Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease.
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SUBMITTER: De Pablo-Fernandez E
PROVIDER: S-EPMC6459129 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Project description:A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD).One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined.Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30).CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target ?-synuclein, tau, or amyloid ? could potentially improve cognitive performance in PD.
| S-EPMC3484250 | biostudies-literature
Project description:ObjectivesBased on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones.MethodsProspective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality.ResultsLCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60).InterpretationPsychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes.
| S-EPMC7448190 | biostudies-literature
Project description:Background and purposePeople with Parkinson disease (PD) present phenotypes that are characterized as tremor-dominant (TD) or postural instability/gait difficulty (PIGD) subtypes. Differentiation of subtypes allows clinicians to predict disease course and adjust treatment. We examined whether brief mobility and balance measures can discriminate PIGD from TD phenotypes.MethodsWe performed a cross-sectional study with individuals with PD (n = 104). Blinded raters assessed participants with the Unified Parkinson's Disease Rating Scale (UPDRS) or Movement Disorders Society revision (MDS-UPDRS), and balance assessments: 360° turn test, one-leg stance, a reactive postural control test, and tandem walk. Participants were classified as PIGD or TD based on the UPDRS or MDS-UPDRS assessment results. Differences in balance variables between subtypes were assessed with univariate analyses. Receiver operating characteristic (ROC) curve analyses were performed to investigate the ability of balance variables to differentiate PD subtypes.ResultsNo differences between subtypes were observed for tandem walk or reactive postural control. Participants with PIGD performed worse on number of steps and time to complete the 360° turn test and on one-leg stance time. ROC curves showed only the 360° turn test discriminated PIGD from TD with high specificity (0.84). Post hoc analyses revealed that the 360° turn test is the most discriminatory for classifying PD subtypes in early stages of the disease. ROC analyses based on combined models including both the 360° test and tandem walk test performance increased the specificity to 0.97.Discussion and conclusionsThe 360° turn test requires minimal time to administer and may be useful in mild-moderate PD for distinguishing PIGD from TD subtypes.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A295).
| S-EPMC6991154 | biostudies-literature
Project description:ObjectiveTo examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes.MethodsWe recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages.ResultsAll three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages.InterpretationParkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.
| S-EPMC8351397 | biostudies-literature
Project description:ObjectiveThe aim of this work was to investigate marker profiles for proposed anxiety subtypes in Parkinson disease (PD).MethodsWe used the persistent anxiety, episodic anxiety, and avoidance behavior subscales of the Parkinson Anxiety Scale as dependent variables in multivariable linear regression analyses using a cross-sectional data set of 311 patients with PD. Independent variables consisted of a range of demographic, psychiatric, and disease-specific markers.ResultsIn the most parsimonious model of persistent anxiety, higher Hamilton Depression Rating Scale scores, a history of anxiety, fewer years of education, lower Mini-Mental State Examination scores, lower Lawton Instrumental Activities of Daily Living scores, female sex, and complications of therapy (higher Unified Parkinson Disease Rating Scale part IV scores) were all associated with more severe persistent anxiety. Markers associated with more severe episodic anxiety included PD-specific disturbances of activities of daily living, complications of therapy, higher Hamilton Depression Rating Scale scores, female sex, and a history of anxiety. Finally, higher Hamilton Depression Rating Scale scores, a history of anxiety, complications of therapy, and longer disease duration were associated with avoidance behavior. After excluding clinically depressed patients with PD, disease severity and longer disease duration were significantly associated with episodic anxiety, but not with persistent anxiety.ConclusionPersistent anxiety is mainly influenced by nonspecific markers, while episodic anxiety seems to be more PD-specific compared to persistent anxiety and may be more situational or contextual. These results provide support for possible distinct underlying constructs for anxiety subtypes in PD.
| S-EPMC5903060 | biostudies-literature
Project description:The biological underpinnings of the PD clusters remain unknown as the existing PD clusters lacks biomarker characterization. We try to identify clinical subtypes of Parkinson Disease (PD) in an Asian cohort and characterize them by comparing clinical assessments, genetic status and blood biochemical markers. A total of 206 PD patients were included from a multi-centre Asian cohort. Hierarchical clustering was performed to generate PD subtypes. Clinical and biological characterization of the subtypes were performed by comparing clinical assessments, allelic distributions of Asian related PD gene (SNCA, LRRK2, Park16, ITPKB, SV2C) and blood biochemical markers. Hierarchical clustering method identified three clusters: cluster A (severe subtype in motor, non-motor and cognitive domains), cluster B (intermediate subtype with cognitive impairment and mild non-motor symptoms) and cluster C (mild subtype and young age of onset). The three clusters had significantly different allele frequencies in two SNPs (Park16 rs6679073 A allele carriers in cluster A B C: 67%, 74%, 89%, p = 0.015; SV2C rs246814 T allele distribution: 7%, 12%, 25%, p = 0.026). Serum homocysteine (Hcy) and C-reactive protein (CRP) levels were also significantly different among three clusters (Mean levels of Hcy and CRP among cluster A B C were: 19.4 ± 4.2, 18.4 ± 5.7, 15.6 ± 5.6, adjusted p = 0.005; 2.5 ± 5.0, 1.5 ± 2.4, 0.9 ± 2.1, adjusted p < 0.0001, respectively). Of the 3 subtypes identified amongst early PD patients, the severe subtype was associated with significantly lower frequency of Park16 and SV2C alleles and higher levels of Hcy and CRP. These biomarkers may be useful to stratify PD subtypes and identify more severe subtypes.
