For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein-mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease.Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free.Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease-free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex-adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM-100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan-Meier 5-year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages.Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages.
Parkinson disease dementia dramatically increases mortality rates, patient expenditures, hospitalization risk, and caregiver burden. Currently, predicting Parkinson disease dementia risk is difficult, particularly in an office-based setting, without extensive biomarker testing.
Objective
To appraise the predictive validity of the Montreal Parkinson Risk of Dementia Scale, an office-based screening tool consisting of 8 items that are simply assessed.
Design, Setting, and Participants
This multicenter study (Montreal, Canada; Tottori, Japan; and Parkinson Progression Markers Initiative sites) used 4 diverse Parkinson disease cohorts with a prospective 4.4-year follow-up. A total of 717 patients with Parkinson disease were recruited between May 2005 and June 2016. Of these, 607 were dementia-free at baseline and followed-up for 1 year or more and so were included. The association of individual baseline scale variables with eventual dementia risk was calculated. Participants were then randomly split into cohorts to investigate weighting and determine the scale's optimal cutoff point. Receiver operating characteristic curves were calculated and correlations with selected biomarkers were investigated.
Main Outcomes and Measures
Dementia, as defined by Movement Disorder Society level I criteria.
Results
Of the 607 patients (mean [SD] age, 63.4 [10.1]; 376 men [62%]), 70 (11.5%) converted to dementia. All 8 items of the Montreal Parkinson Risk of Dementia Scale independently predicted dementia development at the 5% significance level. The annual conversion rate to dementia in the high-risk group (score, >5) was 14.9% compared with 5.8% in the intermediate group (score, 4-5) and 0.6% in the low-risk group (score, 0-3). The weighting procedure conferred no significant advantage. Overall predictive validity by the area under the receiver operating characteristic curve was 0.877 (95% CI, 0.829-0.924) across all cohorts. A cutoff of 4 or greater yielded a sensitivity of 77.1% (95% CI, 65.6-86.3) and a specificity of 87.2% (95% CI, 84.1-89.9), with a positive predictive value (as of 4.4 years) of 43.90% (95% CI, 37.76-50.24) and a negative predictive value of 96.70% (95% CI, 95.01-97.85). Positive and negative likelihood ratios were 5.94 (95% CI, 4.08-8.65) and 0.26 (95% CI, 0.17-0.40), respectively. Scale results correlated with markers of Alzheimer pathology and neuropsychological test results.
Conclusions and Relevance
Despite its simplicity, the Montreal Parkinson Risk of Dementia Scale demonstrated predictive validity equal or greater to previously described algorithms using biomarker assessments. Future studies using head-to-head comparisons or refinement of weighting would be of interest.
This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.
Abstract PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA . Since GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy, we examined the role of PSAP mutations in iRBD. We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP , in three iRBD patients and none in controls (uncorrected p =0.018). Two variants were stop mutations, p.Gln260Ter p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria was 98% or more. These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA , which requires additional studies.
Background: Idiopathic REM sleep behavior disorder (RBD) is characterized by loss of atonia during REM sleep, resulting in motor activity during dreams. Studies estimate that approximately half of patients with RBD will eventually develop Parkinson disease (PD), so RBD may be an indicator of presymptomatic PD. Several potential early diagnostic markers of PD have been proposed, but they have generally not been tested in presymptomatic PD. The authors hypothesized that these markers may be abnormal in idiopathic RBD. Methods: The authors compared 25 patients with polysomnography-confirmed RBD without PD with age- and sex-matched controls. Color vision, olfaction, quantitative motor testing, and indices of depression, personality, and autonomic function were examined. Results: Patients demonstrated significant impairment in color discrimination and olfactory function. Patients had subtle abnormalities on quantitative testing of motor and gait speed. Autonomic symptoms were more common in patients than controls. Abnormalities were heterogeneous, with some patients scoring normally on all domains, whereas others were severely impaired on multiple domains. Dysfunction on tests of olfactory function, color vision, and motor speed were highly correlated, such that patients who performed poorly on one test tended to perform poorly on the others. Conclusions: Many potential early markers of Parkinson disease are significantly abnormal in idiopathic REM sleep behavior disorder. These abnormalities are present in approximately half of the patients, suggesting a heterogenous pathophysiology.
Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
Earlier detection of parkinsonism, specifically during its prodromal stage, may be key to preventing its progression. Previous studies have produced contradictory results on the association between sleep symptoms and prodromal parkinsonism.We conducted a prospective study within the Canadian Longitudinal Study on Aging (CLSA) to determine whether self-reported symptoms of insomnia, somnolence, apnea, and restless legs syndrome predate the diagnosis of parkinsonism after three years of follow-up.At baseline, amongst other information, participants completed a questionnaire for difficulty initiating or maintaining sleep, daytime somnolence, snoring or stopping breathing during sleep, and symptoms of restless legs syndrome. After 3 years of follow-up, baseline responses from participants who self-reported a new diagnosis of parkinsonism (cases) were compared to those who did not (controls). For each case, 10 controls were individually matched by age, sex, education, BMI, caffeine, smoking, and alcohol. Binary unconditional logistic regression models were used to estimate the association between sleep symptoms and new-onset parkinsonism, adjusting for age, sex, education, BMI, smoking, alcohol, and caffeine.We identified 58 incident-parkinsonism cases and 580 matched controls (65.5%male, mean age = 69.60, SD = 8.0). Baseline symptoms of sleep-onset insomnia (12.1%vs. 13.0%, Adjusted OR[95%CI] = 0.87[0.32,2.33]), sleep-maintenance insomnia (24.1%vs. 20.2%, AOR = 1.01[0.46,2.20]), daytime somnolence (8.6%vs. 7.4%, AOR = 1.11[0.37,3.39]), obstructive sleep apnea (27.3%vs. 26.2%, AOR = 0.84[0.40,1.79]), and restless leg syndrome (20.6%vs. 9.9%, AOR = 1.34[0.42,4.25]) were similar among those who developed parkinsonism and those who did not.Symptoms of insomnia, somnolence, apnea, and restless legs did not predate a new diagnosis of parkinsonism over 3 years.
Atypical antipsychotics often cause parkinsonian symptoms. In some cases,1 the drug-induced parkinsonism (DIP) may resolve, only to have Parkinson's disease (PD) develop some time later, suggesting that the medication unmasked compensated subclinical dysfunction.2 This is consistent with dopaminergic neuroimaging studies in early PD, that suggest the existence of compensatory mechanisms for subtle substantia nigra denervation; however, the duration of the prodromal compensatory period is unclear. We identified an individual with defined prodromal PD, who developed transient DIP on atypical antipsychotics, finally developing idiopathic Parkinson's disease (iPD) after a 12-year lag. A 61-year-old man presented with dream-enacting behaviors for 11 years. Polysomnography diagnosed REM sleep behavior disorder (RBD). At baseline visit, he also had orthostatic hypotension (40 mm Hg drop), depressed mood, and hyposmia; however, motor testing was normal (Unified Parkinson Disease Rating Scale Part III = 2). At baseline, he met MDS criteria for prodromal PD, with total LR = 1146, and probability = 93.6%.3 Of note, the MDS prodromal research criteria has been developed recently in 2015 and was retrospectively applied on his baseline clinical data. After baseline visit, an outside physician prescribed him olanzapine 5 mg at bedtime for his depressive symptoms. The following year, we observed clear DIP with a total UPDRS-III of 20, sufficient to meet MDS parkinsonism criteria. Parkinsonism was clearly symmetric, both on UPDRS and quantitative motor testing, with no rest tremor. We suggested stopping olanzapine immediately; however, it was only reduced to 2.5 mg. The following year, UPDRS-III was 11, and we again suggested stopping olanzapine completely. After drug discontinuation, DIP completely resolved, and UPDRS-III score ranged from 1 to 6 in each yearly follow-up, for 10 years (Fig. 1). Over the following 10 years, additional erectile dysfunction, constipation, and urinary dysfunction developed and olfaction and orthostatic hypotension worsened. On the 13th annual follow-up examination, his motor state deteriorated with a UPDRS-III score of 18 (Fig. 1). This time, his motor symptoms were asymmetrical (asymmetry index = 0.58 > 0.3)4 with right-side dominance. This case is noteworthy as most published estimates of the time interval between DIP and iPD average 2 to 3 years,5 however, we found a lag time of 12 years, even with a relatively low dose of a low-potency dopamine-blocker. Although it is possible that this could have been a coincidental association of unrelated events, we feel it unlikely. First, despite normal motor state he already met criteria for prodromal PD, because of documented RBD, hyposmia, and orthostatic hypotension (a diagnosis proved correct by his eventual conversion). Second, he was relatively young at the time of prescription (i.e., 62 years) and had persistent parkinsonism even on the lowest available dose (2.5 mg per day) of a relatively atypical neuroleptic. Even in a patient for whom there was no prior documentation