Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease

Parkinsonism Relat Disord. 2013 Aug 29. pii: S1353-8020(13)00305-2. doi: 10.1016/j.parkreldis.2013.08.011. [Epub ahead of print]

Bunzeck N, Singh-Curry V, Eckart C, Weiskopf N, Perry RJ, Bain PG, Düzel E, Husain M.

Source

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany. 

Abstract

BACKGROUND:

In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population.

METHODS:

Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals.

RESULTS:

We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus.

CONCLUSIONS:

Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease.

Influence of Single Nucleotide Polymorphisms in COMT , MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson's Disease

Neurodegener Dis. 2013 Sep 5. [Epub ahead of print]

Cheshire P, Bertram K, Ling H, O'Sullivan SS, Halliday G, McLean C, Bras J, Foltynie T, Storey E, Williams DR.

Source

Department of Medicine (Neuroscience), Monash University (Alfred Hospital), Melbourne, Vic., Australia.

Abstract

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. Objective: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. Methods: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025). Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.

Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome: Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications

Nancy J. Butcher, Tim-Rasmus Kiehl, Lili-Naz Hazrati, Eva W. C. Chow, Ekaterina Rogaeva, Anthony E. Lang, Anne S. Bassett

JAMA Neurol. Published online September 09, 2013

Importance   Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.

Objective   To evaluate a possible association between 22q11.2 deletions and PD.

Design, Setting, and Participants   An observational study of the occurrence of PD in the world’s largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.

Main Outcomes and Measures   A clinical diagnosis of PD made by a neurologist and neuropathological features of PD.

Results   Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein–positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.

Conclusions and Relevance   These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

Comparison of once-daily versus twice-daily combination of Ropinirole prolonged release in Parkinson's disease

BMC Neurol. 2013 Sep 2;13(1):113. [Epub ahead of print]

Yun JY, Kim HJ, Lee JY, Kim YE, Kim JS, Kim JM, Jeon BS.

Abstract

BACKGROUND:

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease.

METHODS:

This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).

RESULTS:

A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.

CONCLUSION:

RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.Trial registration: This study is registered with ClinicalTrials.gov, number NCT00986245.

Motor fluctuations and Helicobacter pylori in Parkinson's disease

J Neurol. 2013 Sep 4. [Epub ahead of print]

Rahne KE, Tagesson C, Nyholm D.

Source

NeuroCenter Saint Göran Hospital, Stockholm, Sweden.

Abstract

The presence of Helicobacter pylori (HP) in the gastrointestinal tract may limit the absorption of levodopa. The objectives of this study were to investigate whether HP infection may affect the clinical response to levodopa as well as levodopa dose requirement in patients with Parkinson's disease (PD) as well as to investigate whether HP infection may affect plasma levels of vitamin B12, folic acid, and homocysteine. Seventy-five patients with PD diagnosed at least 4 years ago were included. Symptom fluctuations were assessed by UPDRS-IV and the WOQ9 wearing-off-scale. Plasma levels of vitamin B12, folic acid, and homocysteine were analyzed. Screening for HP was performed with a 13C-labeled urea breath test (Diabact UBT). A propensity-matched analysis was made where each patient in the HP-infected group was matched with one patient in the non-infected group with respect to age and gender. Of the 75 included patients, 20 were HP infected (27 %). Median Hoehn & Yahr scores were 3 in both HP infected patients and the matched group (n = 20). HP-infected patients had decreased "complications of therapy" with average total UPDRS-IV score of 4.8 ± 3.0 vs. 7.7 ± 3.8 (p < 0.05), despite no significant difference in levodopa equivalent dose. Wearing-off and sleep disturbance were significantly less common in the HP group (p < 0.05). There were no differences regarding vitamin B12, folic acid, or homocysteine values. HP infection in patients with PD may result in a decreased occurrence of symptom fluctuations according to this small study. This finding may be due to altered absorption of levodopa in the gastrointestinal tract in patients with HP infection, but further studies are required.

Association of stressful life events with incident falls and fractures in older men: the Osteoporotic Fractures in Men (MrOS) Study

Age Ageing. 2013 Sep 3. [Epub ahead of print]

Fink HA, Kuskowski MA, Marshall LM.

