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1.  Research Consent Capacity Varies with Executive Function and Memory in Parkinson's Disease 
Background
We examined the association between cognitive domains and research consent capacity in PD. Our hypothesis was that research consent capacity is best predicted by executive function.
Methods
A cohort of 90 PD patients and 30 normal older adults were administered the MacArthur Competence Assessment Tool for Clinical Research, Dementia Rating Scale-2, and the Montreal Cognitive Assessment. Experts classified patients as either “capable” or “not capable” of providing informed consent to participate in two clinical trials.
Results
MacArthur Competence Assessment Tool for Clinical Research Reasoning scores for both clinical trial types were most associated with executive functions and delayed recall. As scores on these domains improved, the odds of an expert rating of “capable of consent” increased.
Conclusions
These results extend our previous findings by demonstrating that memory and executive abilities appear closely associated with capacity when evaluated using either a structured interview or expert judgment of that interview.
doi:10.1002/mds.26469
PMCID: PMC5213840  PMID: 26861463
Parkinson's disease; decision-making; capacity; cognitive impairment; informed consent
2.  GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson disease 
Background
Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known.
Objectives/Methods
We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at 8 sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing and Trail Making A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (Montreal Cognitive Assessment). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni corrections.
Results
Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio =5.1; p=9.7 × 10−6; E326K, odds ratio =6.4; p=5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected p[pc]=9.0 × 10−4; E326K, pc=0.036), Trail Making B-A (mutations, pc=0.018; E326K, pc=0.018), and Benton Judgment of Line Orientation (mutations, pc=0.0045; E326K, pc=0.0013).
Conclusions
Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.
doi:10.1002/mds.26359
PMCID: PMC4724255  PMID: 26296077
cognition; GBA; neuropsychological tests; visuospatial; working memory
3.  CSF β-amyloid 1-42 predicts progression to cognitive impairment in newly diagnosed Parkinson disease 
BACKGROUND
Low CSF β-amyloid 1-42 has been associated with cognitive decline in advanced Parkinson’s Disease; data from a single cohort suggest β-amyloid 1-42 may be an early marker of cognitive impairment.
DESIGN/METHODS
Newly diagnosed Parkinson’s participants (mean duration: 6.9 months) in the Parkinson’s Progression Markers Initiative (n=341) were assessed at baseline (untreated state) and followed for two years. CSF β-amyloid 1-42, α-synuclein, total tau, and tau phosphorylated at threonine 181 were collected at baseline. Participants were classified as having CI if scores on two of six cognitive tests were 1.5 standard deviations below the standardized mean based on published norms in healthy controls. Multivariable regression analyses was used to determine the association between baseline CSF markers with cognitive impairment, defined by neuropsychological testing performance at two-year follow-up.
RESULTS
55 participants (16.1%) had CI at baseline and were not included in further analyses. 37 of the 286 participants without CI at baseline (12.9%) developed CI at two years. Participants with CI at two years had significantly lower mean baseline CSF β-amyloid 1-42 levels than non-CI participants (343.8 vs. 380.4pg/mL, p<0.01); no significant difference was seen for α-synuclein, T-tau, or P-tau 181. In a regression model of 286 participants without baseline CI adjusted for age, gender, disease duration, education, motor severity, and depression status, lower baseline β-amyloid 1-42 levels were associated with higher odds of CI at two years. (OR10pg/mL=1.04, 95%CI: 1.01–1.08, p<0.05).
CONCLUSION
CSF β-amyloid 1-42 level at disease onset is an independent predictor of cognitive impairment in early Parkinson’s Disease.
doi:10.1007/s12031-015-0647-x
PMCID: PMC4738011  PMID: 26330275
CSF β-amyloid 1-42; cognitive impairment; Parkinson’s Disease; PPMI
4.  Cognition in Individuals at Risk for Parkinson's: Parkinson Associated Risk Syndrome (PARS) Study Findings 
Objectives
The Parkinson Associated Risk Syndrome Study identified a cohort of healthy adults with hyposmia and dopamine transporter binding reduction to characterize individuals at risk for Parkinson's disease (PD). We describe the cognitive profile of this cohort.