of idiopathic RBD, it can be argued that development of parkinsonism on such a low-dose atypical neuroleptic deserves evaluation for potential prodromal PD. This case suggests that the prodromal motor state in some cases of PD can be very long and progression very slow. To our knowledge, there is only one previously-published case of a similarly long prodromal motor interval, based upon video analysis of English soccer player Ray Kennedy, which found a 10 to 14 year interval.6 Early subtle motor disturbances, autonomic dysfunction that presented as excessive perspiration and accompanying feelings of heat, and fatigue were the prodromal features found that case.6 Therefore, it appears that the motor prodromal interval of PD can be longer than average estimates from previous work.7 We acknowledge the limitation of having no access to DaT-scan at the time when DIP was developed in our patient, as DaT-scan can differentiate DIP from iPD. In patients with suspicious DIP, an abnormal DaT-scan may reflect prodromal PD unmasked by the anti-dopaminergic drugs rather than true DIP.8 In patients with prodromal disease and early asymptomatic dopaminergic loss, even low-dose antipsychotics can impair compensatory mechanisms and allow sufficient denervation for motor signs to appear.9 Dopamine antagonists should be used with extreme caution in individuals with high likelihood of prodromal PD, such as patients with idiopathic RBD. 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. S.M.F: 1A, 1B, 1C, 3A, 3B B.K.D.: 1A, 1B, 1C, 3A, 3B A.P.: 1B, 1C, 3B J.Y.M.: 1B, 1C, 3B R.B.P.: 1A, 1B, 1C, 3A, 3B We would like to thank the patient and his family for their patience, cooperation, and permission. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Furthermore, the case has provided a written informed consent. Funding Sources and Conflicts of Interest: The authors report no funding sources for this study and have no conflicts of interest. Financial disclosure for the previous 12 months: S.M. Fereshtehnejad reports the following disclosures: employment with McGill University (Montreal, QC, Canada); grants from Canada First Research Excellence Fund for the Healthy Brains for Healthy Lives (HBHL) Initiative postdoctoral fellowship, Richard and Edith Strauss postdoctoral fellowship (McGill University), Preston Robb fellowship (Montreal Neurological Institute). B.K. Dawson has no disclosures to report. A. Pelletier reports the following disclosures: employment with Research Institute of the McGill University Health Centre (Montreal, QC, Canada). J.Y. Montplaisir reports the following disclosures: employment with Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal and Department of Psychiatry, Université de Montréal (Montreal, QC, Canada); grants from GSK, Merck; honoraria from Valeant, Otsuka Pharmaceutical; advisory board of Sanofi-Aventis, Servier, Merck, Jazz Pharmaceutical, Valeant Pharmaceutical, Impax Laboratory. R.B. Postuma reports the following disclosures: employment with Department of Neurology, Montreal General Hospital (Montreal, QC, Canada); grants from Fonds de la Recherche en Sante Quebec, the Canadian Institute of Health Research, the Parkinson Society of Canada, the Weston-Garfield Foundation, the Michael J. Fox Foundation, and the Webster Foundation; honoraria from Novartis Canada, Teva Neurosciences; and consultancies for Biotie, Roche.
Individuals with Parkinson’s disease present with a complex clinical phenotype, encompassing sleep, motor, cognitive, and affective disturbances. However, characterizations of PD are typically made for the “average” patient, ignoring patient heterogeneity and obscuring important individual differences. Modern large-scale data sharing efforts provide a unique opportunity to precisely investigate individual patient characteristics, but there exists no analytic framework for comprehensively integrating data modalities. Here we apply an unsupervised learning method—similarity network fusion—to objectively integrate MRI morphometry, dopamine active transporter binding, protein assays, and clinical measurements from n = 186 individuals with de novo Parkinson’s disease from the Parkinson’s Progression Markers Initiative. We show that multimodal fusion captures inter-dependencies among data modalities that would otherwise be overlooked by field standard techniques like data concatenation. We then examine how patient subgroups derived from fused data map onto clinical phenotypes, and how neuroimaging data is critical to this delineation. Finally, we identify a compact set of phenotypic axes that span the patient population, demonstrating that this continuous, low-dimensional projection of individual patients presents a more parsimonious representation of heterogeneity in the sample compared to discrete biotypes. Altogether, these findings showcase the potential of similarity network fusion for combining multimodal data in heterogeneous patient populations.
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