Journal of Parkinson's Disease - Volume 5, issue 4

Authors: Skogseth, Ragnhild E. | Bronnick, Kolbjorn | Pereira, Joana B. | Mollenhauer, Brit | Weintraub, Daniel | Fladby, Tormod | Aarsland, Dag

Article Type: Research Article

Abstract: 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, multicenter, 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. Show more

Keywords: Parkinson disease, cerebrospinal fluid, Mild cognitive impairment, alpha-synuclein, amyloid beta-peptides, tau Proteins

DOI: 10.3233/JPD-150682

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 783-792, 2015

Authors: Lucas-Jiménez, Olaia | Díez-Cirarda, María | Ojeda, Natalia | Peña, Javier | Cabrera-Zubizarreta, Alberto | Ibarretxe-Bilbao, Naroa

Article Type: Research Article

Abstract: Background: While significant progress has been made to determine the functional role of specific gray matter areas underlying verbal memory in Parkinson’s disease (PD), very little is known about the relationship between these regions and their underlying white matter structures. Objective: The objectives of this study were (1) to investigate verbal memory, fractional anisotropy and brain activation differences between PD patients and healthy controls (HC), (2) to explore the neuroanatomical and neurofunctional correlates of verbal memory in PD, and (3) to investigate the relationship between these neuroanatomical and neurofunctional verbal memory correlates in PD. Methods: Functional …magnetic resonance imaging (fMRI) while performing a verbal memory paradigm and diffusion tensor imaging data (DTI), were acquired in 37 PD patients and 15 age-, sex-, and education-matched HC. Results: PD patients showed verbal recognition memory impairment, lower fractional anisotropy in the anterior cingulate tract, and lower brain activation in the inferior orbitofrontal cortex compared to HC. Brain activation in the inferior orbitofrontal cortex correlated significantly with verbal recognition memory impairment in PD patients. In addition, a relationship between brain activation in the inferior orbitofrontal cortex and fractional anisotropy of the uncinate fasciculus was found in PD. Conclusions: These results reveal that deficits in verbal memory in PD are accompanied by functional brain activation changes, but also have specific structural correlates related to white matter microstructural integrity. Show more

Keywords: Parkinson’s disease, DTI, fMRI, verbal memory, recognition, learning

DOI: 10.3233/JPD-150623

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 793-804, 2015

Authors: Béland, Sarah-Gabrielle | Postuma, Ronald B. | Latreille, Véronique | Bertrand, Josie-Anne | Panisset, Michel | Chouinard, Sylvain | Wolfson, Christina | Gagnon, Jean-François

Article Type: Research Article

Abstract: Background: Parkinson’s disease is characterized by numerous non-motor symptoms, including sleep disorders. Sleep apnea has been reported in a substantial proportion of patients with Parkinson’s disease, but it is unclear whether it has significant consequences for the quality of life of those affected or whether it is associated with other manifestations of the disease. Objective: To verify whether sleep apnea is associated with more severe motor and non-motor clinical features in Parkinson’s disease. Methods: Parkinson’s disease patients underwent polysomnography to diagnose the presence of sleep apnea (apnea-hypopnoea index >10). Participants also underwent an extensive assessment, blinded …to sleep apnea status, to determine disease severity, quantitative motor indices, motor subtypes, treatment complications, and sleep, autonomic, psychiatric, and sensory dysfunctions. Cognitive status was also determined with a complete neuropsychological assessment. Results were assessed using regression analysis adjusted for age, sex, and disease duration. Results: Of 92 patients examined, 19 had sleep apnea (21%) and 73 did not. We found no significant differences in motor and non-motor symptoms or signs between apneic and non-apneic Parkinson’s disease patients. The use of different apnea-hypopnoea index cut-offs (>5 and >15) produced similar results. Conclusions: Our results show that sleep apnea is not associated with more severe motor or non-motor manifestations in Parkinson’s disease. More studies including control groups are needed to confirm the implications of those results. Show more

Keywords: Parkinson’s disease, sleep apnea, non-motor symptoms, cognition

DOI: 10.3233/JPD-150602

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 805-811, 2015

Authors: Sullivan, Kelly L. | Mortimer, James A. | Wang, Wei | Zesiewicz, Theresa A. | Brownlee, H.J. | Borenstein, Amy R.