Methods
Individuals older than 50 y without PD were recruited. Two hundred twenty-five completed cognitive testing and were included in the final analysis. A neuropsychological test battery was administered and normative scores created for global cognition, memory, executive function/working memory, processing speed/attention, visuospatial abilities, and language domains. Other non-motor symptoms (constipation, depression, anxiety, and rapid eye movement sleep behavior disorder) were assessed through questionnaires.
Results
Individuals with both hyposmia and reduced dopamine transporter binding (n = 38) had lower mean scores for global cognition, executive function/working memory, and memory compared with all other participants (n = 187). In separate multivariate logistic regression models, lower global cognition (odds ratio, 1.97, P = 0.004), and specifically executive function/working memory (odds ratio, 1.84, P = 0.004) scores were associated with membership in the hyposmia with dopamine transporter reduction group. Combining hyposmia with relative impairment on specific cognitive domains increased the odds of dopamine transporter binding reduction compared with hyposmia alone, with the greatest increase in odds for hyposmia plus executive function/working memory relative impairment (68% increase in odds from 4.14 to 6.96).
Conclusion
Changes in global cognitive abilities, and specifically executive function/working memory, are present in individuals at risk for PD. Combining non-motor features, including cognition, improves prediction of dopamine transporter binding reduction.
doi:10.1002/mds.26373
PMCID: PMC4827252  PMID: 26293177
Parkinson's; cognition; prodromal; dopaminergic deficit; hyposmia
5.  Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis 
The Lancet. Neurology  2017;16(1):55-65.
Background
There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD.
Methods
In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender.
Findings
This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.
Interpretation
AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology.
Funding
NIH (NIA/NINDS).
doi:10.1016/S1474-4422(16)30291-5
PMCID: PMC5181646  PMID: 27979356
6.  Arguing Against the Proposed Definition Changes of PD 
As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article entitled, "Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease." In particular, we suggest that the one-year rule distinguishing Parkinson’s disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice, in clinical and basic science research, and in helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype)”, will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions.
doi:10.1002/mds.26721
PMCID: PMC5168716  PMID: 27492190
7.  Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype 
Abstract
Objective
Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.
Methods
We screened 10 SNPs, previously associated with PD risk, for association with tremor‐dominant (TD) versus postural‐instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi‐site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross‐sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha‐synuclein (SNCA) expression in the GTEx (Genotype‐Tissue Expression project) consortium database.
Results
Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni‐corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor‐predominant phenotype and predicted a slower rate of motor progression (1‐point difference in annual rate of UPDRS‐III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).
Interpretation
Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor‐predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.
doi:10.1002/acn3.371
PMCID: PMC5221454  PMID: 28078311
8.  Time to response to citalopram treatment for agitation in Alzheimer's disease 
Background
Agitation is a common and significant problem in Alzheimer’s disease (AD). In the recent Citalopram for Agitation in Alzheimer’s Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment.
Methods
Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) score of 1 or 2, or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction ≥50% from baseline. “Stable early response” was defined as meeting the aforementioned criteria at both weeks 3 and 9, “late response” was response at week 9 but not at week 3, and “unstable response” was response at week 3 but not at week 9.
Results
In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. There were little between-group differences in response rates in the first three weeks of the study (21% vs 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% vs. 8% on CGIC, Fisher’s exact p=0.09; 31% vs. 15% on NBRS-A, Fisher’s exact p=0.02). Approximately half (45–56%) of citalopram responders at end-of-study achieved response later in the study, compared with 30–44% of placebo responders.
Discussion
Treatment with citalopram for agitation in AD needs to be at least nine weeks in duration to allow sufficient time for full response, and study duration is an important factor to consider in the design of clinical trials for agitation in Alzheimer’s disease.
doi:10.1016/j.jagp.2015.05.006
PMCID: PMC4653092  PMID: 26238225
9.  Longitudinal study of normal cognition in Parkinson disease 
Neurology  2015;85(15):1276-1282.
Objective:
To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.
Methods:
A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors.
Results:
We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinson's Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001).
Conclusions:
Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.
doi:10.1212/WNL.0000000000002001
PMCID: PMC4617168  PMID: 26362285
10.  Diagnosis of Parkinson’s disease on the basis of clinical–genetic classification: a population-based modelling study 
The Lancet. Neurology  2015;14(10):1002-1009.