Source

VA Medical Center, Geriatric Research Education and Clinical Center, One Veterans Drive, 11-G, Minneapolis, MN 55417, USA.

Abstract

BACKGROUND:

small, retrospective studies suggest that major life events and/or sudden emotional stress may increase fall and fracture risk. The current study examines these associations prospectively.

METHODS:

a total of 5,152 men aged ≥65 years in the Osteoporotic Fractures in Men study self-reported data on stressful life events for 1 year prior to study Visit 2. Incident falls and fractures were ascertained for 1 year after Visit 2. Fractures were centrally confirmed.

RESULTS:

a total of 2,932 (56.9%) men reported ≥1 type of stressful life event. In men with complete stressful life event, fall and covariate data (n = 3,949), any stressful life event was associated with a 33% increased risk of incident fall [relative risk (RR) 1.33, 95% confidence interval (CI) 1.19-1.49] and 68% increased risk of multiple falls (RR = 1.68, 95% CI = 1.40-2.01) in the year following Visit 2 after adjustment for age, education, Parkinson's disease, diabetes, stroke, instrumental activities of daily living (IADL) impairment, chair stand time, walk speed, multiple past falls, depressive symptoms and antidepressant use. Risk increased with the number of types of stressful life events. Though any stressful life event was associated with a 58% increased age-adjusted risk for incident fracture, this association was attenuated and no longer statistically significant after additional adjustment for total hip bone mineral density, fracture after age 50, Parkinson's disease, stroke and IADL impairment.

CONCLUSIONS:

in this cohort of older men, stressful life events significantly increased risk of incident falls independent of other explanatory variables, but did not independently increase incident fracture risk.

Integrated multidisciplinary care in Parkinson's disease: a non-randomised, controlled trial (IMPACT)

Lancet Neurol. 2013 Aug 23. pii: S1474-4422(13)70196-0. doi: 10.1016/S1474-4422(13)70196-0. [Epub ahead of print]

van der Marck MA, Munneke M, Mulleners W, Hoogerwaard EM, Borm GF, Overeem S, Bloem BR; for the IMPACT study group.

Source

Department of Neurology, Nijmegen Centre for Evidence Based Practice, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

Abstract

BACKGROUND:

A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care.

METHODS:

We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehörigen-kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791.

FINDINGS:

We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1·3 points, 95% CI -2·1 to 2·8; corresponding raw logit score difference 0·1, 95% CI 0·003 to 0·2) as was the average PDQL score (difference 3·0 points, 0·4 to 5·6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0·9 points, 95% CI -0·6 to 2·4; corresponding raw logit score difference 0·1, -0·02 to 0·3) or PDQL (difference 1·7 points, -1·2 to 4·6). Secondary outcomes did not differ between groups (UPDRS III score difference 0·6 points, 95% CI -1·4 to 2·6; BELA-A-k score difference 0·8 points, -0·2 to 1·8; cost difference €742, -€489 to €1950).

INTERPRETATION:

This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits.

FUNDING:

NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation.

Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease

J Neurol. 2013 Aug 30. [Epub ahead of print]

Picillo M, Amboni M, Erro R, Longo K, Vitale C, Moccia M, Pierro A, Santangelo G, De Rosa A, De Michele G, Santoro L, Orefice G, Barone P, Pellecchia MT.

Source

Department of Neurological Sciences, Federico II University, Naples, Italy.

Abstract

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ 2 exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

The Relationship between Thermoregulation and REM Sleep Behaviour Disorder in Parkinson's Disease

PLoS One. 2013 Aug 21;8(8):e72661. doi: 10.1371/journal.pone.0072661.

Zhong G, Bolitho S, Grunstein R, Naismith SL, Lewis SJ.

Source

Parkinson's Disease Research Clinic, Brain and Mind Research Institute, The University of Sydney, Sydney, New South Wales, Australia.

Abstract

BACKGROUND:

This study explored the relationship between symptoms of rapid eye movement sleep behaviour disorder, thermoregulation and sleep in Parkinson's Disease.

METHODS:

The study group comprised 12 patients with Parkinson's Disease and 11 healthy age-matched controls. We investigated markers of thermoregulation (core-body temperature profile), circadian rhythm (locomotor actigraphy) and sleep (polysomnography).