Article Type: Research Article

Abstract: Background: Associations have been reported between the risk of Parkinson’s disease (PD) and employment in certain fields. Most studies have focused on toxic exposures as potential causal explanations. However, PD also has been associated with personality characteristics that may influence occupational choices and patterns. Objective: This study evaluates the role of personality as indicated by occupational choices and employment patterns in the risk for PD. Methods: In-person interviews were conducted to assess occupational histories and early-adult personality indicators among 89 PD patients and 99 controls. Results: PD cases had fewer lifetime jobs than controls …(mean for cases = 4.38 ± 2.20; mean for controls = 5.00 ± 2.26; p  = 0.03). Among women, PD was positively associated with more complex work with people (OR = 1.45, 95% CI 1.12–1.89), representing a 95% increased risk for PD comparing women with the greatest complexity of work with those requiring the least complexity of work with people. Women PD cases also performed less complex work with things compared with controls (OR = 0.69 (95% CI 0.53–0.90)), translating into a 13-fold increased risk for PD among women whose work involved the least complex work with things compared with the most. The numbers of jobs and job types were associated with taking more activity risks as a young-adult (r  = 0.19, p  = 0.02; r  = 0.26, p  = 0.001, respectively). Conclusions: Cases with PD held fewer lifetime jobs compared with controls. Occupational complexity was associated with the risk for PD among women, but not men. Further consideration of the possible influence of personality on occupational choices is warranted. Show more

Keywords: Employment, novelty-seeking, risk-taking, premorbid, risk factors

DOI: 10.3233/JPD-150635

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 813-820, 2015

Authors: Yang, Panzao | Pavlovic, Darja | Waldvogel, Henry | Dragunow, Mike | Synek, Beth | Turner, Clinton | Faull, Richard | Guan, Jian

Article Type: Research Article

Abstract: Background: String vessels are collapsed basement membrane without endothelium and have no function in circulation. String vessel formation contributes to vascular degeneration in Alzheimer disease. By comparing to age-matched control cases we have recently reported endothelial degeneration in brain capillaries of human Parkinson disease (PD). Objective: Current study evaluated changes of basement membrane of capillaries, string vessel formation and their association with astrocytes, blood-brain-barrier integrity and neuronal degeneration in PD. Methods: Brain tissue from human cases of PD and age-matched controls was used. Immunohistochemical staining for collagen IV, GFAP, NeuN, tyrosine hydroxylase, fibrinogen and Factor VIII …was evaluated by image analysis in the substantia nigra, caudate nucleus and middle frontal gyrus. Results: While the basement-membrane-associated vessel density was similar between the two groups, the density of string vessels was significantly increased in the PD cases, particularly in the substantia nigra. Neuronal degeneration was found in all brain regions. Astrocytes and fibrinogen were increased in the caudate nuclei of PD cases compared with control cases. Conclusions: Endothelial degeneration and preservation of basement membrane result in an increase of string vessel formation in PD. The data may suggest a possible role for cerebral hypoperfusion in the neuronal degeneration characteristic of PD, which needs further investigation. Elevated astrocytosis in the caudate nucleus of PD cases could be associated with disruption of the blood-brain barrier in this brain region. Show more

Keywords: Capillaries, Parkinson’s disease, age and human

DOI: 10.3233/JPD-140454

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 821-836, 2015

Authors: Nausieda, Paul A. | Hsu, Ann | Elmer, Lawrence | Gil, Ramon A. | Spiegel, Joerg | Singer, Carlos | Khanna, Sarita | Rubens, Robert | Kell, Sherron | Modi, Nishit B. | Gupta, Suneel

Article Type: Research Article

Abstract: Background: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. Objective: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. Methods: Patients had ≥2.5 hours/day of “off” time despite a stable IR or CLE regimen. Suggested initial dosing conversion …tables based on prior LD daily dosage were provided. Results: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily “off” time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. Conclusions: Among PD patients with substantial “off” time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia. Show more

Keywords: Levodopa, Parkinson’s disease, dyskinesia, off-time, on-time, extended-release

DOI: 10.3233/JPD-150622

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 837-845, 2015

Authors: Haaxma, Charlotte A. | Horstink, Martin W.I.M. | Zijlmans, Jan C. | Lemmens, Wim A.J.G. | Bloem, Bastiaan R. | Borm, George F.