Background
Accurate diagnosis and early detection of complex disease has the potential to be of enormous benefit to clinical trialists, patients, and researchers alike. We sought to create a non-invasive, low-cost, and accurate classification model for diagnosing Parkinson’s disease risk to serve as a basis for future disease prediction studies in prospective longitudinal cohorts.
Methods
We developed a simple disease classifying model within 367 patients with Parkinson’s disease and phenotypically typical imaging data and 165 controls without neurological disease of the Parkinson’s Progression Marker Initiative (PPMI) study. Olfactory function, genetic risk, family history of PD, age and gender were algorithmically selected as significant contributors to our classifying model. This model was developed using the PPMI study then tested in 825 patients with Parkinson’s disease and 261 controls from five independent studies with varying recruitment strategies and designs including the Parkinson’s Disease Biomarkers Program (PDBP), Parkinson’s Associated Risk Study (PARS), 23andMe, Longitudinal and Biomarker Study in PD (LABS-PD), and Morris K. Udall Parkinson’s Disease Research Center of Excellence (Penn-Udall).
Findings
Our initial model correctly distinguished patients with Parkinson’s disease from controls at an area under the curve (AUC) of 0.923 (95% CI = 0.900 – 0.946) with high sensitivity (0.834, 95% CI = 0.711 – 0.883) and specificity (0.903, 95% CI = 0.824 – 0.946) in PPMI at its optimal AUC threshold (0.655). The model is also well-calibrated with all Hosmer-Lemeshow simulations suggesting that when parsed into random subgroups, the actual data mirrors that of the larger expected data, demonstrating that our model is robust and fits well. Likewise external validation shows excellent classification of PD with AUCs of 0.894 in PDBP, 0.998 in PARS, 0.955 in 23andMe, 0.929 in LABS-PD, and 0.939 in Penn-Udall. Additionally, when our model classifies SWEDD as PD, they convert within one year to typical PD more than would be expected by chance, with 4 out of 17 classified as PD converting to PD during brief follow-up; while SWEDD not classified as PD showed one conversion to PD out of 38 participants (test of proportions, p-value = 0.003).
Interpretation
This model may serve as a basis for future investigations into the classification, prediction and treatment of Parkinson’s disease, particularly those planning on attempting to identify prodromal or preclinical etiologically typical PD cases in prospective cohorts for efficient interventional and biomarker studies.
Funding
Please see the acknowledgements and funding section at the end of the manuscript.
doi:10.1016/S1474-4422(15)00178-7
PMCID: PMC4575273  PMID: 26271532
11.  Associations between Cerebrospinal Fluid Biomarkers and Cognition in Early Untreated Parkinson's Disease 
Journal of Parkinson's disease  2015;5(4):783-792.
Background
Mild cognitive impairment and dementia are common, clinically important features of Parkinson's disease (PD). The underlying disease pathology is heterogeneous and not yet well characterized. Biomarkers for cognitive impairment in PD could aid in diagnostic and prognostic evaluation and in the development of new cognitive enhancing treatments.
Objective
To examine the relationship between CSF markers and cognition in a large, multicentre, cohort study of early, untreated PD, and compare marker concentrations between PD patients with and without MCI and healthy, age-matched controls.
Methods
414 early, untreated PD (34% with mild cognitive impairment) and 189 healthy, cognitively intact controls with baseline neuropsychological testing and CSF abeta42, t-tau, p-tau181 and α-synuclein results were included. Multiple linear regression models were constructed with a composite cognition factor, or memory-, or visuospatial- or executive-attention domains as dependent variables, and CSF markers, demographic characteristics and MDS-UPDRS III score as predictors.
Results
Lower α-synuclein was associated with reduced performance on the executive-attention domain and the composite cognition factor in the whole PD-group. Abeta42 was significantly decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates, while values in PD without MCI were identical to healthy controls.
Conclusions
The association between reduced CSF α-synuclein concentrations and cognition suggests that α-synuclein pathology contributes to early cognitive impairment in PD, in particular to executive-attentional dysfunction. Longitudinal analyses are needed to determine if this and other CSF biomarkers in early Parkinson's disease are associated with the risk of future cognitive decline and dementia.
doi:10.3233/JPD-150682
PMCID: PMC5031486  PMID: 26599300
Parkinson disease; cerebrospinal fluid; Mild cognitive impairment; alpha-synuclein; amyloid beta-peptides; tau Proteins
12.  Caregiver report of apathy predicts dementia in Parkinson’s disease 
Parkinsonism & related disorders  2015;21(8):992-995.
