Latent Cognitive Phenotypes in De Novo Parkinson’s Disease: A Person-Centered Approach

AbstractObjectives: Cognitive impairment is an important aspect of Parkinson’s disease (PD), but there is considerable heterogeneity in its presentation. This investigation aims to identify and characterize latent cognitive phenotypes in early PD. Methods: Latent class analysis, a data-driven, person-centered, cluster analysis was performed on cognitive data from the Parkinson’s Progressive Markers Initiative baseline visit. This analytic method facilitates identification of naturally occurring endophenotypes. Resulting classes were compared across biomarker, symptom, and demographic data. Results: Six cognitive phenotypes were identified. Three demonstrated consistent performance across indicators, representing poor (“Weak-Overall”), average (“Typical-Overall”), and strong (“Strong-Overall”) cognition. The remaining classes demonstrated unique patterns of cognition, characterized by “Strong-Memory,” “Weak-Visuospatial,” and “Amnestic” profiles. The Amnestic class evidenced greater tremor severity and anosmia, but was unassociated with biomarkers linked with Alzheimer’s disease. The Weak-Overall class was older and reported more non-motor features associated with cognitive decline, including anxiety, depression, autonomic dysfunction, anosmia, and REM sleep behaviors. The Strong-Overall class was younger, more female, and reported less dysautonomia and anosmia. Classes were unrelated to disease duration, functional independence, or available biomarkers. Conclusions: Latent cognitive phenotypes with focal patterns of impairment were observed in recently diagnosed individuals with PD. Cognitive profiles were found to be independent of traditional biomarkers and motoric indices of disease progression. Only globally impaired class was associated with previously reported indicators of cognitive decline, suggesting this group may drive the effects reported in studies using variable-based analysis. Longitudinal and neuroanatomical characterization of classes will yield further insight into the evolution of cognitive change in the disease. (JINS, 2017, 23, 551–563)

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Cognitive Decline in Parkinson’s Disease: A Subgroup of Extreme Decliners Revealed by a Data-Driven Analysis of Longitudinal Progression

Frontiers in Psychology ◽

10.3389/fpsyg.2021.729755 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sara Andersson ◽

Maria Josefsson ◽

Lars J. Stiernman ◽

Anna Rieckmann

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Cognitive Performance ◽

Latent Class ◽

Cognitive Change ◽

Csf Biomarkers ◽

Latent Classes ◽

Motor Symptoms ◽

Progression Marker

Cognitive impairment is an important symptom of Parkinson’s disease (PD) and predicting future cognitive decline is crucial for clinical practice. Here, we aim to identify latent sub-groups of longitudinal trajectories of cognitive change in PD patients, and explore predictors of differences in cognitive change. Longitudinal cognitive performance data from 349 newly diagnosed PD patients and 145 healthy controls from the Parkinson Progression Marker Initiative were modeled using a multivariate latent class linear mixed model. Resultant latent classes were compared on a number of baseline demographics and clinical variables, as well as cerebrospinal fluid (CSF) biomarkers and striatal dopamine transporter (DAT) density markers of neuropathology. Trajectories of cognitive change in PD were best described by two latent classes. A large subgroup (90%), which showed a subtle impairment in cognitive performance compared to controls but remained stable over the course of the study, and a small subgroup (10%) which rapidly declined in all cognitive performance measures. Rapid decliners did not differ significantly from the larger group in terms of disease duration, severity, or motor symptoms at baseline. However, rapid decliners had lower CSF amyloidß42 levels, a higher prevalence of sleep disorder and pronounced loss of caudate DAT density at baseline. These data suggest the existence of a distinct minority sub-type of PD in which rapid cognitive change in PD can occur uncoupled from motor symptoms or disease severity, likely reflecting early pathological change that extends from motor areas of the striatum into associative compartments and cortex.

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Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

Neurodegenerative Diseases ◽

10.1159/000493103 ◽

2018 ◽

Vol 18 (5-6) ◽

pp. 233-238

Author(s):

Frederic Sampedro ◽

Juan Marín-Lahoz ◽

Saul Martínez-Horta ◽

Javier Pagonabarraga ◽

Jaime Kulisevsky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

De Novo ◽

Brain Regions ◽

Cortical Atrophy ◽

Csf Biomarkers ◽

Gene Encoding ◽

Cortical Thinning ◽

Age Related

The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

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Cognitive decline in Parkinson’s disease: A prospective longitudinal study

Journal of the International Neuropsychological Society ◽

10.1017/s1355617709090614 ◽

2009 ◽

Vol 15 (3) ◽

pp. 426-437 ◽

Cited By ~ 90

Author(s):

