The aim of this substudy was to determine the agreement between 2 approaches for measuring health care resource utilization (eg, number of hospital visits, number of primary care physician visits) in trial participants with Parkinson’s disease (PD).
A substudy of the 1-year multicenter futility trial of GPI-1485 and coenzyme Q10 (FS-TOO) was performed to assess health care resource utilization agreement by measuring participant utilization recall after 12 months versus measuring participant utilization recall at regular 3-month intervals. Trial participants were selected from patients in the National Institutes of Health-sponsored FS-TOO multicenter study. Persons aged ≥30 years with confirmed PD diagnosis within the previous 5 years were eligible for inclusion in the substudy. Participants were also required to have at least 2 of 3 cardinal manifestations of PD (tremor, rigidity, and bradykinesia). Participants were excluded from the study if they had presence of atypical Parkinson’s syndromes due to drugs, metabolic identified neurogenetic disorders, encephalitis, or other degenerative diseases. Agreement was determined using Lin’s concordance and Cohen’s kappa statistics.
Between March and July of 2004, a total of 424 potential subjects were identified and evaluated for trial eligibility. Of these, 213 subjects (139 men, 74 women; mean [SD] age, 61.5 [10.3] years) met entry criteria and were included in the study. Trial participants were randomized equally to 1 of 3 groups. The 3 groups had similar baseline characteristics in terms of demographic data (age, race, sex, employment status, and annual income), total Unified Parkinson Disease Rating Scale (UPDRS) score, and UPDRS subscores. In this substudy, 141 participants had a true baseline visit, indicating a clinical baseline date, and 182 participants completed the Baseline Resource Utilization Form within 3 months of the true baseline visit. The comparison of concordance between the summed information over 3-month recalls and the 12-month recall from baseline was derived from these 182 participants. The level of agreement between the 2 approaches was high, ranging from 64.4% to 95.1%. Where disagreement was identified, the more frequent measurement approach (every 3 months) led to higher estimates, ranging from 20.4% to 77.4%.
The results of this trial indicate internal consistency with the self-reported measures of health care resource utilization, suggesting that these simple measures might provide reliable information about units of health care resource utilization in the context of clinical trials for PD.
health care resources; Parkinson’s disease; clinical trials
Falls are frequent in Parkinson’s disease (PD), and may be influenced by daytime sleepiness. We reviewed the records of 120 men with PD. Mean Epworth Sleepiness Scale (ESS) values were significantly different between non-fallers and fallers (6.0 vs. 9.7, p<0.01). In multivariate analysis, ESS remained significantly associated with falls (OR 1.2, 95% CI 1.1–1.4, p=0.02), along with cognitive impairment (OR 4.4 95% CI 1.0–18.7, p=0.04) and postural instability/gait dysfunction (OR 1.6 95% CI 1.0–2.4, p=0.03) in non-depressed patients. In conclusion, non-depressed PD patients are 20% more likely to fall for every one unit increase in the ESS measure of sleepiness.
Parkinson’s disease; falls; sleepiness; depression; cognitive impairment
Mild Parkinsonian Signs (MPS) are early features that, when present, increase risk of neurodegenerative disease and mortality. Current methods to identify MPS are limited to neurological examination. Our objective was to assess the ability of a 9-item Parkinson’s Disease Screening Questionnaire (PDSQ), which has high sensitivity in the detection of overt Parkinson’s disease (PD), to detect Mild Parkinsonian Signs.
Measures including the PDSQ, Unified Parkinson’s Disease Rating Scale and University of Pennsylvania Smell Identification Test were administered to 267 participants without neurodegenerative disease. Two published definitions of MPS were used to classify cases.
PDSQ scores were higher for cases compared to controls (p < 0.001 for the first case definition and 0.07 for the second). However, the questionnaire had low sensitivity (47 and 59%) and specificity (62 and 63%) in the detection of MPS. Adding factors such as age, gender, and smell test score to the questionnaire in a predictive model only marginally improved the test characteristics.
The results show the screening questionnaire does not accurately identify Mild Parkinsonian Signs. More accurate tests are needed to improve detection of this early syndrome which can lead to motor disability, neurodegenerative disease and mortality.
