Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease

There are now many lines of evidence to suggest that E326K has a role in determining the course of PD. Even though it is not a recognised cause of Gaucher's disease, it has come up frequently in genetic studies looking at PD-related GBA variants and functional work supports the claim... my experience fits with the observations in this study and those of others... the tendency is towards akinetic rigidity, gait problems and cognitive impairment, rather than a tremor predominant form of PD...

JAMA Neurol. 2016 Aug 29. doi: 10.1001/jamaneurol.2016.2245. [Epub ahead of print]

Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, Quinn JF, Chung KA, Peterson-Hiller AL, Rosenthal LS, Dawson TM, Albert MS, Goldman JG, Stebbins GT, Bernard B, Wszolek ZK, Ross OA, Dickson DW, Eidelberg D, Mattis PJ, Niethammer M, Yearout D, Hu SC, Cholerton BA, Smith M, Mata IF, Montine TJ, Edwards KL, Zabetian CP.

http://archneur.jamanetwork.com/article.aspx?articleid=2546252

IMPORTANCE:

Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.

OBJECTIVE:

To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.

DESIGN, SETTING, AND PARTICIPANTS:

The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.

MAIN OUTCOMES AND MEASURES:

Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.

RESULTS:

Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia.

CONCLUSIONS AND RELEVANCE:

GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Correlation of Quantitative Motor State Assessment Using a Kinetograph and Patient Diaries in Advanced PD: Data from an Observational Study

The PKG is one of the better examples of wearable tech that is available for monitoring PD. Clearly there remains some improvements to be made, but it has already entered the clinical arena and is being used to supplement patient care. Other studies that used it showed improvements in total 'On' time and reductions in 'dyskinesia time'. One problem with the present study is that the home diary method is not without its flaws. Sometimes it is hard to marry up exactly what one sees objectively and what the patient experiences subjectively...

PLoS One. 2016 Aug 24;11(8):e0161559. doi: 10.1371/journal.pone.0161559. eCollection 2016.

Ossig C, Gandor F, Fauser M, Bosredon C, Churilov L, Reichmann H, Horne MK, Ebersbach G, Storch A.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161559

INTRODUCTION:

Effective management and development of new treatment strategies for response fluctuations in advanced Parkinson's disease (PD) largely depends on clinical rating instruments such as the PD home diary. The Parkinson's kinetigraph (PKG) measures movement accelerations and analyzes the spectral power of the low frequencies of the accelerometer data. New algorithms convert each hour of continuous PKG data into one of the three motor categories used in the PD home diary, namely motor Off state and On state with and without dyskinesia.

OBJECTIVE:

To compare quantitative motor state assessment in fluctuating PD patients using the PKG with motor state ratings from PD home diaries.

METHODS:

Observational cohort study on 24 in-patients with documented motor fluctuations who completed diaries by rating motor Off, On without dyskinesia, On with dyskinesia, and asleep for every hour for 5 consecutive days. Simultaneously collected PKG data (recorded between 6 am and 10 pm) were analyzed and calibrated to the patient's individual thresholds for Off and dyskinetic state by novel algorithms classifying the continuous accelerometer data into these motor states for every hour between 6 am and 10 pm.

RESULTS:

From a total of 2,040 hours, 1,752 hours (87.4%) were available for analyses from calibrated PKG data (7.5% sleeping time and 5.1% unclassified motor state time were excluded from analyses). Distributions of total motor state hours per day measured by PKG showed moderate-to-strong correlation to those assessed by diaries for the different motor states (Pearson's correlations coefficients: 0.404-0.658), but inter-rating method agreements on the single-hour-level were only low-to-moderate (Cohen's κ: 0.215-0.324).

CONCLUSION:

The PKG has been shown to capture motor fluctuations in patients with advanced PD. The limited correlation of hour-to-hour diary and PKG recordings should be addressed in further studies.

Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls

This is a well conducted study and there are surprisingly few of these high-quality incident PD cohorts in the world... the survival times are worryingly low at first glance and much shorter than we tend to quote. The authors draw attention to this but much of it will be driven by age. The average age in the incident cases is pretty high at 75 years old... the average age of diagnosis of PD is usually quoted as 65 years old. Playing devils advocate, for PD at least, the average survival of 6 years means that patients tend to die around the normal UK life expectancy mark (late 70's, early 80's)... 

The other thing that varies tremendously is access to high quality care around the UK... the Parkinson's UK Excellence Network is trying to achieve equal care for all...

