Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Neurobiol Aging. 2014 Jun 2. pii: S0197-4580(14)00388-1. doi: 10.1016/j.neurobiolaging.2014.05.025. [Epub ahead of print]

Hatano T, Funayama M, Kubo SI, Mata IF, Oji Y, Mori A, Zabetian CP, Waldherr SM, Yoshino H, Oyama G, Shimo Y, Fujimoto KI, Oshima H, Kunii Y, Yabe H, Mizuno Y, Hattori N.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

Cardiac 123I-MIBG uptake in de novo Brazilian patients with Parkinson's disease without clinically defined dysautonomia

Arq Neuropsiquiatr. 2014 Jun;72(6):430-4.

Leite MA, Nascimento OJ, Pereira JS, Amaral C, Mesquita CT, Azevedo JC, Brito AS, Pedras FV.

Abstract

Myocardial scintigraphy with meta-iodo-benzyl-guanidine (123I cMIBG) has been studied in Parkinson's disease (PD), especially in Asian countries, but not in Latin America. Most of these studies include individuals with PD associated to a defined dysautonomia. Our goal is to report the cardiac sympathetic neurotransmission in de novo Brazilian patients with sporadic PD, without clinically defined dysautonomia. We evaluated retrospectively a series of 21 consecutive cases with PD without symptoms or signs of dysautonomia assessed by the standard bedside tests. This number was reduced to 14 with the application of exclusion criteria. 123I cMIBG SPECT up-take was low or absent in all of them and the heart/mediastinum ratio was low in 12 of 14. We concluded that 123I cMIBG has been able to identify cardiac sympathetic neurotransmission disorder in Brazilian de novo PD patients without clinically defined dysautonomia.

Cardiac stress test is normal in pre-motor Parkinson's disease

Mov Disord. 2014 Jun 20. doi: 10.1002/mds.25943. [Epub ahead of print]

Yahalom G, Maor E, Hassin-Baer S, Segev S, Sidi Y, Kivity S.

Abstract

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow-up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 ± 8.82 vs. 48.91 ± 10.60 years, P < 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD.

Grey matter hypometabolism and atrophy in Parkinson's disease with cognitive impairment: a two-step process

Brain. 2014 Jun 20. pii: awu159. [Epub ahead of print]

González-Redondo R, García-García D, Clavero P, Gasca-Salas C, García-Eulate R, Zubieta JL, Arbizu J, Obeso JA, Rodríguez-Oroz MC.

Abstract

The pathophysiological process underlying cognitive decline in Parkinson's disease is not well understood. Cerebral atrophy and hypometabolism have been described in patients with Parkinson's disease and dementia or mild cognitive impairment with respect to control subjects. However, the exact relationships between atrophy and hypometabolism are still unclear. To determine the extension and topographical distribution of hypometabolism and atrophy in the different cognitive states of Parkinson's disease, we examined 46 patients with Parkinson's disease (19 female, 27 male; 71.7 ± 5.9 years old; 14.6 ± 4.2 years of disease evolution; modified Hoehn and Yahr mean stage 3.1 ± 0.7). Cognitive status was diagnosed as normal in 14 patients, as mild cognitive impairment in 17 and as dementia in 15 patients. Nineteen normal subjects (eight female, 11 male; 68.1 ± 3.2 years old) were included as controls. 18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging scans were obtained, co-registered, corrected for partial volume effect and spatially normalized to the Montreal Neurological Institute space in each subject. Smoothing was applied to the positron emission tomography and magnetic resonance imaging scans to equalize their effective smoothness and resolution (10 mm and 12 mm full-width at half-maximum and Gaussian kernel, respectively). Z-score maps for atrophy and for hypometabolism were obtained by comparing individual images to the data set of control subjects. For each group of patients, a paired Student's t-test was performed to statistically compare the two Z-map modalities (P < 0.05 false discovery rate corrected) using the direct voxel-based comparison technique. In patients with mild cognitive impairment, hypometabolism exceeded atrophy in the angular gyrus, occipital, orbital and anterior frontal lobes. In patients with dementia, the hypometabolic areas observed in the group with mild cognitive impairment were replaced by areas of atrophy, which were surrounded by extensive zones of hypometabolism. Areas where atrophy was more extended than hypometabolism were found in the precentral and supplementary motor areas in both patients with mild cognitive impairment and with dementia, and in the hippocampus and temporal lobe in patients with dementia. These findings suggest that there is a gradient of severity in cortical changes associated with the development of cognitive impairment in Parkinson's disease in which hypometabolism and atrophy represent consecutive stages of the same process in most of the cortical regions affected.