Mild Parkinsonian Signs; screening questionnaire; validity; sensitivity; specificity
While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).
Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.
Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
This is the first analysis to estimate the costs of commercially insured patients with Parkinson’s disease (PD) in the USA. Prior analyses of PD have not examined costs in patients aged under 65 years, a majority of whom are in the workforce.
Our objective was to estimate direct and indirect costs associated with PD in patients under the age of 65 years who are newly diagnosed or have evidence of advanced PD.
PD patients were selected from a commercially insured claims database (N > 12,000,000; 1999–2009); workloss data were available for a sub-sample of enrollees. Newly diagnosed patients with evidence of similar disorders were excluded. Patients with evidence of advanced PD disease, including ambulatory assistance device users (PDAAD) and institutionalized (PDINST) patients, as well as newly diagnosed PD patients, were analyzed. Each PD cohort was age-, gender- and region-matched to controls without PD. Direct (i.e. insurer payments to providers) and indirect (i.e. workloss) costs were reported in $US, year 2010 values, and were descriptively compared using Wilcoxon rank sum tests.
Patients had excess mean direct PD-related costs of $US4,072 (p < 0.001; N = 781) in the year after diagnosis. The PDAAD cohort (N = 214) had excess direct PD-related costs of $US26,467 (p < 0.001) and the PDINST cohort (N = 156) had excess direct PD-related costs of $US37,410 (p < 0.001) in the year after entering these states. Outpatient care was the most expensive cost source for newly diagnosed patients, while inpatient care was the most expensive for PDAAD and PDINST patients. Excess indirect costs were $US3,311 (p < 0.05; N = 173) in the year after initial diagnosis.
Direct costs for newly diagnosed PD patients exceeded costs for controls without PD, and increased with PD progression. Direct costs were approximately 6–7 times higher in patients with advanced PD than in matched controls. Indirect costs represented 45 % of total excess costs for newly diagnosed PD patients.
Parkinson’s disease (PD) has a prodromal phase during which non-motor clinical features as well as physiological abnormalities may be present. These pre-motor markers could be used to screen for PD before motor abnormalities are present. The technology to identify PD before it reaches symptomatic Braak Stage 3 (substantia nigra compacta (SNc) involvement) already exists. The current challenge is to define the appropriate scope of use of predictive testing for PD. Imaging technologies, like dopamine transporter imaging, currently offer the highest degree of accuracy for identifying pre-motor PD, but they are expensive as screening tools and abnormalities on these studies would only be evident at Braak Stage 3 or higher. Efficiency is greatly enhanced by combining imaging with a pre-screening test, such as olfactory testing. This two-step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Alternatively, or in concert with this approach, evaluating high-risk populations (e.g. patients with rapid eye movement behavior disorder (RBD) or LRRK2 mutations) would enrich the sample for cases with underlying PD. Ultimately, the role of pre-clinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large-scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Future research will establish more definitive biomarkers capable of revealing the presence of disease in advance of SNc involvement with the promise of the potential for introducing disease modifying therapy even before the development of evidence for dopamine deficiency.
Parkinson’s disease; early detection; sensitivity; specificity
Clinical studies employ the Unified Parkinson’s Disease Rating Scale (UPDRS) to measure the severity of Parkinson’s disease. Evaluations often fail to consider the health-related quality of life (HrQoL) or apply disease-specific instruments. Health-economic studies normally use estimates of utilities to calculate quality-adjusted life years. We aimed to develop an estimation algorithm for EuroQol- 5 dimensions (EQ-5D)-based utilities from the clinical UPDRS or disease-specific HrQoL data in the absence of original utilities estimates.
Linear and fractional polynomial regression analyses were performed with data from a study of Parkinson’s disease patients (n=138) to predict the EQ-5D index values from UPDRS and Parkinson’s disease questionnaire eight dimensions (PDQ-8) data. German and European weights were used to calculate the EQ-5D index. The models were compared by R2, the root mean square error (RMS), the Bayesian information criterion, and Pregibon’s link test. Three independent data sets validated the models.