RESULTS:

The mesor (the mean value around which the core temperature rhythm oscillates) of the core-body temperature in patients with Parkinson's Disease was significantly lower than that of controls. In addition, the nocturnal fall in CBT (the difference between the mesor and the nadir temperature) was also significantly reduced in PD patients relative to controls. Furthermore, in patients the reduction in the amplitude of their core-body temperature profile was strongly correlated with the severity of self-reported rapid eye movement sleep behaviour disorder symptom, reduction in the percentage of REM sleep and prolonged sleep latency. By contrast, these disturbances of thermoregulation and sleep architecture were not found in controls and were not related to other markers of circadian rhythm or times of sleep onset and offset.

CONCLUSIONS:

These findings suggest that the brainstem pathology associated with disruption of thermoregulation in Parkinson's disease may also contribute to rapid eye movement sleep behavioural disorder. It is possible that detailed analysis of the core-body temperature profile in at risk populations such as those patients with idiopathic rapid eye movement sleep behaviour disorder might help identify those who are at high risk of transitioning to Parkinson's Disease.

The applause sign in Parkinson's disease patients is related to dysexecutive syndrome.

J Clin Neurosci. 2013 Aug 20. pii: S0967-5868(13)00226-9. doi: 10.1016/j.jocn.2013.02.024. [Epub ahead of print]

Tomic S, Vladetic M, Solic K, Misevic S, Soldo SB.

Source

Department of Neurology, Osijek University Hospital Center, J. Huttlera 4, HR-31000 Osijek, Croatia. 

Abstract

Recent publications report that a positive applause sign is not only present in patients with neurodegenerative diseases where the subcortical structures are affected but also in patients with cortical dementia. The nature of this sign remains unknown. This study aimed to determine the frequency of the applause sign and its correlation with cognitive impairment in patients with idiopathic Parkinson's disease. The study included 30 non-depressed patients diagnosed with idiopathic Parkinson's disease. Study patients underwent the Unified Parkinson Disease Rating Scale part III, Dementia Rating Scale (DRS), Raven's Colored Progressive Matrices, and Mill Hill Vocabulary tests. Statistical analysis was performed by use of the parametric Student's t-test, nonparametric Mann-Whitney U test and Fisher's exact test, with the level of significance set at p<0.05. Negative applause sign was recorded in 66.7% and positive applause sign in 33.3% of patients. There were no between-group differences according to age, disease duration, or severity of motor symptoms. The positive applause sign group had significantly lower scores on the initiation/perseveration subscale of the DRS and a significantly higher frequency of scores below the cut-off score on the conceptualization and construction subscales of the DRS. The applause sign appears to be part of a broader dysexecutive syndrome in idiopathic Parkinson's disease.

The use of University of Pennsylvania Smell Identification Test in the diagnosis of Parkinson's disease in Italy

Neurol Sci. 2013 Aug 22. [Epub ahead of print]

Picillo M, Pellecchia MT, Erro R, Amboni M, Vitale C, Iavarone A, Moccia M, Allocca R, Orefice G, Barone P.

Source

Department of Neurological Sciences, University Federico II, Naples, Italy.

Abstract

Hyposmia is a common finding in Parkinson's disease (PD). The 40-item University of Pennsylvania Smell Identification Test (UPSIT-40) has been adapted and administered in several countries as a diagnostic tool in the diagnosis of PD. We have developed a culturally adapted version of the UPSIT-40 and applied it to 61 nondemented Italian controls and to 68 PD patients. Multiple linear regression analysis was performed to assess the factors that independently influence UPSIT-40 and logistic regression analysis was employed to study the usefulness of UPSIT-40 to predict PD diagnosis. Multiple linear regression analysis showed that PD diagnosis (p < 0.001), age (p = 0.006), gender (p = 0.003) and smoking status (p = 0.03) were significant independent predictors of the UPSIT-40 total score. Using diagnosis as dependent variable, logistic regression analysis showed that UPSIT-40 total score (p < 0.001) was an independent predictor of PD. Using a score ≤21/40 as a cut-off point for assigning subjects to PD group, the UPSIT-40 total score differentiated PD and control subjects with 82 % sensitivity and 88.2 % specificity. The adapted version of UPSIT-40 may be useful in addition to clinical examination to improve accuracy of diagnosis of PD in Italian population.