Patients with scans without evidence of dopaminergic deficit: A long-term follow-up study.

The more information we get on SWEDDs the better....

http://onlinelibrary.wiley.com/doi/10.1002/mds.26018/full

Mov Disord. 2014 Oct 28. doi: 10.1002/mds.26018. [Epub ahead of print]

Batla A, Erro R, Stamelou M, Schneider SA, Schwingenschuh P, Ganos C, Bhatia KP.

BACKGROUND:

We previously reported on a cohort of dystonic tremor and patients with scans without evidence of dopaminergic deficit (SWEDDs). We aim to report the long-term clinical and imaging follow-up of these patients.

PATIENTS AND METHODS:

Patients with at least 5-year follow-up were included. These patients had an asymmetric arm tremor, a previous diagnosis of Parkinson's disease (PD), and a subsequent normal DaTscan. The imaging and clinical follow-up was done on the clinical basis.

RESULTS:

Sixteen patients were included. The mean gap between the first and subsequent scans was 5.4 years. Two patients (12.5%) had reduced nigrostriatal uptake on follow-up DaTscan, whereas 14 continued to have normal dopaminergic imaging.

CONCLUSION:

This is the longest follow up of patients with asymmetric rest tremor and normal DaT scans (SWEDDs) reported to date. We show here that only a minority of them show reduced striatonigral uptake over long term follow up.

Genetic Movement Disorders in Patients of Jewish Ancestry

Interesting and helpful. Especially for those of us that work in London or other areas where we see a lot of people with Jewish ancestry...

JAMA Neurol. 2014 Oct 27. doi: 10.1001/jamaneurol.2014.1364. [Epub ahead of print]

Inzelberg R, Hassin-Baer S, Jankovic J.

IMPORTANCE:

Genetic diseases often cluster in different ethnic groups and may present with recognizable unique clinical manifestations.

OBJECTIVE:

To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry.

EVIDENCE REVIEW:

We searched PubMed and the OMIM and Israeli National Genetic Databases for articles published from 1969 through March 31, 2014, using the search terms Parkinson's disease,movement disorders, ataxia, dystonia, chorea, and Creutzfeldt-Jakob with and Jewish. The final reference list was generated by giving priority to articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews.

FINDINGS:

About one-third of patients with sporadic Parkinson disease (PD) and more than 40% of patients with familial PD of Ashkenazi Jewish descent likely carry the G2019S mutation in the LRRK2 gene, a mutation in the glucocerebrosidase (GBA) gene, or both. This finding contrasts with only a 10% frequency of these mutations in patients with PD who are of non-Jewish ancestry. A dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A-related dystonia. Familial Creutzfeldt-Jakob disease and cerebrotendinous xanthomatosis tend to cluster among Jews of North African descent, and Machado-Joseph disease is particularly frequent in Yemenite Jews.

CONCLUSIONS AND RELEVANCE:

Genetic forms of PD are much more common in patients of Ashkenazi Jewish ancestry with sporadic and familial PD than in the non-Jewish population. The recognition of the particular movement disorder phenotype, coupled with information about the ethnic origin of the patients, may point to specific genetic testing and lead to early and correct diagnosis.

Disease Penetrance of Late-Onset Parkinsonism: A Meta-analysis

JAMA Neurol. 2014 Oct 20. doi: 10.1001/jamaneurol.2014.1909. [Epub ahead of print]

Trinh J, Guella I, Farrer MJ.

IMPORTANCE:

Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely.

OBJECTIVE:

To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism.

DATA SOURCES:

Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014.

STUDY SELECTION:

Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study.

DATA EXTRACTION AND SYNTHESIS:

The age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death.

MAIN OUTCOMES AND MEASURES:

Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals.

RESULTS:

All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001).

CONCLUSIONS AND RELEVANCE:

Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

This is an important study that helps us understand more about the non-motor features of LRRK2-associated PD...

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0108982

PLoS One. 2014 Oct 17;9(10):e108982. doi: 10.1371/journal.pone.0108982. eCollection 2014.

Gaig C, Vilas D, Infante J, Sierra M, García-Gorostiaga I, Buongiorno M, Ezquerra M, Martí MJ, Valldeoriola F, Aguilar M, Calopa M, Hernandez-Vara J, Tolosa E.

BACKGROUND:

Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined.

OBJECTIVE:

To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients.

METHODS:

The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated.

RESULTS:

University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination.

CONCLUSION:

Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

A Validation Study of Administrative Data Algorithms to Identify Patients with Parkinsonism with Prevalence and Incidence Trends

Neuroepidemiology. 2014 Oct 16;43(1):28-37. [Epub ahead of print]

Butt DA, Tu K, Young J, Green D, Wang M, Ivers N, Jaakkimainen L, Lam R, Guttman M.