Parkinsonism Relat Disord. 2016 Aug 12. pii: S1353-8020(16)30307-8. doi: 10.1016/j.parkreldis.2016.08.010. [Epub ahead of print]

Fielding S, Macleod AD, Counsell CE.

http://www.sciencedirect.com/science/article/pii/S1353802016303078

BACKGROUND:

The best data on prognosis comes from population-based incident cohorts but few such cohorts exist for Parkinson's disease and atypical parkinsonism.

METHODS:

The PINE study is a prospective follow-up study of an incident cohort of people with degenerative or vascular parkinsonism and age-sex matched controls. Participants have annual follow-up from diagnosis until death with review of primary/secondary care records and linkage to the UK death register. Data are collected on survival, disability (dependency on others for activities of daily living) and institutionalization. Research criteria are used to guide the clinical diagnosis, which is updated annually. We compared all-cause mortality, disability and institutionalization in patients (subdivided by diagnosis) and controls, adjusted for important confounders.

RESULTS:

323 incident parkinsonian patients (199 Parkinson's disease, 124 atypical parkinsonism, mean age at diagnosis 75yrs) and 262 controls (mean age 75yrs) had 1349 and 1334 person-years follow-up respectively (maximum follow-up 10 years). All outcomes were worse in parkinsonian patients than controls, especially in atypical parkinsonism (adjusted mortality hazards ratios Parkinson's disease 2.49, 95%CI 1.72-3.58, atypical parkinsonism, 6.85, 95%CI 4.78-9.81). Median survival times for Parkinson's disease and atypical parkinsonism were 7.8 and 2.7 years respectively but were very age-dependent. At three years the rates of death or dependency were controls 21%, Parkinson's disease 46%, atypical parkinsonism 96% whilst overall institutionalization rates were 5%, 15% and 55% respectively.

CONCLUSION:

The prognosis of Parkinson's disease and atypical parkinsonism in this unselected incident cohort was significantly worse than previously reported. This has important implications for patient management.

Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cerebral peduncle angle: Unreliable in differentiating progressive supranuclear palsy from other neurodegenerative diseases

Not to be confused with the cerebellar pontine angle... this CPA (the cerebral peduncle angle) is seen in axial MRI imaging... in PSP the angle is said to widen, which along with midbrain atrophy, gives the appearance of Mickey Mouse's face... see below

Parkinsonism Relat Disord. 2016 Aug 11. pii: S1353-8020(16)30306-6. doi: 10.1016/j.parkreldis.2016.08.009. [Epub ahead of print]

Tipton PW, Konno T, Broderick DF, Dickson DW, Wszolek ZK.

http://www.prd-journal.com/article/S1353-8020(16)30306-6/abstract

INTRODUCTION:

The significant symptom overlap between progressive supranuclear palsy (PSP) and other parkinsonian neurodegenerative diseases frequently results in misdiagnosis. However, neuroimaging can be used to quantify disease-related morphological changes and specific markers. The cerebral peduncle angle (CPA) has been shown to differentiate clinically diagnosed PSP from other parkinsonian diseases but this result has yet to be confirmed in autopsy-proven disease.

METHODS:

Magnetic resonance imaging (MRI) scans were obtained for 168 patients representing 69 medical facilities. Following randomization, the images were divided into two groups (Type 1 and Type 2) based upon midbrain morphological differences. Two readers were blinded and independently measured the CPA of 146 patients with autopsy-proven progressive supranuclear palsy (PSP; n = 54), corticobasal degeneration (n = 16), multiple system atrophy (MSA; n = 11) and Lewy body disease (n = 65).

RESULTS:

Applying two separate measurement techniques revealed no statistically significant differences in CPA measurements among any study groups regardless of classification measurement approach. The interobserver agreement showed significant differences in measurements using the Type 2 approach.

CONCLUSION:

Measuring the CPA on MRI is not a reliable way of differentiating among patients with PSP, corticobasal degeneration, MSA, or Lewy body disease.

The second image is taken from Fatterpekar et al. AJR 2015

Visual signs and symptoms of corticobasal degeneration

Nice review of the visual features of corticobasal syndrome... we tend to call the clinical picture corticobasal syndrome because the underlying pathology can be due to corticobasal degeneration, progressive supranuclear palsy or Alzheimer's pathology (or a number of rarer entities too)...