Parkinson's disease and REM sleep behavior disorder result in increased non-motor symptoms

Sleep Med. 2014 May 10. pii: S1389-9457(14)00170-1. doi: 10.1016/j.sleep.2014.04.009. [Epub ahead of print]

Neikrug AB, Avanzino JA, Liu L, Maglione JE, Natarajan L, Corey-Bloom J, Palmer BW, Loredo JS, Ancoli-Israel S.

OBJECTIVE:

Rapid eye movement (REM)-sleep behavior disorder (RBD) is often comorbid with Parkinson's disease (PD). The current study aimed to provide a detailed understanding of the impact of having RBD on multiple non-motor symptoms (NMS) in patients with PD.

METHODS:

A total of 86 participants were evaluated for RBD and assessed for multiple NMS of PD. Principal component analysis was utilized to model multiple measures of NMS in PD, and a multivariate analysis of variance was used to assess the relationship between RBD and the multiple NMS measures. Seven NMS measures were assessed: cognition, quality of life, fatigue, sleepiness, overall sleep, mood, and overall NMS of PD.

RESULTS:

Among the PD patients, 36 were classified as having RBD (objective polysomnography and subjective findings), 26 as not having RBD (neither objective nor subjective findings), and 24 as probably having RBD (either subjective or objective findings). RBD was a significant predictor of increased NMS in PD while controlling for dopaminergic therapy and age (p=0.01). The RBD group reported more NMS of depression (p=0.012), fatigue (p=0.036), overall sleep (p=0.018), and overall NMS (p=0.002).

CONCLUSION:

In PD, RBD is associated with more NMS, particularly increased depressive symptoms, sleep disturbances, and fatigue. More research is needed to assess whether PD patients with RBD represent a subtype of PD with different disease progression and phenomenological presentation.

Differentiating drug-induced parkinsonism from Parkinson's disease: An update on non-motor symptoms and investigations

Parkinsonism Relat Disord. 2014 Jun 3. pii: S1353-8020(14)00214-4. doi: 10.1016/j.parkreldis.2014.05.011. [Epub ahead of print]

Brigo F, Erro R, Marangi A, Bhatia K, Tinazzi M.

Abstract

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.

Salivary DJ-1 could be an indicator of Parkinson's disease progression

Good correlations with SPECT imaging but unfortunately not at differentiating patients from controls...

Front Aging Neurosci. 2014 Jun 6;6:102. doi: 10.3389/fnagi.2014.00102. eCollection 2014.

Kang WY, Yang Q, Jiang XF, Chen W, Zhang LY, Wang XY, Zhang LN, Quinn TJ, Liu J, Chen SD.

Abstract

Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinson's disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) ((99m)Tc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of (99m)Tc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD.

Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial

Good to see these data reported from this important study in large numbers of patients...

Lancet. 2014 Jun 10. pii: S0140-6736(14)60683-8. doi: 10.1016/S0140-6736(14)60683-8. [Epub ahead of print]

Pd Med Collaborative Group.

BACKGROUND:

Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease.

METHODS:

In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316.

FINDINGS:

Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001).

INTERPRETATION:

Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists.

FUNDING:

UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.

Quality of Life and Mild Cognitive Impairment in Early Parkinson's Disease: Does Subtype Matter?