Article Type: Research Article

Abstract: Background: Response fluctuations and dyskinesias develop during the use of both levodopa (LD) and dopamine agonists (DA), but may not be equally disabling. Objective: To compare the risk and time of onset of disabling response fluctuations and dyskinesias (DRFD) among patients with Parkinson’s disease (PD) who were initially treated with either LD or DA. Methods: Open cohort study of all consecutive de-novo PD patients in routine clinical practice, included over a period of 15 years (median follow-up: 8.1 years, range 1.1–17.7), since embarking on LD or DA. Older patients and patients with more severe PD were …started on LD (n  = 77), younger patients on a DA (n  = 50). Therapy was adjusted according to generally accepted guidelines. The primary endpoints were: the onset of response fluctuations, dyskinesias, and the moment when these complications became disabling (DRFD). Results: LD-starters developed response fluctuations 0.8 years earlier than DA-starters (p  = 0.07), while dyskinesias appeared around 2.5 years earlier (p  = 0.003). However, the risk and time of onset of DRFD did not differ statistically between the groups (LD-starters: 60% , median interval 7.3 years, DA-starters: 52% , 6.1 years, p  = 0.63). DA-starters displayed a 0.19 points lower adjusted mean improvement in motor scores than LD-starters (p  = 0.002). Adjustments for age and severity of PD at start of dopaminergic therapy did not change these results. Conclusions: In routine clinical practice, the risk and time of onset of DRFD is comparable for LD-starters versus DA-starters, but motor functioning is worse in DA-starters. These results support the use of LD as initial therapy for PD. Show more

Keywords: Parkinson’s disease, levodopa, dopamine agonists, dyskinesia, response fluctuations

DOI: 10.3233/JPD-150532

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 847-853, 2015

Authors: Almeida, Lorena R.S. | Sherrington, Catherine | Allen, Natalie E. | Paul, Serene S. | Valenca, Guilherme T. | Oliveira-Filho, Jamary | Canning, Colleen G.

Article Type: Research Article

Abstract: Background: Predictors of falls in people with Parkinson’s disease (PD) who have not previously fallen are yet to be identified. Objectives: We aimed to identify predictors of all falls and recurrent falls in people with PD who had not fallen in the previous year and to explore the timing of falls in a 12-month follow-up period. Methods: Participants with PD (n  = 130) were assessed by disease-specific, self-report and balance measures. Falls were recorded prospectively for 12 months. Univariate and multivariate analyses were performed. Kaplan-Meier survival analysis was used to investigate time to falling. Results: …Forty participants (31%) had ≥1 fall during follow-up and 21 (16%) had ≥2 falls. Disability, reduced balance confidence and greater concern about falling were associated with ≥1 fall in univariate analyses. Additionally, PD duration and severity, freezing of gait and impaired balance were associated with ≥2 falls (p  <  0.05). Disability (Schwab and England scale, Odds Ratio [OR] = 0.56 per 10 points increase; 95% confidence interval [CI] 0.39–0.80; p  = 0.002) was associated with ≥1 fall in the final multivariate model (area under the receiver operating characteristic curve [AUC] = 0.65; 95% CI 0.55–0.76; p  = 0.005). Disability (Unified Parkinson’s Disease Rating Scale activities of daily living, OR = 1.20; 95% CI 1.07–1.34; p  = 0.001) and levodopa equivalent dose (OR = 1.11 per 100 mg increase; 95% CI 0.95–1.30; p  = 0.19) were associated with ≥2 falls in the final multivariate model (AUC = 0.72; 95% CI 0.60–0.84; p  = 0.001). Recurrent fallers experienced their first fall earlier than single fallers (p  <  0.05). Conclusions: Self-reported disability was the strongest single predictor of all falls and recurrent falls. Show more