Introduction
Apathy is a common, troublesome symptom in Parkinson’s disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia.
Methods
Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson’s Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥ 1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors.
Results
Of 132 PD patients 12.1% (N=16) scored in the apathetic range at baseline. A total of 19.6% (N=26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR=3.56; 95% CI=1.09–11.62; p=0.04).
Conclusions
A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia.
doi:10.1016/j.parkreldis.2015.06.009
PMCID: PMC4509809  PMID: 26117435
Epidemiology; Non-motor symptoms; Cognition; Neuropsychiatric Inventory
13.  Change in agitation in Alzheimer's disease in the placebo arm of a 9-week controlled trial 
International psychogeriatrics / IPA  2015;27(12):2059-2067.
Background
Placebo responses raise significant challenges for design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (AD).
Methods
In the Citalopram for Agitation in Alzheimer's Disease (Cit AD) study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for 9 weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Results
Agitation outcomes improved over 9 weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by 3 weeks and was sustained through 9 weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
Conclusions
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
doi:10.1017/S1041610215001106
PMCID: PMC4669064  PMID: 26305876
Alzheimer's disease; Agitation; Randomized Clinical Trial; Neuropsychiatric symptoms
14.  Cognitive Performance and Neuropsychiatric Symptoms in Early, Untreated Parkinson’s Disease 
This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson’s disease (PD).
Background
Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS.
Methods
Parkinson’s Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy.
Results
Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P < 0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P < 0.001) and apathy (P < 0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P = 0.51).
Conclusions
Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS.
doi:10.1002/mds.26170
PMCID: PMC4855523  PMID: 25737166
anxiety; apathy; cognition; depression; impulse control disorder; Parkinson’s disease; psychosis
15.  Fatigue in Parkinson's disease: report from a mutidisciplinary symposium 
NPJ Parkinson's disease  2016;2:15025.
Fatigue is a severe problem for many people living with Parkinson's disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson's Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer—disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD.
doi:10.1038/npjparkd.2015.25
PMCID: PMC4883681  PMID: 27239558
16.  Lower plasma ApoA1 levels are found in Parkinson’s disease and associate with APOA1 genotype 
Background
The discovery of novel plasma-based biomarkers could lead to new approaches in the treatment of Parkinson’s disease (PD). Here we explore the role of plasma Apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels.
Methods
Plasma ApoA1 and the single nucleotide polymorphism rs670 were assayed in a discovery cohort (Cohort 1) of 301 PD, 80 normal controls, and 165 subjects with other neurodegenerative diseases, as well as a cohort (Cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1494 PD and 925 normal control subjects from both clinical sites.
Results
Compared with both normal and disease controls, PD patients have lower plasma ApoA1 (p<0.001 for both comparisons). Moreover, in PD patients, plasma ApoA1 levels are correlated with genotype at the APOA1 promoter polymorphism, rs670. Specifically, lower plasma ApoA1 levels were found in rs670 major allele (G) homozygotes in both Cohort 1 (p=0.009) and in a replication cohort (Cohort 2, n=158 PD patients, p=0.024). Finally, evaluating rs670 genotype frequencies in 1930 PD cases vs. 997 normal controls, the rs670 GG genotype shows a trend towards association (OR: 1.1; p=0.10) with PD.
Conclusions
Our results are compatible with a model whereby circulating ApoA1 levels may be useful in risk-stratifying subjects for the development of PD, with higher ApoA1 levels suggesting relative protection. Future studies evaluating modulation of ApoA1 as a novel therapeutic strategy in PD are warranted.
doi:10.1002/mds.26022
PMCID: PMC4362847  PMID: 25227208
Apolipoprotein A1; Biomarker; Parkinson’s disease; Genotype
17.  OLFACTORY DYSFUNCTION IN PARKINSON’S DISEASE: POSITIVE EFFECT OF CIGARETTE SMOKING 
Background
There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinson’s disease (PD). In general, those who currently smoke cigarettes, as well as those with a past history of such smoking, have a reduced risk of PD compared to those who have never smoked. Recently it has been suggested that a cardinal non-motor sensory symptom of PD, olfactory dysfunction, may be less severe in PD patients who smoke than in PD patients who do not, in contrast to the negative effect of smoking on olfaction described in the general population.
