoxon signed-rank tests with Bonferroni correction for multiple comparisons, the authors compared the two videotapes for each tic domain as well as the composite tic disability score. RESULTS: Ninety percent of adult patients still had tics. Adult patients who considered themselves tic-free were often inaccurate in their self-assessment: 50% had objective evidence of tics. Mean objective tic disability diminished in comparison to childhood (mean composite tic disability score childhood 9.58 vs adulthood 7.52, p = 0.014). All domains improved by adulthood, and significant improvements occurred in motor tic severity (p = 0.008). The improvements in tic disability did not relate to medication use, as only 13% of adults received medications for tics, compared with 81% of children. CONCLUSIONS: In GTS syndrome, tics objectively improve over time but most adults have persistent tics.

Longitudinal outcome of Parkinson's disease patients with psychosis.

OBJECTIVES: To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved. METHODS: Baseline data available from 59 patients enrolled in the PSYCLOPS (PSychosis and CLOzapine in PD Study) trial included age, age at onset of PD, duration of PD and psychosis, character of psychosis, medications, living setting, and scores for Mini-Mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale, Hoehn and Yahr Scale, and Clinical Global Impression Scale. Longitudinal data were collected 26 months later regarding four outcomes: death, nursing home placement, diagnosis of dementia, and persistence of psychosis. Logistic regression was used to explore whether any baseline characteristics were associated with an increased likelihood of one of these outcomes. RESULTS: At baseline, 56% of patients had an MMSE score of <25, 12% were in a nursing home, 95% had hallucinations, and 60% had paranoia. On follow-up, 25% were dead, nursing home placement occurred in 42%, psychosis was persistent in 69%, and dementia was diagnosed in 68%. Select baseline characteristics predicted individual outcomes: Nursing home placement was associated with the presence of paranoia and older age; persistent psychosis was associated with younger age at onset of PD and longer disease duration; dementia was associated with older age at PD onset and lower initial MMSE score; no characteristics predicted death. Whether psychosis persisted or not had no significant effect on the development of the other three outcomes. The prevalence of hallucinations at follow-up was not different between groups currently receiving antipsychotics vs those on no treatment. CONCLUSIONS: Psychosis in PD requiring antipsychotic therapy is frequently associated with death, nursing home placement, development and progression of dementia, and persistence of psychosis. Still, it appears the prognosis has improved with atypical antipsychotic therapy based on the finding that 28% of NH patients died within 2 years compared with 100% in a previous study done prior to availability of this treatment.

[Progressive supranuclear palsy]. / La paralysie supranucléaire progressive.

Progressive supranuclear palsy (PSP) is a parkinsonian syndrome 20 to 30 times less common than Parkinson's disease. PSP and Parkinson's disease share certain symptoms, but also present distinctive features. The histopathological features of PSP are highly specific and enable certain diagnosis. Since no biological marker has been identified, clinical signs must be recognized to establish the probability of the histopathological diagnosis. The NINDS program distinguishes two categories: probable PSP and possible PSP with distinctive characteristics. The sensitivity of probable PSP is only 50 p. 100, but the specificity and positive predictive value are 100 p. cent. For possible PSP, specificity is 83 p. cent (93 p. cent if diagnostic errors are included) and the positive predictive value is lower (83 p. cent). Although there number is smaller, patients with probable PSP are retained for research on new treatments. There have been few, non-controlled therapeutic trials in PSP. No drug and no surgical procedure has been demonstrated to be highly effective. Neuroprotection is a new avenue of research which requires knowledge of the natural course of clinical incapacity. A longitudinal study of 50 patients with probable PSP has provided mid-term results on symptom onset and on the development of three key signs, detected with the standard Unified Parkinson's Disease Rating Scale: incapacity to stand alone without help, incapacity to speak intelligently, incapacity to eat (tube feeding). The Kaplan-Meier curves show that the mean duration of the disease before development of one of these signs is 50 months. Research on protocols designed to stop disease progression should be centered on this period.

Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).

Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.