The regression analyses resulted in a single best prediction model (R2: 0.713 and 0.684, RMS: 0.139 and 13.78 for indices with German and European weights, respectively) consisting of UPDRS subscores II, III, IVa-c as predictors. When the PDQ-8 items were utilised as independent variables, the model resulted in an R2 of 0.60 and 0.67. The independent data confirmed the prediction models.
The best results were obtained from a model consisting of UPDRS subscores II, III, IVa-c. Although a good model fit was observed, primary EQ-5D data are always preferable. Further validation of the prediction algorithm within large, independent studies is necessary prior to its generalised use.
Parkinson’s disease; Quality of life; EuroQoL/EQ-5D; UPDRS; PDQ-8; Prediction
Parkinson’s disease (PD) is a common, treatable movement disorder that often remains undiagnosed despite clinically manifest symptoms. Screening for parkinsonism could lead to improved detection and earlier treatment, and facilitate research studies of PD prevalence. In order to determine the feasibility of screening, this study evaluated the validity of previously developed screening questionnaires. We systematically searched online databases PubMed and EMBASE for English-language studies published between 1980 and 2009. In each database a “Parkinson(s) disease” or “parkinsonism” term was combined with a screening term (“screening instrument,” screening questionnaire,” “screen” or “prevalence survey”) and a validity term (“validation,” “sensitivity” and “specificity”). Included studies reported the psychometric properties of at least one self-report questionnaire for parkinsonism. Twenty-seven studies met the inclusion criteria. From these studies, 9 screening questionnaires were identified. Sensitivity and specificity estimates varied widely. Sensitivity estimates were as high as 100% when questionnaires were tested among previously diagnosed PD patients and included a high number of parkinsonism-specific items, but were as low as 48% when tested among early cases in a community-based sample. Specificity estimates were lower, ranging from 22–100%. An older sample, presence of multiple co-morbid conditions and lower literacy led to lower specificity estimates. Higher specificity estimates were seen when the screening questionnaires were administered by a physician. Screening questionnaires can detect symptomatic parkinsonism. However, the performance of these questionnaires varied based on the individual items, study sample, and method of administration. The performance of screening questionnaires in the detection of early or mild parkinsonism was modest.
Parkinson’s disease; early detection; instruments; sensitivity; specificity
Prior work has related sentence processing to executive deficits in non-demented patients with Parkinson’s disease (PD). We extended this investigation to patients with dementia with Lewy bodies (DLB) and PD dementia (PDD) by examining grammatical and working memory components of sentence processing in the full range of patients with Lewy body spectrum disorder (LBSD). Thirty-three patients with LBSD were given a two-alternative, forced-choice sentence-picture matching task. Sentence type, working memory, and grammatical structure were systematically manipulated in the sentences. We found that patients with PDD and DLB were significantly impaired relative to non-demented PD patients and healthy controls. The deficit in PDD/DLB was most pronounced for sentences lengthened by the strategic placement of an additional prepositional phrase and for sentences with an additional proposition due to a center-embedded clause. However, there was no effect for subject-relative versus object-relative grammatical structure. An MRI voxel-based morphometry analysis in a subset of patients showed significant gray matter thinning in the frontal lobe bilaterally, and this extended to temporal, parietal and occipital regions. A regression analysis related sentence processing difficulty in LBSD to frontal neocortex, including inferiorprefrontal, premotor, and dorsolateral prefrontal regions, as well as right superior temporal cortex. These findings are consistent with the hypothesis that patients with PDD and DLB have difficulty processing sentences with increased working memory demands and that this deficit is related in part to their frontal disease.
Lewy body; Parkinson’s; sentence processing; working memory; MRI; prefrontal
Few studies have examined connected speech in demented and non-demented patients with Parkinson’s disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions.
Parkinson’s disease; speech; language; fluency; dementia with Lewy bodies
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson’s disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time.
dopamine agonists; impulse control disorder; Parkinson’s disease
While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson’s disease (PD), Parkinson’s dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb’s statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.