DINO MUSLIMOVIĆ ◽

BART POST ◽

JOHANNES D. SPEELMAN ◽

ROB J. DE HAAN ◽

BEN SCHMAND

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Disease Onset ◽

Cognitive Change ◽

Newly Diagnosed ◽

Psychomotor Speed ◽

Prospective Longitudinal Study ◽

Normative Comparisons ◽

Prospective Longitudinal

AbstractThis controlled prospective study examined the evolution and predictors of cognitive decline in Parkinson’s disease (PD). Consecutive patients diagnosed at baseline with PD (n = 89), established PD (EPD) patients (n = 52) with a mean disease duration of 6.5 years, and healthy control subjects (n = 64) underwent extensive neuropsychological assessment twice, approximately 3 years apart. A standardized regression-based method, normative data, and multivariate normative comparisons were used to assess the cognitive course of PD. Cognitive performance of newly diagnosed patients decreased significantly over time, particularly on measures of psychomotor speed and attention and to a lesser extent on tests of memory, visuospatial skills, and executive functions. About 50% of the patients showed cognitive decline and 9% developed dementia. Similar results were observed in EPD patients. None of the baseline features predicted cognitive change in newly diagnosed patients, whereas age at disease onset and axial impairment (postural and gait disorders) contributed to decline in established patients. We conclude that within few years after diagnosis, PD patients show faster rate of cognitive decline than matched healthy subjects, particularly in domains of attention and psychomotor speed. Selection bias probably led to underestimation of the true extent of cognitive decline in established patients. (JINS, 2009, 15, 426–437.)

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White Matter Hyperintensities and Cognitive Decline in de Novo Parkinson’s Disease Patients

10.1101/230896 ◽

2017 ◽

Author(s):

Mahsa Dadar ◽

Yashar Zeighami ◽

Yvonne Yau ◽

Seyed-Mohammad Fereshtehnejad ◽

Josefina Maranzano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

De Novo ◽

Cognitive Test ◽

Cortical Thinning

AbstractObjectiveWhite Matter Hyperintensities (WMHs) are associated with cognitive decline in normative aging and Alzheimer’s disease. However, the pathogenesis of cognitive decline in Parkinson’s disease (PD) is not directly related to vascular causes, and therefore the role of WMHs in PD remains unclear. If WMH has a higher impact on cognitive decline in PD, vascular pathology should be assessed and treated with a higher priority in this population. Here we investigate whether WMH leads to increased cognitive decline in PD, and if these effects relate to cortical thinningMethodsTo investigate the role of WMHs in PD, it is essential to study recently-diagnosed/non-treated patients.De novoPD patients and age-matched controls (NPD=365,NControl=174) with FLAIR/T2-weighted scans at baseline were selected from Parkinson’s Progression Markers Initiative (PPMI). WMHs and cortical thickness were measured to analyse the relationship between baseline WMHs and future cognitive decline (follow-up:4.09±1.14 years) and cortical thinning (follow-up:1.05±0.10 years).ResultsHigh WMH load (WMHL) at baseline in PD was associated with increased cognitive decline, significantly more than i) PDs with low WMHL and ii) controls with high WMHL. Furthermore, PD patients with higher baseline WMHL showed more cortical thinning in right frontal lobe than subjects with low WMHL. Cortical thinning of this region also predicted decline in performance on a cognitive test.InterpretationPresence of WMHs inde novoPD patients predicts greater future cognitive decline and cortical thinning than in normal aging. Recognizing WMHs as a potential predictor of cognitive deficit in PD provides an opportunity for timely interventions.

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Apathy as a behavioural marker of cognitive impairment in Parkinson’s disease: a longitudinal analysis

Journal of Neurology ◽

10.1007/s00415-019-09538-z ◽

2019 ◽

Vol 267 (1) ◽

pp. 214-227 ◽

Cited By ~ 3

Author(s):

Glen P. Martin ◽

Kathryn R. McDonald ◽

David Allsop ◽

Peter J. Diggle ◽

Iracema Leroi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Psychiatric Symptoms ◽

Cognitive Change ◽

Longitudinal Change ◽

Random Intercept ◽

Behavioural Factors ◽

Over Time

Abstract Background Understanding the longitudinal course of non-motor symptoms, and finding markers to predict cognitive decline in Parkinson’s disease (PD), are priorities. Previous work has demonstrated that apathy is one of the only behavioural symptoms that differentiates people with PD and intact cognition from those with mild cognitive impairment (MCI-PD). Other psychiatric symptoms emerge as dementia in PD develops. Objective We explored statistical models of longitudinal change to detect apathy as a behavioural predictor of cognitive decline in PD. Methods We followed 104 people with PD intermittently over 2 years, undertaking a variety of motor, behavioural and cognitive measures. We applied a linear mixed effects model to explore behavioural factors associated with cognitive change over time. Our approach goes beyond conventional modelling based on a random-intercept and slope approach, and can be used to examine the variability in measures within individuals over time. Results Global cognitive scores worsened during the two-year follow-up, whereas the longitudinal evolution of self-rated apathy scores and other behavioural measures was negligible. Level of apathy was negatively (− 0.598) correlated with level of cognitive impairment and participants with higher than average apathy scores at baseline also had poorer cognition. The model indicated that departure from the mean apathy score at any point in time was mirrored by a corresponding departure from average global cognitive score. Conclusion High levels of apathy are predictive of negative cognitive and behavioural outcomes over time, suggesting that apathy may be a behavioural indicator of early cognitive decline. This has clinical and prognostic implications.

