Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

It will be interesting to see whether this leads to better prognostication...

Eur J Nucl Med Mol Imaging. 2014 May 28. [Epub ahead of print]

Kaasinen V, Kinos M, Joutsa J, Seppänen M, Noponen T.

PURPOSE:

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor.

METHODS:

[123I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates.

RESULTS:

Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen.

CONCLUSION:

The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor.

Prodromal symptoms and early detection of Parkinson's disease in general practice: a nested case-control study

Fam Pract. 2014 May 28. pii: cmu025. [Epub ahead of print]

Plouvier AO, Hameleers RJ, van den Heuvel EA, Bor HH, Olde Hartman TC, Bloem BR, van Weel C, Lagro-Janssen AL.

BACKGROUND:

Timely diagnosis of Parkinson's disease (PD), facilitating early intervention, depends largely on the GP's awareness of early symptomatology. For general practice, it is unknown which prodromal symptoms (symptoms preceding the typical motor symptoms of PD) demand the GP's alertness.

OBJECTIVE:

To assess prodromal symptoms that should alert the GP to the possibility of PD in primary care patients.

METHODS:

A nested case-control study was carried out in a population of approximately 12000 patients registered in the Continuous Morbidity Registration database affiliated with the University of Nijmegen in the Netherlands. The database pools subject data from four primary care practices. The subjects comprised all 86 patients diagnosed with PD between 1972 and 2007, and 78 controls, matched by sex, age, socioeconomic status and primary care practice. The primary measures of outcome were the prodromal symptoms presenting in the two years prior to the diagnosis of PD. The number (and type) of referrals and diagnostic tests were also assessed.

RESULTS:

In the two-year period prior to diagnosis, PD patients more often presented with functional somatic symptoms, constipation, hyperhidrosis and sleep disorders than controls. Patients also more frequently experienced more than one prodromal symptom and were more often referred within the primary care team or to a medical specialist.

CONCLUSIONS:

Prodromal symptoms of PD are encountered in general practice. GPs should be alert when patients present with multiple prodromal symptoms in a two-year period, especially considering the benefits of early intervention, and the future possibilities for disease-modifying therapy.

[¹²³I]FP-CIT SPECT (DaTSCAN) may be a useful tool to differentiate between Parkinson's disease and vascular or drug-induced parkinsonisms: a meta-analysis.

Eur J Neurol. 2014 Apr 30. doi: 10.1111/ene.12444. [Epub ahead of print]

Brigo F, Matinella A, Erro R, Tinazzi M.

Abstract

BACKGROUND AND PURPOSE:

Differentiating idiopathic Parkinson's disease from secondary parkinsonian syndromes is crucial since their management and prognosis differ considerably. Functional imaging of the dopaminergic pathway by means of [¹²³I]FP-CIT SPECT (DaTSCAN) might be useful in this regard, but its role is still controversial. The accuracy of DaTSCAN in the differential diagnosis between Parkinson's disease and vascular or drug-induced parkinsonism was therefore systematically reviewed.

METHODS:

MEDLINE and CENTRAL were searched for studies aiming to determine accuracy measures (sensitivity, specificity, diagnostic odds ratio, positive and negative likelihood ratios) of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism.

RESULTS:

Five studies were included. Pooled accuracy measures in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism were relatively high, with sensitivity and specificity values above 85% and 80%, respectively.

CONCLUSIONS:

DaTSCAN might accurately differentiate between early Parkinson's disease and secondary parkinsonian conditions, namely vascular or drug-induced, in patients with clinically unclear parkinsonism. However, all the studies reviewed here show several methodological limits, which prevent definitive conclusions on the role of DaTSCAN being drawn in this context. Further studies are needed to confirm our results and definitely evaluate the utility of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism.

Bradykinesia-Akinesia Incoordination Test: Validating an Online Keyboard Test of Upper Limb Function

Our new paper on the validation of the BRAIN test which we use in PREDICT-PD for remote assessment of upper limb speed and accuracy...

PLoS One. 2014 Apr 29;9(4):e96260. doi: 10.1371/journal.pone.0096260. eCollection 2014.

Noyce AJ, Nagy A, Acharya S, Hadavi S, Bestwick JP, Fearnley J, Lees AJ, Giovannoni G.

Abstract

BACKGROUND:

The Bradykinesia Akinesia Incoordination (BRAIN) test is a computer keyboard-tapping task that was developed for use in assessing the effect of symptomatic treatment on motor function in Parkinson's disease (PD). An online version has now been designed for use in a wider clinical context and the research setting.