Clin Exp Optom. 2016 Aug 23. doi: 10.1111/cxo.12429. [Epub ahead of print]

Armstrong RA.

http://onlinelibrary.wiley.com/doi/10.1111/cxo.12429/abstract;jsessionid=8FDD16D7204032C199513A21D8E6E161.f01t03?systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+3rd+September+2016+at+08.30+BST%2F+03%3A30+EDT%2F+15%3A30+SGT+for+5+hours+and+Sunday+4th+September+at+10%3A00+BST%2F+05%3A00+EST%2F+17%3A00+SGT+for+1+hour++for+essential+maintenance.+Apologies+for+the+inconvenience

Corticobasal degeneration is a rare, progressive neurodegenerative disease and a member of the 'parkinsonian' group of disorders, which also includes Parkinson's disease, progressive supranuclear palsy, dementia with Lewy bodies and multiple system atrophy. The most common initial symptom is limb clumsiness, usually affecting one side of the body, with or without accompanying rigidity or tremor. Subsequently, the disease affects gait and there is a slow progression to influence ipsilateral arms and legs. Apraxia and dementia are the most common cortical signs. Corticobasal degeneration can be difficult to distinguish from other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid clinical diagnosis. Typical ocular features include increased latency of saccadic eye movements ipsilateral to the side exhibiting apraxia, impaired smooth pursuit movements and visuo-spatial dysfunction, especially involving spatial rather than object-based tasks. Less typical features include reduction in saccadic velocity, vertical gaze palsy, visual hallucinations, sleep disturbance and an impaired electroretinogram. Aspects of primary vision such as visual acuity and colour vision are usually unaffected. Management of the condition to deal with problems of walking, movement, daily tasks and speech problems is an important aspect of the disease.

Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) - A systematic review on potential biomarkers for neurodegeneration

RBD cohorts are one of the best candidate groups for neuroprotective trials in PD (if sufficient case numbers are be identified)... robust imaging biomarkers that predict the neurodegenerative disease diagnosis that follows (i.e. PD, DLB or MSA) and the likely time course of that will be very valuable, and may mean reductions in the overall numbers that are required for clinical trials to have adequate statistical power....

Sleep Med Rev. 2016 Jun 25. pii: S1087-0792(16)30057-0. doi: 10.1016/j.smrv.2016.06.006. [Epub ahead of print]

Heller J, Brcina N, Dogan I, Holtbernd F, Romanzetti S, Schulz JB, Schiefer J, Reetz K.

http://www.smrv-journal.com/article/S1087-0792(16)30057-0/abstract

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of physiological atonia of skeletal muscles with abnormal behavior during dream sleep. RBD may be the initial manifestation of neurodegenerative diseases, particularly of α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, gauging the individual risk of subsequent phenoconversion and making assumptions on the type of disease that may subsequently follow RBD is challenging. Over the past years, a growing number of studies have sought to establish reliable neuroimaging markers to detect neurodegenerative brain changes in RBD subjects at the earliest possible stage. The present review summarizes recent advances in brain imaging in RBD and provides recommendations for the application of currently available structural and functional neuroimaging modalities to monitor disease progression and risk of subsequent phenoconversion. Further imaging research applying multimodal approaches is encouraged to enhance accuracy of prognoses. Additionally, more longitudinal studies are warranted to validate findings from cross-sectional studies on RBD progression and risk of subsequent phenoconversion. Aside from enabling reliable prognoses on a single-subject-level in the near future, this might give further insight into RBD pathophysiology, and finally augment the development of intervention strategies and disease-modifying therapies.

A case of lithium-induced parkinsonism presenting with typical motor symptoms of Parkinson's disease in a bipolar patient

I have seen parkinsonism in a couple of patients on therapeutic doses of lithium (i.e. not toxic)... lithium is classically associated with a tremor that does not look very parkinsonian... someone I saw recently was on lithium, quetiapine and sodium valproate... all mood stabilisers and all (now) reported to cause parkinsonism... sometimes it can be very difficult to pick these cases apart and find the true cause of the symptoms...