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White matter hyperintensities are linked to future cognitive decline in de novo Parkinson's disease patients

NeuroImage Clinical ◽

10.1016/j.nicl.2018.09.025 ◽

2018 ◽

Vol 20 ◽

pp. 892-900 ◽

Cited By ~ 27

Author(s):

Mahsa Dadar ◽

Yashar Zeighami ◽

Yvonne Yau ◽

Seyed-Mohammad Fereshtehnejad ◽

Josefina Maranzano ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

De Novo

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Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-212535 ◽

2021 ◽

pp. 1-11

Author(s):

Ling-Zhi Ma ◽

Can Zhang ◽

Han Wang ◽

Ya-Hui Ma ◽

Xue-Ning Shen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Cox Regression ◽

De Novo ◽

Rate Of Change ◽

Neurofilament Light ◽

Baseline Serum ◽

Axon Damage ◽

High Concentrations

Background: Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Objective: Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson’s disease (PD) remains unclear. Methods: In this research, 144 healthy controls and 301 de novo PD patients from Parkinson’s Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. Results: We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= –0.014, p < 0.001; β= –0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62–15.29, p < 0.001). Conclusion: In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

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In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease

Brain ◽

10.1093/brain/awx310 ◽

2017 ◽

Vol 141 (1) ◽

pp. 165-176 ◽

Cited By ~ 32

Author(s):

Nicola J Ray ◽

Steven Bradburn ◽

Christopher Murgatroyd ◽

Umar Toseeb ◽

Pablo Mir ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Basal Forebrain ◽

De Novo ◽

Cholinergic Basal Forebrain

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Cognitive Change in Newly-Diagnosed Patients with Parkinson's Disease: A 5-Year Follow-up Study

Journal of the International Neuropsychological Society ◽

10.1017/s1355617713000295 ◽

2013 ◽

Vol 19 (6) ◽

pp. 695-708 ◽

Cited By ~ 48

Author(s):

Mark Broeders ◽

Daan C. Velseboer ◽

Rob de Bie ◽

Johannes D. Speelman ◽

Dino Muslimovic ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Age At Onset ◽

Cognitive Change ◽

Healthy Controls ◽

Newly Diagnosed ◽

Cognitive Changes ◽

Cognitive Domains ◽

Healthy Elderly

AbstractCognitive change is frequently observed in patients with Parkinson's disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here. (JINS, 2013, 19, 1–14)

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Potential Sex-Specific Effects of Apolipoprotein E ɛ4 on Cognitive Decline in Early Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202288 ◽

2020 ◽

pp. 1-9

Author(s):

Ryul Kim ◽

Sangmin Park ◽

Dallah Yoo ◽

Young Ju Suh ◽

Jin-Sun Jun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Apolipoprotein E ◽

De Novo ◽

Sensitivity Analyses ◽

Specific Effects ◽

E4 Allele ◽

Generalized Linear Mixed Effects

Background/Objective: To compare the longitudinal trajectories of cognition according to the presence of the apolipoprotein E (APOE) ɛ4 allele in male and female Parkinson’s disease (PD) patients. Methods: This study included a total of 361 patients with recently diagnosed de novo PD (mean age [standard deviation], 61.4 [9.8] years). The patients were classified into the following groups: APOE ɛ4 + /M (n = 65), APOE ɛ4-/M (n = 173), APOE ɛ4 + /F (n = 25), and APOE ɛ4-/F (n = 98). Cognitive decline was assessed annually over 5 years of follow-up using the Montreal Cognitive Assessment (MoCA). To assess the sex-specific impacts of the APOE ɛ4 status on cognitive decline, we used generalized linear mixed effects (GLME) models separately for men, women, and the two sexes combined. Results: In the sex-stratified GLME models adjusted for covariates, the interaction results showed that the males with APOE ɛ4 had a steeper rate of cognitive decline than those without APOE ɛ4. In contrast, there was no significant interaction between APOE ɛ4 and time on longitudinal MoCA performance in the females. The main effect of APOE ɛ4 on the change in the MoCA score was not significant for either men or women. When the data from both men and women were used, the APOE ɛ4 + /M group exhibited a steeper rate of cognitive decline than did the APOE ɛ4 + /F and APOE ɛ4-/F groups. These results were consistent with those of sensitivity analyses. Conclusion: Sex may be considered when APOE ɛ4-related vulnerability to early cognitive decline is evaluated in PD patients.

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