Abstract

Background: Epidemiological studies for identifying patients with Parkinson's disease (PD) or Parkinsonism (PKM) have been limited by their nonrandom sampling techniques and mainly veteran populations. This reduces their use for health services planning. The purpose of this study was to validate algorithms for the case ascertainment of PKM from administrative databases using primary care patients as the reference standard. Methods: We conducted a retrospective chart abstraction using a random sample of 73,003 adults aged ≥20 years from a primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Physician diagnosis in the EMR was used as the reference standard and population-based administrative databases were used to identify patients with PKM from the derivation of algorithms. We calculated algorithm performance using sensitivity, specificity, and predictive values and then determined the population-level prevalence and incidence trends with the most accurate algorithms. Results: We selected, '2 physician billing codes in 1 year' as the optimal administrative data algorithm in adults and seniors (≥65 years) due to its sensitivity (70.6-72.3%), specificity (99.9-99.8%), positive predictive value (79.5-82.8%), negative predictive value (99.9-99.7%), and prevalence (0.28-1.20%), respectively. Conclusions: Algorithms using administrative databases can reliably identify patients with PKM with a high degree of accuracy.

Examining the relationship between head trauma and neurodegenerative disease: A review of epidemiology, pathology and neuroimaging techniques

J Alzheimers Dis Parkinsonism. 2014 Jan 31;4. pii: 137.

Sundman MH, Hall EE, Chen NK.

Abstract

Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern.

Efficacy of Bisphosphonates against Hip Fracture in Elderly Patients with Stroke and Parkinson Diseases: Meta-analysis of Randomized Controlled Trials

J Stroke Cerebrovasc Dis. 2014 Oct 11. pii: S1052-3057(14)00304-8. doi: 10.1016/j.jstrokecerebrovasdis.2014.06.022. [Epub ahead of print]

Zhang W, Zhu C, Sun M, Ge Y, Yan G.

Stroke and Parkinson disease cause disability and immobilization that increase the risk for fractures. The purpose of the present research was to clarify the efficacy of 3 different bisphosphonates against hip fracture in elderly patients with these neurologic diseases. A literature search was performed in Medline, Embase, CBMdisc, and the Cochrane Library until March 1, 2014, with respect to strictly conducted randomized controlled trials (RCTs) and a meta-analysis was conducted. Every study was evaluated using the Jadad scale. Eight RCTs met the criteria including 5 RCTs for stroke and 3 for Parkinson disease. According to the results of RCTs, the relative risks (95% confidence interval [CI]) for hip fracture with bisphosphonates treatment compared with control treatment were .20 (.07-.54) for stroke and .26 (.13-.52) for Parkinson disease. Overall, the total relative risk (95% CI) for hip fracture with bisphosphonates treatment was .24 (.14-.42), suggesting hip fracture risks with bisphosphonates treatment were reduced significantly in elderly patients compared with the control group in the 2 neurologic diseases (heterogeneity, .86; P = 1.00 and overall effect, 4.99; P < .0001). Meanwhile, after bisphosphonates treatment, bone mineral density, intact parathyroid hormone, and 1,25-dihydroxyvitamin D increased, and serum ionized calcium, urinary deoxypyridinoline decreased compared with the placebo group. No severe adverse events were reported for bisphosphonates treatment. The results of a meta-analysis of strictly conducted RCTs suggest that there is efficacy against hip fracture with bisphosphonates treatment in patients with stroke and Parkinson disease.

7 tesla magnetic resonance imaging: A closer look at substantia nigra anatomy in Parkinson's disease

http://onlinelibrary.wiley.com/doi/10.1002/mds.26043/abstract

Mov Disord. 2014 Oct 12. doi: 10.1002/mds.26043. [Epub ahead of print]

Lehéricy S, Bardinet E, Poupon C, Vidailhet M, François C.

A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation is commonly imaged using radiotracer imaging in target structures such as the striatum. Until recently, imaging made only a modest contribution to detecting neurodegenerative changes in the substantia nigra (SN) directly. Histologically, the SN is subdivided into the ventral pars reticulata and the dorsal pars compacta, which is composed of dopaminergic neurons. In humans, dopaminergic neurons, which are known to accumulate neuromelanin, form clusters of cells (nigrosomes) that penetrate deep into the SN pars reticulata (SNr). The SNr contains higher levels of iron than the SNc in normal subjects. Neuromelanin and T2*-weighted imaging therefore better detect the SNc and the SNr, respectively. The development of ultra-high field 7 Tesla (7T) magnetic resonance imaging (MRI) provided the increase in spatial resolution and in contrast that was needed to detect changes in SN morphology. 7T MRI allows visualization of nigrosome-1 as a hyperintense signal area on T2*-weighted images in the SNc of healthy subjects and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition. This review is designed to provide a better understanding of the correspondence between the outlines and subdivisions of the SN detected using different MRI contrasts and the histological organization of the SN. The recent findings obtained at 7T will then be presented in relation to histological knowledge.