Parkinson’s; Lewy body; syntactic ambiguity; working memory; frontal
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
Narrative discourse is an essential component of day-to-day communication, but little is known about narrative in Lewy Body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). We performed a detailed analysis of a semi-structured speech sample in 32 non-aphasic patients with LBSD, and we related their narrative impairments to gray matter (GM) atrophy using voxel-based morphometry. We found that patients with PDD and DLB have significant difficulty organizing their narrative speech. This was correlated with deficits on measures of executive functioning and speech fluency. Regression analyses associated this deficit with reduced cortical volume in inferior frontal and anterior cingulate regions. These findings are consistent with a model of narrative discourse that includes executive as well as language components and with an impairment of the organizational component of narrative discourse in patients with PDD and DLB.
Parkinson's disease; discourse; speech; language; Dementia with Lewy bodies
Hyposmia, psychiatric disorders and cognitive problems are common non-motor manifestations in Parkinson's Disease but how they are related remains unclear.
To investigate the relationship between olfactory dysfunction and neuropsychiatric manifestations we performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London-Drexel and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification test.
There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%, p<0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean(standard deviation) 6.2(3.2) vs. 8.4(2.8), p<0.001) and executive performance (Tower of London total moves, 52(38) vs. 34(21), p<0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex and disease characteristics in logistic regression models.
The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common non-motor symptoms.
Parkinson's Disease; olfaction; non-motor symptoms; psychiatric symptoms; cognitive symptoms
Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129, along withtotal α-synuclein, in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein CSF concentrations, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether PS-129 CSF concentrations will be useful for diagnosing PD and for monitoring PD severity and progression.
The cognitive profile of early onset Parkinson’s disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers.
EOPD probands and their first-degree relatives who did not have Parkinson’s disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N=43) and without (N=52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD.
No significant differences in neuropsychological test performance were found between parkin carrier and non-carrier probands. Performance also did not differ between EOPD non-carriers and carrier subgroups (i.e. heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives.
Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to non-carriers. The cognitive functioning of parkin carriers over time warrants further study.
Parkinson’s disease; genetics; neuropsychological assessment; genotype; PARK2; parkin mutation
Racial differences in the observed prevalence of Parkinson's disease (PD) may be due to delayed diagnosis among African-Americans. We sought to compare the stage at which African-American and white PD patients present for healthcare, and determine whether perception of disability accounts for racial differences.
Using records of veterans with newly diagnosed PD at the Philadelphia Veterans Affairs Medical Center, we calculated differences in reporting of symptoms as the difference in z-scores on the Unified Parkinson Disease Rating Scale part 2 (disability) and part 3 (motor impairment). Ordinal logistic regression was used to determine predictors of stage at diagnosis.
African-American (n = 16) and white (n = 58) veterans with a mean age of 70.1 years were identified. African-Americans presented at a later PD stage than whites (median Hoehn + Yahr stage 2.5 vs. 2.0, p = 0.02) and were more likely to under-report disability relative to motor impairment (81 vs. 40%, p < 0.01). Multivariate analysis showed that under-reporting of disability accounted for much of the effect of race on stage of diagnosis.
Under-reporting of disability among African-Americans may account for later stages of PD diagnosis than whites. This study begins to explain the mechanisms underlying observed racial disparities in PD.
African-American; Delay; Diagnosis; Health services; Parkinsonism; Race
Most people with Parkinson's disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD.
A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, i.e. proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.
Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p<0.001); many of the other 10 analytes co-varied with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an eightfold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.
Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
Epidermal growth factor; EGF; Parkinson's Disease; Parkinson's Disease with Dementia; Biomarker; Plasma
The most common genetic contributor to late-onset Parkinson disease (PD) is the LRRK2 gene. In order to effectively integrate LRRK2 genetic testing into clinical practice, a strategy tailored to the PD population must be developed. We assessed 168 individuals with PD for baseline knowledge of genetics, perceived risk, and interest and opinions regarding genetic counseling and testing. Most participants felt that they were familiar with general genetics terms but overall knowledge levels were low, with an average score of 55%. The majority of participants thought it was likely they inherited a PD gene (72%), believed genetic testing for PD would be useful (86%), and were interested in genetic testing (59%) and genetic counseling (56%). However, only a few participants had heard of any genetic tests for PD (29%) or LRRK2 (10%). There appears to be a significant level of interest in genetics and genetic testing within the PD population, but a considerable deficit in genetics knowledge and an over-estimation of risk. Genetic education and counseling tools to address these needs were developed to provide patients with the ability to make informed and knowledgeable genetic testing decisions.