J Parkinsons Dis. 2014 Jun 11. [Epub ahead of print]

Lawson RA, Yarnall AJ, Duncan GW, Khoo TK, Breen DP, Barker RA, Collerton D, Taylor JP, Burn DJ.

Abstract

We evaluated the association between mild cognitive impairment (MCI) subtypes and quality of life (QoL) in 219 newly diagnosed Parkinson's disease (PD) patients without dementia. Participants completed neuropsychological tests of attention, executive function, visuospatial function, memory, and language, and reported QoL using the Parkinson's Disease Questionnaire. Impairments were most common in executive function, memory and attention. MCI subtypes were classified according to Movement Disorder Society Task Force criteria. More severe cognitive impairment was associated with poorer quality of life (p = 0.01), but subtype of impairment was not (p > 0.10), suggesting that the nature of cognitive impairment is less significant than its severity.

Motor progression of Parkinson's disease with the leucine-rich repeat kinase 2 G2019S mutation.

Interesting and important observation as momentum builds around the study of manifesting and non manifesting carriers of LRRK2 mutations...

Mov Disord. 2014 Jun 5. doi: 10.1002/mds.25931. [Epub ahead of print]

Yahalom G, Orlev Y, Cohen OS, Kozlova E, Friedman E, Inzelberg R, Hassin-Baer S.

INTRODUCTION:

In this retrospective study, we compared motor disease progression in Ashkenazi-Jewish (AJ) Parkinson's disease (PD) patients carrying the LRRK2*G2019S mutation with that of noncarriers.

METHODS:

Consecutive PD patients were recruited between 2004 and 2011. Disease progression of carriers versus noncarriers was compared using survival analysis, where the end-point was the time from PD onset to reaching Hoehn and Yahr stage 3 (HY3).

RESULTS:

Overall, 405 AJ PD patients (males = 241[60%]) were genotyped, of whom 60 (males = 30) were LRRK2*G2019S mutation carriers. Time to HY3 did not differ significantly between mutation carriers and noncarriers (hazard ratio = 1.21, 95%CI = 0.83-1.77, P = 0.33). Age at PD onset was younger for carriers than for noncarriers (59.1 ± 9.8 vs. 63.2 ± 12.0 years, respectively; P = 0.005). In both groups, young age at onset was strongly associated with longer time to HY3, (P < 0.001).

CONCLUSION:

The LRRK2*G2019S mutation status has no discernible effect on the rate of motor disease progression in AJ PD patients.

A Prospective Analysis of Airborne Metal Exposures and Risk of Parkinson Disease in the Nurses Health Study Cohort

Environ Health Perspect. 2014 Jun 6. [Epub ahead of print]

Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F.

Abstract

BACKGROUND:

Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD).

OBJECTIVES:

We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD.

METHODS:

We linked the Environmental Protection Agency's Air Toxics tract-level data with the Nurses Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 to 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury and nickel, as well as total (sum) metal exposure. To estimate Hazard Ratios (HRs) and 95% confidence intervals (CI), we used the Cox Proportional Hazards model adjusting for age, smoking, and population density.

RESULTS:

In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury.

CONCLUSIONS:

Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies.

Hospitalisation and comorbidities in Parkinson's disease: a large Australian retrospective study.

J Neurol Neurosurg Psychiatry. 2014 May 29. pii: jnnp-2014-307822. doi: 10.1136/jnnp-2014-307822. [Epub ahead of print]

Lubomski M, Rushworth RL, Tisch S.

OBJECTIVES:

Patients with Parkinson's disease (PD) require higher levels of care during hospitalisation. Management of comorbidities in these patients aims to optimise function while minimising complications. The objective of this study was to examine patterns of hospitalisation of patients with PD in NSW with regards to sociodemographic factors, comorbidities and aspects of clinical management.

METHODS:

A retrospective study of all patients with idiopathic PD and a control group of non-PD patients admitted for acute care to NSW hospitals between 2008 and 2012.