| S-EPMC9424224 | biostudies-literature
Project description:ObjectiveTo assess differences in gray matter (GM) atrophy between 2 Parkinson disease (PD) subtypes: the tremor dominant (TD) subtype and the postural instability gait difficulty (PIGD) subtype.MethodsPatients were classified as belonging to the predominately PIGD (n = 30) or predominately TD (n = 29) subtype. Voxel-based morphometry was used to compare GM in these 2 subtypes and to evaluate correlations between predefined regions of interest and the degree of symptoms. In the regions where GM atrophy was associated with symptoms, the relationship between GM volumes and functional connectivity was examined.ResultsGM was reduced in the predominately PIGD group, compared with the predominately TD group, in areas that involve motor, cognitive, limbic, and associative functions (p < 0.05, false discovery rate corrected). Lower GM volumes in the pre-supplementary motor area (SMA) and in the primary motor area were associated with increased severity of PIGD symptoms (r = -0.42, p < 0.001; r = -0.38, p < 0.003, respectively). Higher GM volumes within the pre-SMA were associated with stronger functional connectivity between the pre-SMA and the putamen (r = 0.415, p < 0.025) in the patients with predominately PIGD.ConclusionsIn patients with PD, PIGD symptoms are apparently associated with GM atrophy in motor-related regions and decreased functional connectivity. GM degeneration and a related decrease in spontaneous coactivation between cortical and subcortical motor-planning areas may partially account for the unique clinical characteristics of a subset of patients with PD.
| S-EPMC3662357 | biostudies-literature
Project description:ImportanceCorticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD.ObjectiveTo investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes.Design, setting, and participantsIn this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings.Main outcomes and measuresDemographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation.ResultsIn total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n?=?163), lower in typical AD (10 [5-16]; n?=?937), and lowest in limbic predominant AD (8 [5-11], n?=?163) (P?<?.001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n?=?148), higher in typical AD (25 [19-30]; n?=?727), and highest in limbic predominant AD (26 [19-32]; n?=?127) (P?=?.002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (?, -1.5; 95% CI, -2.9 to -0.15; P?=?.03) and typical AD (?, -3.2; 95% CI, -3.9 to -2.4; P?<?.001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (?, 2.5; 95% CI, 1.4-3.5; P?<?.001), apolipoprotein E ?4 allele (?, 1.3; 95% CI, 0.15-2.5; P?=?.03), and lower Mini-Mental State Examination scores (?, -1.8; 95% CI, -3.2 to -0.31; P?=?.02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases.Conclusions and relevanceThese data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.
| S-EPMC6820048 | biostudies-literature
Project description:ObjectiveTo elucidate whether Parkinson's disease (PD) subtypes show a differential pattern of FP-CIT-SPECT binding during the disease course.MethodsWe examined 27 patients (10 female, 17 male, mean age 61.68±11.24 years, 14 tremordominant, 13 akinetic-rigid) with [(123)I]FP-CIT-SPECT and clinical ratings including UPDRS III after at baseline and after a mean period of 2.47 years. Patients had been classified at baseline as tremordominant or akinetic-rigid according to a "tremor score" and "non-tremor score". These subgroups were compared for differences in disease progression. Means of clinical ratings and the quantitative analyses of FP-CIT-SPECT for ipsi- and contralateral putamen and caudate nucleus were calculated and compared between baseline and follow-up.ResultsThere were no statistical differences concerning age, disease duration, L-Dopa equivalent dose, disease severity (UPDRS III) or dopaminergic uptake in FP-CIT-SPECT at baseline between both subgroups. At follow-up, akinetic-rigid patients showed a distinct and statistically significant reduction of the dopaminergic uptake associated with significant progression of the clinical symptoms (UPDRS III). In contrast, in tremor patients the aggravation of clinical symptoms and dopaminergic deficit was less pronounced without statistical significance among assessments.ConclusionsThis study shows for the first time a considerable progression of clinical symptoms and in-vivo dopaminergic deficit of akinetic-rigid compared to tremordominant PD patients over time. Our data may help to improve strategic planning of further therapeutic trials and to provide a clearer prognosis for patients regarding the perspective of their disease.
| S-EPMC3466171 | biostudies-literature
Project description:BackgroundWithin Parkinson's there is a spectrum of clinical features at presentation which may represent sub-types of the disease. However there is no widely accepted consensus of how best to group patients.ObjectiveUse a data-driven approach to unravel any heterogeneity in the Parkinson's phenotype in a well-characterised, population-based incidence cohort.Methods769 consecutive patients, with mean disease duration of 1.3 years, were assessed using a broad range of motor, cognitive and non-motor metrics. Multiple imputation was carried out using the chained equations approach to deal with missing data. We used an exploratory and then a confirmatory factor analysis to determine suitable domains to include within our cluster analysis. K-means cluster analysis of the factor scores and all the variables not loading into a factor was used to determine phenotypic subgroups.ResultsOur factor analysis found three important factors that were characterised by: psychological well-being features; non-tremor motor features, such as posture and rigidity; and cognitive features. Our subsequent five cluster model identified groups characterised by (1) mild motor and non-motor disease (25.4%), (2) poor posture and cognition (23.3%), (3) severe tremor (20.8%), (4) poor psychological well-being, RBD and sleep (18.9%), and (5) severe motor and non-motor disease with poor psychological well-being (11.7%).ConclusionOur approach identified several Parkinson's phenotypic sub-groups driven by largely dopaminergic-resistant features (RBD, impaired cognition and posture, poor psychological well-being) that, in addition to dopaminergic-responsive motor features may be important for studying the aetiology, progression, and medication response of early Parkinson's.
| S-EPMC4923737 | biostudies-literature