Keywords: Parkinson’s disease, accidental falls, risk factors, postural balance

DOI: 10.3233/JPD-150651

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 855-864, 2015

Authors: Tan, Ai Huey | Tan, Chong Tin | Marras, Connie | Loh, Kwong Weng | Wye Ho, Niki Wai | Lim, Quan Hziung | Tan, Pei Wen | Lim, Chee Chean | Cheong, Yee Weai | Kong, Sik Thien | Schee, Jie Ping | Tan, Kean Hoong | Soo, Suet Ker | Vanderschaaf, Cheryl | Lai Heong Lew, Sara | Mahamad, Ummi Affah | Goh, Khean Jin | Yong, Hoi Sen | Lim, Shen-Yang

Article Type: Research Article

Abstract: Background: Public knowledge regarding Parkinson’s disease (PD) is important to facilitate good health-seeking behavior, but the literature on this topic is scarce. Objective: We aimed to explore the level of public knowledge regarding PD in a large multiethnic urban Asian cohort, and (as a secondary aim) in a smaller cohort of PD patients and caregivers. Methods: A Knowledge of PD Questionnaire (KPDQ) was developed and administered to members of the Malaysian general public, and to PD patients and caregivers. The KPDQ tests recognition of PD symptoms and general knowledge regarding PD. Results: 1,258 members of …the general public completed the KPDQ. Tremor was the most widely recognized symptom (recognized by 79.0% of respondents); however, 83.7% incorrectly believed that all PD patients experience tremor. Memory problem was the most widely recognized NMS. Overall, motor symptoms were better recognized than NMS. Common misperceptions were that there is a cure for PD (49.8%) and that PD is usually familial (41.4%). Female gender, Chinese ethnicity, tertiary education, healthcare-related work, and knowing someone with PD were independently associated with higher KPDQ scores. PD patients (n  = 116) and caregivers (n  = 135) demonstrated superior knowledge compared with the general public group, but one-third of them believed that PD is currently curable. Conclusions: This is the only study on public knowledge regarding PD in Asia. Important gaps in knowledge were evident, which could present a barrier to early diagnosis and appropriate treatment of PD. This highlights the need for targeted education campaigns and further research in this area. Show more

Keywords: Parkinson’s disease, epidemiology, knowledge, awareness, education, cure, stem cells, Asia

DOI: 10.3233/JPD-150594

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 865-879, 2015

Authors: Hall, Julie M. | Shine, James M. | O’Callaghan, Claire | Walton, Courtney C. | Gilat, Moran | Naismith, Sharon L. | Lewis, Simon J.G.

Article Type: Research Article

Abstract: Background: Freezing of gait is a common disabling symptom of Parkinson’s disease (PD) with limited treatment options. The pathophysiological mechanisms of freezing behaviour are still contentious. Objective: To investigate the prevalence of freezing of gait and its associations with increasing disease severity to gain a better understanding of the underlying pathophysiology. Methods: This exploratory study included 389 idiopathic PD patients, divided into four groups; early and advanced PD with freezing of gait, and early and advanced PD without freezing of gait. Motor, cognitive and affective symptoms, REM sleep behaviour disorder and autonomic function were assessed. …Results: Regardless of disease stage, patients with freezing of gait had more severe motor symptoms and a predominant non-tremor phenotype. In the early stages, freezers had a selective impairment in executive function and had more marked REM sleep behaviour disorder. Autonomic disturbances were not associated with freezing of gait across early or advanced disease stages. Conclusion: These findings support the notion that impairments across the frontostriatal pathways are intricately linked to the pathophysiology underlying freezing of gait across all stages of PD. Features of REM sleep behaviour disorder suggest a contribution to freezing from brainstem pathology but this does not extend to more general autonomic dysfunction. Show more

Keywords: Parkinson’s disease, freezing of gait, disease stage, pathophysiology, executive function

DOI: 10.3233/JPD-150581

Citation: Journal of Parkinson's Disease, vol. 5, no. 4, pp. 881-891, 2015