RESULTS:

The study group comprised 5637 cases and 8143 controls. The mean PD patient age was 75.0 years (±10.9). Patients with PD had a significantly longer hospital stay (median 7 days, IQR 3-13 vs 1 day, IQR 1-7, p<0.001) than control patients. Patients with PD were five times more likely to be treated for delirium, three times more likely to experience an adverse drug event and syncope, more than twice as likely to require management of falls/fractures, dementia, gastrointestinal complications, genitourinary infections, reduced mobility and other trauma but half as likely to require hospitalisation for chronic airways disease and neoplasia, including melanoma, than the control group (all p<0.001).

CONCLUSIONS:

Patients with PD are more likely to suffer serious health problems, including delirium, adverse drug reactions, syncope, falls and fractures than controls. These findings highlight PD as a multisystem neuropsychiatric disorder in which motor and non-motor features contribute to morbidity. Increased awareness of the added risk PD poses in acute hospitalised patients can be used to inform strategies to improve patient outcomes.

Living with Parkinson's disease: Priorities for research suggested by patients

Parkinsonism Relat Disord. 2014 May 10. pii: S1353-8020(14)00178-3. doi: 10.1016/j.parkreldis.2014.04.025. [Epub ahead of print]

Schipper K, Dauwerse L, Hendrikx A, Leedekerken JW, Abma TA.

PURPOSE:

To describe a study in which patients with Parkinson's disease (PD) were engaged to list priorities for research to complement the professionals' research agenda.

METHOD:

The study was conducted by researchers and people with PD or relatives. Interviews and focus groups were held to develop a research agenda from patients' perspectives. A questionnaire was completed by patients to prioritize the research topics. Voiceover group meetings and meetings with the advisory group were organized to obtain feedback on the research process and to deliberate the preliminary findings. Finally, dialog meetings were organized with stakeholders to discuss the agenda and to achieve a shared research agenda.

RESULTS:

Patients prioritized 18 research themes. Top priorities included fundamental research, research on medication, coping, family & relations and good care. Patients asked for applied and multidisciplinary research. Professionals and charitable funding bodies acknowledged the importance of such research but did not feel capable of judging such proposals. Patients furthermore asked for more attention to be paid to living with the illness in the here-and-now to complement fundamental research.

CONCLUSIONS:

The patients' research agenda can be used to match research with patients' needs and to adapt the clinical support of professionals to patients' wishes.

The Parkinson Anxiety Scale (PAS): Development and validation of a new anxiety scale

May prove an important addition. There always seems to be many more depression scales than there are anxiety scales...

Mov Disord. 2014 May 23. doi: 10.1002/mds.25919. [Epub ahead of print]

Leentjens AF, Dujardin K, Pontone GM, Starkstein SE, Weintraub D, Martinez-Martin P.

Abstract

Existing anxiety rating scales have limited construct validity in patients with Parkinson's disease (PD). This study was undertaken to develop and validate a new anxiety rating scale, the Parkinson Anxiety Scale (PAS), that would overcome the limitations of existing scales. The general structure of the PAS was based on the outcome of a Delphi procedure. Item selection was based on a canonical correlation analysis and a Rasch analysis of items of the Hamilton Anxiety Rating Scale (HARS) and the Beck Anxiety Inventory (BAI) from a previously published study. Validation was done in a cross-sectional international multicenter study involving 362 patients with idiopathic PD. Patients underwent a single screening session in which the PAS was administered, along with the Hamilton Depression Rating Scale, the HARS, and the BAI. The Mini International Neuropsychiatric Interview was administered to establish Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses of anxiety and depressive disorders. The PAS is a 12-item observer or patient-rated scale with three subscales, for persistent, episodic anxiety and avoidance behavior. Properties for acceptability and reliability met predetermined criteria. The convergent and known groups validity was good. The scale has a satisfactory factorial structure. The area under the receiver operating characteristics curve and Youden index of the PAS are higher than that of existing anxiety rating scales. The PAS is a reliable and valid anxiety measure for use in PD patients. It is easy and brief to administer, and has better clinimetric properties than existing anxiety rating scales. The sensitivity to change of the PAS remains to be assessed.