Parkinson disease; Genetic testing; Genetic knowledge; Attitudes; Perceived risk
Olfactory deficits appear early in the course of Parkinson’s disease (PD) but their prognostic significance is not known. The goal of this study was to determine whether the severity of olfactory impairment is associated with subsequent risk of developing complications of PD. One hundred patients with PD self-administered the University of Pennsylvania Smell Identification Test (UPSIT). Testing was done, on average, 3.6 years from the time of initial diagnosis. The incidence of neuropsychiatric features of PD, including cognitive decline and visual hallucinations, was ascertained through chart review after an average of 6.8 years of follow-up. Incidence of motor outcomes including falls and dyskinesias was also obtained. There was a significant trend for increased risk of neuropsychiatric complications across declining quartiles of olfactory test scores. In addition, subjects in the lowest quartile of olfactory performance had a significantly higher adjusted risk of hallucinations (HR = 4.70, 95% CI 1.64, 13.42) and cognitive decline (HR = 3.10, 95% CI 1.05, 9.21) than those in the reference quartile. There was no association between olfactory dysfunction and dyskinesias, and a very modest association with risk of falls. These findings suggest that severity of olfactory impairment early in the disease course may be a useful marker for the risk of neuropsychiatric complications of PD.
Parkinson’s disease; olfaction; dementia; visual hallucinations
Questions exist regarding the validity of patient-reporting of psychiatric symptoms in Parkinson’s disease (PD). We assessed observer variability and validity in reporting of impulse control disorder (ICD) symptoms in PD by using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP). PD patients and their informants (71 pairs) completed the QUIP to assess four ICDs (compulsive gambling, buying, sexual behavior, and eating) in patients. Trained raters then administered a diagnostic interview. Sensitivity of the QUIP for a diagnosed ICD was 100% for both patient- and informant-completed instruments, and specificity was 75% for both raters. Approximately 40% of patients without an ICD diagnosis had a positive QUIP, suggesting that many PD patients experience subsyndromal ICD symptoms that require ongoing monitoring. Agreement between patient- and informant-reporting of any ICD behaviors on the QUIP was moderate (kappa = 0.408), and for individual ICDs was highest for gambling (kappa = 0.550). Overall, a negative QUIP from either the patient or informant rules out the possibility of an ICD, while a positive QUIP requires a follow-up diagnostic interview and ongoing monitoring to determine if symptoms currently are, or in the future become, clinically significant.
Impulse control disorders; Parkinson’s disease; QUIP
A range of impulse control disorders (ICDs) are reported to occur in Parkinson’s disease (PD). However, alterations in brain activity at rest and during risk taking occurring with ICDs in PD are not well understood.
We used both arterial spin labeling (ASL) perfusion fMRI to directly quantify resting cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) fMRI to measure neural responses to risk taking during performance on the Balloon Analogue Risk Task (BART).
18 PD patients, either with a diagnosis of one or more ICDs (N=9) or no lifetime ICD history (N=9), participated. BOLD fMRI data demonstrated that PD patients without an ICD activate the mesocorticolimbic pathway during risk taking. Compared with non-ICD patients, ICD patients demonstrated significantly diminished BOLD activity in the right ventral striatum during risk taking and significantly reduced resting CBF in the right ventral striatum.
ICDs in PD are associated with reduced right ventral striatal activity at rest and diminished striatal activation during risk taking, suggesting that a common neural mechanism may underlie ICDs in individuals with PD and those without PD. Thus, treatments for ICDs in non-PD patients warrant consideration in PD patients with ICDs.
While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.
Parkin; Leucine-rich repeat kinase-2; Glucocerebrosidase; Parkinson; Cognition; Mini-Mental State Examination; Genetics