METHODS:

Validation of the online BRAIN test was undertaken in 58 patients with Parkinson's disease (PD) and 93 age-matched, non-neurological controls. Kinesia scores (KS30, number of key taps in 30 seconds), akinesia times (AT30, mean dwell time on each key in milliseconds), incoordination scores (IS30, variance of travelling time between key presses) and dysmetria scores (DS30, accuracy of key presses) were compared between groups. These parameters were correlated against total motor scores and sub-scores from the Unified Parkinson's Disease Rating Scale (UPDRS).

RESULTS:

Mean KS30, AT30 and IS30 were significantly different between PD patients and controls (p≤0.0001). Sensitivity for 85% specificity was 50% for KS30, 40% for AT30 and 29% for IS30. KS30, AT30 and IS30 correlated significantly with UPDRS total motor scores (r = -0.53, r = 0.27 and r = 0.28 respectively) and motor UPDRS sub-scores. The reliability of KS30, AT30 and DS30 was good on repeated testing.

CONCLUSIONS:

The BRAIN test is a reliable, convenient test of upper limb motor function that can be used routinely in the outpatient clinic, at home and in clinical trials. In addition, it can be used as an objective longitudinal measurement of emerging motor dysfunction for the prediction of PD in at-risk cohorts.

STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice

Mov Disord Clin Pract (Hoboken). 2014 Apr 1;1(1):24-35.

Williams NR, Foote KD, Okun MS.

Abstract

When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson's disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient's outcome? and 2- Should this patient's DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson's disease cases (Figure 1). This bilateral STN "one-size-fits-all" approach was challenged by an editorial entitled "STN vs. GPi: The Rematch," which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi 'rematch' studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson's disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom specific approach will be proposed to optimize outcomes of PD DBS therapy. Finally, the importance of an interdisciplinary care team for screening and effective management of DBS patients will be reaffirmed. Interdisciplinary teams can facilitate the proposed patient-specific DBS treatment planning and provide a more thorough analysis of the risk-benefit ratio for each patient.

Accurate Detection of Parkinson's Disease in Tremor Syndromes Using Olfactory Testing

Be careful not to sniff too hard with stick number 16!

Eur Neurol. 2014 Apr 26;72(1-2):1-6. [Epub ahead of print]

Wolz M, Hähner A, Meixner L, Löhle M, Reichmann H, Hummel T, Storch A.

Abstract

Background/Aims: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson's disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. Methods: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using 'Sniffin' Sticks', resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. Results: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80-0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. Conclusion: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients.

Reproductive factors and Parkinson's disease risk in Danish women

Our previous meta-analysis did not suggest these female factors were associated with Parkinson's

Eur J Neurol. 2014 Apr 22. doi: 10.1111/ene.12450. [Epub ahead of print]

Greene N, Lassen CF, Rugbjerg K, Ritz B.

Abstract

BACKGROUND AND PURPOSE:

Parkinson's disease is more common in men than women by a ratio of about 1.5:1 and yet there is no consensus to date as to whether female reproductive factors including hormone use affect Parkinson's disease risk. Our objective was to examine the relationship between Parkinson's disease and female reproductive factors in the largest population-based Parkinson's disease case-control study to date.

METHODS:

Seven hundred and forty-three female Parkinson's disease cases diagnosed between 1996 and 2009 were selected from the Danish National Hospital Register, diagnoses confirmed by medical record review, and the cases were matched by birth year to 765 female controls randomly selected from the Danish Civil Registration System. Covariate information was collected in computer-assisted telephone interviews covering an extensive array of topics including reproductive and lifestyle factors.

RESULTS:

After adjusting for smoking, caffeine and alcohol use, education, age, and family Parkinson's disease history, inverse associations between Parkinson's disease and early menarche (first period at ≤11 years), oral contraceptives, high parity (≥4 children) and bilateral oophorectomy were found; adjusted odds ratios and 95% confidence limits were respectively 0.68 (0.45-1.03) for early menarche, 0.87 (0.69-1.10) for oral contraceptives, 0.79 (0.59-1.06) for high parity and 0.65 (0.45-0.94) for bilateral oophorectomy. Little support for associations between Parkinson's disease and fertile life length, age at menopause or post-menopausal hormone treatment was found.

CONCLUSIONS:

Reproductive factors related to women's early- to mid-reproductive lives appear to be predictive of subsequent Parkinson's disease risk whereas factors occurring later in life seem less important.

CSF Aβ42 predicts early-onset dementia in Parkinson disease.

Neurology. 2014 Apr 18. [Epub ahead of print]

Alves G, Lange J, Blennow K, Zetterberg H, Andreasson U, Førland MG, Tysnes OB, Larsen JP, Pedersen KF.

Abstract

OBJECTIVE:

To test in vivo the proposal from clinicopathologic studies that β-amyloid (Aβ) pathology shortens the time to dementia in Parkinson disease (PD), and to explore the utility of CSF Aβ and related measures as early prognostic biomarkers of dementia in an incident PD cohort.