Methods
We evaluated University of Pennsylvania Smell Identification Test (UPSIT) scores from 323 Parkinson’s patients and 323 controls closely matched individually on age, sex, and smoking history (never, past, current).
Results
The patients exhibited much lower UPSIT scores than did the controls (P<0.0001). The relative decline in dysfunction of the current PD smokers was less than that of the never- and past-PD smokers (respective Ps=0.0005 & 0.0019). The female PD patients outperformed their male counterparts by a larger margin than did the female controls (3.66 vs. 1.07 UPSIT points; respective Ps < 0.0001 & 0.06). Age-related declines in UPSIT scores were generally present (P < 0.0001). No association between the olfactory measure and smoking dose, as indexed by pack years, was evident.
Conclusions
PD patients who currently smoke do not exhibit the smoking-related decline in olfaction observed in non-PD control subjects who currently smoke. The physiologic basis of this phenomenon is yet to be defined.
doi:10.1002/mds.26126
PMCID: PMC4439272  PMID: 25545729
Parkinson’s disease; olfaction; psychophysics; UPSIT; cigarette smoking; L-DOPA
18.  Cognitive Profile of LRRK2-related Parkinson’s Disease 
Background
There is increasing evidence that genetic factors play a role in the variability associated with cognitive performance in Parkinson’s disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2-related PD is not well-characterized.
Methods
A cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.
Results
LRRK2 mutation carriers (n=29) demonstrated better performance on the Mini Mental State Examination (P=0.03) and the Letter-Number Sequencing Test (P=0.005). A smaller proportion of LRRK2 carriers were demented (P=0.03).
Conclusions
Our cross-sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2-related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline.
doi:10.1002/mds.26161
PMCID: PMC4397146  PMID: 25650144
cognition; LRRK2; neuropsychological tests; Parkinson disease; working memory
20.  Plasma EGF and cognitive decline in Parkinson's disease and Alzheimer's disease 
Abstract
Objective
Cognitive decline occurs in multiple neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Shared underlying mechanisms may exist and manifest as shared biomarker signatures. Previously, we nominated plasma epidermal growth factor (EGF) as a biomarker predicting cognitive decline in patients with established PD. Here, we investigate EGF as a predictive biomarker in prodromal PD, as well as AD.
Methods
A cohort of PD patients (n = 236) was recruited to replicate our finding that low baseline EGF levels predict future cognitive decline. Additionally, plasma EGF and cognitive outcome measures were obtained from individuals with normal cognition (NC, n = 58), amnestic mild cognitive impairment (AD‐MCI, n = 396), and Alzheimer's disease (AD, n = 112) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate whether low EGF levels correlate with cognitive status and outcome in AD‐MCI and AD. Third, plasma EGF and cognitive measures were evaluated in the high‐risk asymptomatic Parkinson's Associated Risk Study (PARS) cohort (n = 165) to investigate the association of EGF and cognitive performance in a PD prodromal context.
Results
In both PD and AD‐MCI, low baseline plasma EGF predicted poorer long‐term cognitive outcomes. In asymptomatic individuals at highest risk for developing PD from the PARS cohort, low baseline plasma EGF associated with poorer performance in the visuospatial domain but not in other cognitive domains.
Interpretation
Low plasma EGF at baseline predicts cognitive decline in both AD and PD. Evidence for this signal may exist in prodromal stages of both diseases.
doi:10.1002/acn3.299
PMCID: PMC4863747  PMID: 27231704
Alzheimer's disease; biomarker; cognition; EGF; epidermal growth factor; Parkinson's disease; plasma
21.  An Alzheimer’s Disease-Derived Biomarker Signature Identifies Parkinson’s Disease Patients with Dementia 
PLoS ONE  2016;11(1):e0147319.