Int Psychogeriatr. 2016 Aug 12:1-4. [Epub ahead of print]

Hermida AP, Janjua AU, Glass OM, Vaughan CP, Goldstein F, Trotti LM, Factor SA.

http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=10462722&fileId=S1041610216001101

Lithium is a mood stabilizer rarely associated with drug-induced parkinsonism (DIP). We present a case of an elderly woman with bipolar disorder who developed parkinsonian symptoms after chronic lithium administration despite therapeutic serum levels. Upon evaluation, classic parkinsonian signs of muscle rigidity, tremor, bradykinesia, freezing of gait, and cognitive decline were observed. Initially, she was diagnosed with Parkinson's disease (PD); however, DaTscan SPECT imaging clarified the diagnosis as DIP. As the daily lithium dosage was reduced, the patient's motor symptoms improved. This report emphasizes close monitoring of lithium levels in geriatric populations and the need to consider lithium-induced parkinsonism when PD symptoms appear in chronic lithium users.

The combined effect of REM sleep behavior disorder and hyposmia on cognition and motor phenotype in Parkinson's disease

Further evidence that RBD and hyposmia are probably indicative of more severe form of PD with greater akinetic-rigidity and cognitive impairment... I think this is already known, but it is nice to see concordant results in other settings. This likely has implications about the burden and distribution of PD pathology....

J Neurol Sci. 2016 Sep 15;368:374-8. doi: 10.1016/j.jns.2016.07.057. Epub 2016 Jul 26.

Kang SH, Lee HM, Seo WK, Kim JH, Koh SB.

http://www.jns-journal.com/article/S0022-510X(16)30470-1/abstract

BACKGROUND:

Olfactory dysfunction and REM sleep behavior disorder (RBD) are recognized as pre-motor symptoms of Parkinson's disease (PD). Cognitive dysfunction is observed at a high rate even in the early stages of PD as an important non-motor symptom. PD has been classified in different subtypes and it is unknown if olfactory dysfunction and RBD occur more often in one particular subtype. We investigated the relationship between olfactory impairment, RBD, initial cognitive performance and motor phenotype in PD.

METHOD:

Nighty-eight patients with drug-naïve idiopathic PD who visited the Movement Disorders Unit of Korea University Guro Hospital, Seoul, Korea from March 2012 to February 2014 were retrospectively included. Patients were divided into tremor-dominant-type and akinetic-rigid-type PD subgroups using part III of the Unified Parkinson's Disease Rating Scale. Olfaction was assessed by the Cross Cultural Smell Identification Test. RBD was screened using screening questionnaires. Initial cognitive function was assessed with Mini-Mental State Examination.

RESULT:

The PD-normosmia group had higher MMSE scores (p=0.008). PD patients who have both RBD and olfactory dysfunction had lower MMSE scores (p=0.013). Presence of both RBD and hyposmia in PD patients was more strongly correlated with poor cognitive dysfunction. PD patients with RBD and/or hyposmia primarily exhibited the akinetic-rigidity phenotype.

CONCLUSION:

Olfactory dysfunction and RBD differed according to the motor phenotypes of PD. This suggests that olfactory dysfunction and RBD might relate to prognosis in patients with PD. Patients who have both hyposmia and RBD were more likely to exhibit cognitive dysfunction.

Copyright © 2016 Elsevier B.V. All rights reserved.

Risk Factors, Epidemiology and Treatment Strategies for Metabolic Bone Disease in Patients with Neurological Disease

Total silence for about a month as I have started back in the full time clinical neurology. So whilst I expect the post to be a little less frequent, they will be starting again from now...
This is a new review by a colleague Ruth Dobson on bone health in PD and multiple sclerosis... she and I have previously co-authored a few articles on this topic... bone fracture is a major reason for people with PD to be admitted to hospital and a cause of deterioration physcially and in terms of symptom control. As is often the case, prevention is better than cure, so one should always be mindful of the risk of fracture in PD patients.... and start bone protection therapy where necessary.

Curr Osteoporos Rep. 2016 Aug 15. [Epub ahead of print]

Binks S, Dobson R.

http://link.springer.com/article/10.1007%2Fs11914-016-0320-5

Metabolic bone disease is a major public health concern, especially when it manifests as hip fracture which carries significant morbidity and mortality. Individuals with neurological disease are at higher risk of osteopenia, osteoporosis and fragility fracture compared to age-matched controls, yet this is under-appreciated by these patients. Clinician attention to this topic is therefore of importance and should address the bone health of men as well as women, a group in whom it may be an under-recognised problem. Evidence for optimal management of bone health in neurological disease remains to be defined, but a growing literature provides some useful guidance. This review focuses on two conditions, multiple sclerosis and Parkinson's disease, where research has been active over recent years. In neuroinflammation, shared immunological pathways between bone and brain are a current domain of interest and it will be intriguing to interrogate the action of emerging immunotherapies on these dual compartments.