METHODS:

We assessed a population-based incident cohort of 104 patients with PD who underwent lumbar puncture at diagnosis. We analyzed CSF concentrations of Aβ42, Aβ40, and Aβ38 using a multiplexed immunoassay with electrochemiluminescence (ECL) detection and levels of Aβ42, total tau, and phosphorylated tau using ELISA. Patients were followed prospectively for 5 years. Dementia was diagnosed according to published criteria.

RESULTS:

CSF levels of Aβ42 were significantly decreased in patients who developed dementia (n = 20, 19.2%) compared to those who did not (n = 84, 80.8%), as measured by ECL (-33%, p = 0.006) as well as ELISA (-36%, p < 0.001). No differences were observed for other markers. Low Aβ42 values predicted a substantially increased risk for subsequent dementia at high sensitivity (≥85%), with hazard ratios of 9.9 (95% confidence interval 2.3-43.5, p = 0.002) for Aβ42ECL <376 pg/mL and 7.6 (2.2-26.4, p = 0.001) for Aβ42ELISA <443 pg/mL, after adjustment for baseline age and PD-mild cognitive impairment (MCI) status. Aβ42 reductions tended to precede the onset of PD-MCI that progressed to dementia.

CONCLUSIONS:

These in vivo data support the role of Aβ pathology in the etiology and highlight the potential utility of CSF Aβ42 as an early prognostic biomarker of dementia associated with PD.

Insights from the Global Longitudinal Study of Osteoporosis in Women (GLOW).

The GLOW study has informed a lot of our recent work on fracture risk in Parkinson's

Nat Rev Endocrinol. 2014 Apr 22. doi: 10.1038/nrendo.2014.55. [Epub ahead of print]

Watts NB.

Abstract

GLOW is an observational, longitudinal, practice-based cohort study of osteoporosis in 60,393 women aged ≥55 years in 10 countries on three continents. In this Review, we present insights from the first 3 years of the study. Despite cost analyses being frequently based on spine and hip fractures, we found that nonvertebral, nonhip fractures were around five times more common and doubled the use of health-care resources compared with hip and spine fractures combined. Fractures not at the four so-called major sites in FRAX® (upper arm, forearm, hip and clinical vertebral fractures) account for >40% of all fractures. The risk of fracture is increased by various comorbidities, such as Parkinson disease, multiple sclerosis and lung and heart disease. Obesity, although thought to be protective against all fractures, substantially increased the risk of fractures in the ankle or lower leg. Simple assessment by age plus fracture history has good predictive value for all fractures, but risk profiles differ for first and subsequent fractures. Fractures diminish quality of life as much or more than diabetes mellitus, arthritis and lung disease, yet women substantially underestimate their own fracture risk. Treatment rates in patients at high risk of fracture are below those recommended but might be too frequent in women at low risk. Comorbidities and the limits of current therapeutic regimens jeopardize the efficacy of drugs; new regimens should be explored for severe cases.

Gut feelings about smoking and coffee in Parkinson's disease.

Mov Disord. 2014 Apr 21. doi: 10.1002/mds.25882. [Epub ahead of print]

Derkinderen P, Shannon KM, Brundin P.

Abstract

Strong epidemiologic evidence suggests that smokers and coffee drinkers have a lower risk of Parkinson's disease (PD). The explanation for this finding is still unknown, and the discussion has focused on two main hypotheses. The first suggests that PD patients have premorbid personality traits associated with dislike for coffee-drinking and smoking. The second posits that caffeine and nicotine are neuroprotective. We propose an alternative third hypothesis, in which both cigarette and coffee consumption change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation. This, in turn, would lead to less misfolding of the protein alpha-synuclein in enteric nerves, reducing the risk of PD by minimizing propagation of the protein aggregates to the central nervous system, where they otherwise can induce neurodegeneration. 

Comparison of Parkinson Risk in Ashkenazi Jewish Patients With Gaucher Disease and GBA Heterozygotes

Roy N. Alcalay; Tama Dinur; Timothy Quinn; Karina Sakanaka; Oren Levy; Cheryl Waters; Stanley Fahn; Tsvyatko Dorovski; Wendy K. Chung, MD; Michael Pauciulo; William Nichols; Huma Q. Rana; Manisha Balwani; Louise Bier; Deborah Elstein; Ari Zimran

JAMA Neurol. Published online April 21, 2014. doi:10.1001/jamaneurol.2014.313

Importance  Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations.

Objective  To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes.

Design, Setting, and Participants  The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson’s Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation.

Main Outcomes and Measures  The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test.

Results  Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P = .008, log-rank test) and in heterozygotes than noncarriers (P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P = .07, log-rank test).

Conclusions and Relevance  Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.