Biomarkers from multiple modalities have been shown to correlate with cognition in Parkinson’s disease (PD) and in Alzheimer’s disease (AD). However, the relationships of these markers with each other, and the use of multiple markers in concert to predict an outcome of interest, are areas that are much less explored. Our objectives in this study were (1) to evaluate relationships among 17 biomarkers previously reported to associate with cognition in PD or AD and (2) to test performance of a five-biomarker classifier trained to recognize AD in identifying PD with dementia (PDD). To do this, we evaluated a cross-sectional cohort of PD patients (n = 75) across a spectrum of cognitive abilities. All PD participants had 17 baseline biomarkers from clinical, genetic, biochemical, and imaging modalities measured, and correlations among biomarkers were assessed by Spearman’s rho and by hierarchical clustering. We found that internal correlation among all 17 candidate biomarkers was modest, showing a maximum pairwise correlation coefficient of 0.51. However, a five-marker subset panel derived from AD (CSF total tau, CSF phosphorylated tau, CSF amyloid beta 42, APOE genotype, and SPARE-AD imaging score) discriminated cognitively normal PD patients vs. PDD patients with 80% accuracy, when employed in a classifier originally trained to recognize AD. Thus, an AD-derived biomarker signature may identify PDD patients with moderately high accuracy, suggesting mechanisms shared with AD in some PDD patients. Based on five measures readily obtained during life, this AD-derived signature may prove useful in identifying PDD patients most likely to respond to AD-based crossover therapies.
doi:10.1371/journal.pone.0147319
PMCID: PMC4727929  PMID: 26812251
22.  Development and Initial Testing of the Penn Parkinson's Daily Activities Questionnaire 
Objective
The aim of this work was to describe the development and psychometric analysis of the Penn Parkinson's Daily Activities Questionnaire. The questionnaire is an item response theory-based tool for rating cognitive instrumental activities of daily living in PD.
Methods
Candidate items for the Penn Parkinson's Daily Activities Questionnaire were developed through literature review and focus groups of patients and knowledgeable informants. Item selection and calibration of item-response theory parameters were performed using responses from a cohort of PD patients and knowledgeable informants (n = 388). In independent cohorts of PD patients and knowledgeable informants, assessments of test-retest reliability (n = 50), and construct validity (n = 68) of the questionnaire were subsequently performed. Construct validity was assessed by correlating questionnaire scores with measures of motor function, cognition, an existing activities of daily living measure, and directly observed daily function.
Results
Fifty items were retained in the final questionnaire item bank. Items were excluded owing to redundancy, difficult reading level, and when item-response theory parameters could not be calculated. Test-retest reliability was high (intraclass correlation coefficient = 0.97; P < 0.001). The questionnaire correlated strongly with cognition (r = 0.68; P < 0.001) and directly observed daily function (r = 0.87; P < 0.001), but not with motor impairment (r = 0.08; P = 0.53). The questionnaire score accurately discriminated between PD patients with and without dementia (receiver operating characteristic curve = 0.91; 95% confidence interval: 0.85–0.97).
Conclusions
The Penn Parkinson's Daily Activities Questionnaire shows strong evidence of reliability and validity. Item response theory-based psychometric analysis suggests that this questionnaire can discriminate across a range of daily functions.
doi:10.1002/mds.26339
PMCID: PMC4724261  PMID: 26249849
Parkinson's disease; instrumental activities of daily living; cognition; item response theory
24.  Conversion Between Mini-Mental State Examination, Montreal Cognitive Assessment, and Dementia Rating Scale-2 Scores in Parkinson’s Disease 
Cognitive impairment is one of the earliest, most common, and most disabling non-motor symptoms in Parkinson’s disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale-2 (DRS-2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS-2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS-2 using equipercentile equating and log-linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients.
doi:10.1002/mds.26062
PMCID: PMC4371590  PMID: 25381961
Parkinson’s disease; Mini-Mental State Examination; Montreal Cognitive Assessment; Dementia Rating Scale-2; cognitive screening scales
25.  A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer’s disease patients with agitation 
The citalopram for Alzheimer’s disease trial evaluated citalopram for the management for agitation in Alzheimer’s disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient-specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S-citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S-citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer’s disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s10928-015-9457-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10928-015-9457-6
PMCID: PMC4720707  PMID: 26611790
Citalopram; Pharmacokinetics; Agitation; Alzheimer’s disease

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