Imaging prodromal Parkinson disease: The Parkinson Associated Risk Syndrome Study

Eagerly awaited results from the PARS study...

Neurology. 2014 Oct 8. pii: 10.1212/WNL.0000000000000960. [Epub ahead of print]

Jennings D, Siderowf A, Stern M, Seibyl J, Eberly S, Oakes D, Marek K; For the PARS Investigators.

http://www.neurology.org/content/early/2014/10/08/WNL.0000000000000960.long

OBJECTIVES:

The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD).

METHODS:

In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires). Tier 2 assessments (neurologic examination, DAT imaging, and other biomarker assessments) were completed by 303 subjects. The main outcome of the study is to compare age-expected [123I]β-CIT striatal binding ratio in hyposmic and normosmic subjects.

RESULTS:

Tier 1 assessments were mailed to 9,398 eligible subjects and returned by 4,999; 669 were hyposmic. Three hundred three subjects (203 hyposmic, 100 normosmic) completed baseline evaluations. DAT deficit was present in 11% of hyposmic subjects compared with 1% of normosmic subjects. Multiple logistic regression demonstrates hyposmia (odds ratio [OR] 12.4; 95% confidence interval [CI] 1.6, 96.1), male sex (OR 5.5; 95% CI 1.7, 17.2), and constipation (OR 4.3; 95% CI 1.6, 11.6) as factors predictive of DAT deficit. Combining multiple factors (hyposmia, male sex, and constipation) increased the percentage of subjects with a DAT deficit to >40%.

CONCLUSION:

Subjects with DAT deficit who do not meet criteria for a diagnosis of PD can be identified by olfactory testing. Sequential biomarker assessment may identify those at risk of PD. Selecting hyposmic individuals enriches the population for DAT deficit, and combining hyposmia with other potential risk factors (male sex, constipation) increases the percentage of subjects with a DAT deficit compatible with prodromal PD.

Safinamide for the treatment of Parkinson's disease.

Expert Rev Clin Pharmacol. 2014 Oct 10:1-13. [Epub ahead of print]

Kandadai RM, Jabeen SA, Kanikannan MA, Borgohain R.

Parkinson's disease (PD) is a neurodegenerative disease caused by a complex interaction of loss of dopaminergic and non-dopaminergic neurotransmitter systems. Drugs acting on the dopaminergic pathways are the mainstay of treatment for motor symptoms today. Safinamide (NW-1015) is a novel drug with multiple actions. It is a monoamine oxidase B inhibitor and improves dopaminergic transmission. In addition, it has antiglutamatergic effects and can thus reduce dyskinesias, which is a side effect limiting most dopaminergic therapy. In Phase III trials, safinamide has been found to be a useful adjunctive to dopamine agonists in early PD and has been shown to increase time without increasing troublesome dyskinesias when used as an adjunct to levodopa in patients with advanced PD. A possible neuroprotective role in inhibiting PD disease progression is envisaged and warrants future studies.

Under-reporting of Parkinson's disease on death certificates: A population-based study (NEDICES).

This is an important observation given that other studies use death certificates to estimate prevalence and for case finding....

J Neurol Sci. 2014 Oct 2. pii: S0022-510X(14)00644-3. doi: 10.1016/j.jns.2014.08.048. [Epub ahead of print]

Benito-León J, Louis ED, Villarejo-Galende A, Romero JP, Bermejo-Pareja F.

BACKGROUND:

Parkinson's disease is frequently omitted as a cause of death from death certificates. A limitation of previous studies that attempted to assess the validity of death certificates is that population-dwelling cases, with milder, undiagnosed Parkinson's disease were likely excluded. As a result, those studies likely overestimated the validity of death certificates because they did not include these milder cases. We assessed the validity of death certificates in a prospective population-based study (NEDICES), which includes previously undiagnosed Parkinson's disease cases detected during the assessment.

METHODS:

3926 community-dwelling elderly subjects with and without Parkinson's disease were followed during a median of 12.6years, after which the death certificates of those who died were examined. We calculated the proportion of cases of clinically diagnosed Parkinson's disease for whom a diagnosis of Parkinson's disease was certified as the basic cause of death on death certificates.

RESULTS:

1791 (45.6%) of the 3926 participants died over a median follow-up of 7.1years, including 82 (73.9%) deaths among 111 participants with Parkinson's disease. Parkinson's disease was rarely certified as the basic cause of death (14.6%). Gender, disease stage and the period during which the study was conducted (i.e., 1994 to 2007) did not influence the likelihood that Parkinson's disease would be reported.

CONCLUSIONS:

Our findings reinforce the notion that the reporting of Parkinson's disease on death certificates remains poor. This suggests a lack of awareness of the importance of Parkinson's disease as a cause of death.