Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease

PLoS One. 2013;8(4):e60691. doi: 10.1371/journal.pone.0060691. Epub 2013 Apr 3.

Petit GH, Berkovich E, Hickery M, Kallunki P, Fog K, Fitzer-Attas C, Brundin P.

Source

Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, BMC B11, Lund University, Lund, Sweden.

Abstract

Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

Depressive symptoms in Parkinson's disease and in non-neurological medical illnesses

Neuropsychiatr Dis Treat. 2013;9:389-96. doi: 10.2147/NDT.S40013. Epub 2013 Mar 21.

Assogna F, Fagioli S, Cravello L, Meco G, Pierantozzi M, Stefani A, Imperiale F, Caltagirone C, Pontieri FE, Spalletta G.

Source

I.R.C.C.S. Santa Lucia Foundation, Rome, Italy.

Abstract

BACKGROUND:

Patients with neurological and non-neurological medical illnesses very often complain of depressive symptoms that are associated with cognitive and functional impairments. We compared the profile of depressive symptoms in Parkinson's disease (PD) patients with that of control subjects (CS) suffering from non-neurological medical illnesses.

METHODS:

One-hundred PD patients and 100 CS were submitted to a structured clinical interview for identification of major depressive disorder (MDD) and minor depressive disorder (MIND), according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR), criteria. The Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) were also administered to measure depression severity.

RESULTS:

When considering the whole groups, there were no differences in depressive symptom frequency between PD and CS apart from worthlessness/guilt, and changes in appetite reduced rates in PD. Further, total scores and psychic and somatic subscores of HDRS and BDI did not differ between PD and CS. After we separated PD and CS in those with MDD, MIND, and no depression (NODEP), comparing total scores and psychic/somatic subscores of HDRS and BDI, we found increased total depression severity in NODEP PD and reduced severity of the psychic symptoms of depression in MDD PD, with no differences in MIND. However, the severity of individual symptom frequency of depression was not different between PD and CS in MDD, MIND, and NODEP groups.

CONCLUSION:

Although MDD and MIND phenomenology in PD may be very similar to that of CS with non-neurological medical illnesses, neurological symptoms of PD may worsen (or confound) depression severity in patients with no formal/structured DSM-IV-TR, diagnosis of depressive mood disorders. Thus, a thorough assessment of depression in PD should take into consideration the different impacts of neurological manifestations on MDD, MIND, and NODEP.

Prevalence of Parkinson Disease and Parkinson Disease Dementia in Community Nursing Homes

Am J Geriatr Psychiatry. 2013 Jan 11. pii: S1064-7481(12)00104-2. doi: 10.1016/j.jagp.2012.12.007. [Epub ahead of print]

Hoegh M, Ibrahim AK, Chibnall J, Zaidi B, Grossberg GT.

Source

Saint Louis University School of Medicine, Saint Louis, Missouri.

Abstract

OBJECTIVE:

To estimate the prevalence of Parkinson disease (PD) and Parkinson disease dementia (PDD) in community nursing homes. To estimate how many residents who meet criteria for PDD have been diagnosed with PDD and prescribed a Federal Drug Administration (FDA)-approved treatment for PDD.

SETTING:

Three private Saint Louis metropolitan area nursing homes.

PARTICIPANTS:

Fifty-five residents with a chart diagnosis of PD from a total of 714 residents were identified. Sixteen subjects or families did not give consent and two were excluded from the study because advanced stage of the illness impaired evaluation. Thirty-seven subjects with an established diagnosis of PD participated in the study.

DESIGN AND MEASUREMENTS:

A chart review was used to identify the study sample: residents with an established diagnosis of PD. Consent was obtained from the nursing home administration, families or guardians, and the residents themselves (where applicable). Study data were obtained from review of residents' medical charts, family/caregiver interview, resident interview, resident cognitive testing (Mini-Mental State Examination, clock drawing test), and resident depression assessment (15-item Geriatric Depression Scale). Diagnosis of PDD was defined using existing literature and described below. Data were analyzed using SPSS version 15.

RESULT:

Of the 714 nursing home residents, 55 (7.7%) met criteria for PD. Of these, 37 participated in the study and 18 (48.6%) met criteria for PDD. None were diagnosed with PDD in the charts and 11.1% (2 of 18) were on FDA-approved treatment.

CONCLUSION:

In this sample of nursing home residents, the prevalence of PD was 7.7% and the overall prevalence of PDD was 3.7%. PDD remains an unrecognized entity in the nursing home setting. Close to half (48.65%) of nursing home residents with PD may have PDD at any given time and they remain undiagnosed and largely undertreated.

Determinants of delayed diagnosis in Parkinson's disease

J Neurol. 2013 Apr 10. [Epub ahead of print]

Breen DP, Evans JR, Farrell K, Brayne C, Barker RA.

Source

Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK

Abstract

The early and accurate diagnosis of Parkinson's disease (PD) is the first step towards optimal patient management. The aim of this study was to investigate the major determinants of delayed diagnosis in PD. We recruited a population-representative cohort of 239 newly-diagnosed PD patients who underwent clinical and neuropsychological evaluation. Non-parametric methods were used to define the factors associated with diagnostic delay. The median time from motor symptom onset to primary care physician (PCP) presentation was considerably longer than the time from PCP presentation to PD diagnosis (11 vs. 1 months). Male sex and presenting motor phenotype were independently associated with delayed PCP presentation on Cox regression analysis. Patients presenting with gait disturbance experienced the longest delay, whilst those presenting with tremor had the shortest. In summary, male sex and presenting motor phenotype are key determinants of delayed diagnosis in PD.

Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Cochrane Database Syst Rev. 2012 Mar 14;3:CD006504. doi: 10.1002/14651858.CD006504.pub2.

Rolinski M, Fox C, Maidment I, McShane R.

Source

Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford, UK.

Abstract

BACKGROUND:

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement.

OBJECTIVES:

To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease).

SEARCH METHODS:

The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials.

SELECTION CRITERIA:

Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD).

DATA COLLECTION AND ANALYSIS:

Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0.

MAIN RESULTS:

Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03).

AUTHORS' CONCLUSIONS:

The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson's disease - A randomized study

Parkinsonism Relat Disord. 2013 Apr 2. pii: S1353-8020(13)00119-3. doi: 10.1016/j.parkreldis.2013.03.003. [Epub ahead of print]

Rios Romenets S, Creti L, Fichten C, Bailes S, Libman E, Pelletier A, Postuma RB.

Source

Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada.

Abstract

INTRODUCTION:

Although a variety of pharmacologic and non-pharmacologic treatments are effective for insomnia in the general population, insomnia in Parkinson's disease differs in important ways and may need different treatments. No studies have conclusively demonstrated effective insomnia treatments in Parkinson's disease.

METHODS:

We conducted a three-arm six-week randomized pilot study assessing non-pharmacologic treatment (cognitive behavioural therapy with bright light therapy) or doxepin (10 mg daily), compared to an inactive placebo in Parkinson's patients with insomnia. Sleep outcomes included insomnia scales, clinical global impression, sleep diaries and actigraphy. Secondary outcomes included motor severity, fatigue, depression and quality of life.

RESULTS:

18 patients were randomized, 6 to each group. Compared to placebo, doxepin improved the Insomnia Severity Index (-9 ± 5.4 vs. -2 ± 3.9, p = 0.03), the SCOPA-night score (-5.2 ± 1.5 vs. -2.3 ± 2.8, p = 0.049), the Pittsburgh Sleep Quality Index-sleep disturbances subscale (-0.5 ± 0.5 vs 0.2 ± 0.4, p = 0.02), and both patient and examiner-rated clinical global impression of change (1.7 ± 0.8 vs. 0.5 ± 0.8, p = 0.03 and 1.4 ± 0.5 vs. 0.3 ± 0.5, p = 0.003). On secondary outcomes doxepin reduced the fatigue severity scale (p = 0.02) and improved scores on the Montreal Cognitive Assessment (p = 0.007). Non-pharmacological treatment reduced the Insomnia Severity Index (-7.8 ± 3.8 vs. -2.0 ± 3.9, p = 0.03), and the examiner-reported clinical global impression of change (p = 0.006), but was associated with decline in Parkinson Disease Questionnaire-39. There were no changes in other primary and secondary outcomes, including actigraphy outcomes. Adverse events were comparable in all groups.

CONCLUSION:

Doxepin and non-pharmacologic treatment substantially improved insomnia in Parkinson's disease. These potential benefits must be replicated in a full confirmatory randomized controlled trial.

Discontinuities in slow finger movements in patients with Parkinson's disease

Neurosci Lett. 2013 Apr 2. pii: S0304-3940(13)00262-0. doi: 10.1016/j.neulet.2013.02.068. [Epub ahead of print]

Bettray LM, Eggers C, Quatuor EL, Florin E, Reck C, Pauls AK, Barbe MT, Fink GR, Timmermann L.

Source

Department of Neurology, University of Cologne, Cologne, Germany.

Abstract

Slow finger movements in healthy humans are characterized by discontinuous rhythmic changes in a low frequency band about 8Hz. These pulsatile changes in velocity are thought to present the central output of an oscillatory cerebello-thalamo-cortical network in the same frequency. Hypothesizing that patients with Parkinson's Disease (PD) in the dopaminergic OFF- and ON-condition show changes in the characteristics of discontinuities compared to healthy humans, we used a 3 D-ultrasound device to measure slow finger movements of 16 patients with PD and 12 age-matched controls. We provide evidence that slow finger movements of patients with PD are characterized by discontinuities in acceleration, which are significantly slower in the OFF- but not in the ON-condition compared to healthy controls. Correlation analysis between clinical motor improvement after dopaminergic medication and changes of peak frequencies and peak power of discontinuities was not significant. We conclude that the oscillatory brain network of slow finger movements is affected in PD, presenting in a lower frequency in the OFF-condition. We suggest that one factor of the modulation of this network is a dopaminergic stimulation.

Substantia nigra hyperechogenicity in healthy controls: a [18Fluoro] Dopa-PET follow-up study

J Neurol. 2013 Apr 7. [Epub ahead of print]

Schroeder U, Behnke S, Buchholz HG, Fassbender K, Schreckenberger M, Berg D.

Source

Department of Neurology, Saarland University Hospital, Kirrberger Str, 66421, Homburg/Saar, Germany.

Abstract

In order to assess nigrostriatal function over time in healthy subjects with substantia nigra hyperechogenicity (SN+) believed to be at higher risk for Parkinson's disease (PD), ten healthy SN+ subjects underwent [18Fluoro] Dopa positron emission tomography (PET) twice-at baseline and after a mean of 7.3 years. Neurological examination took place at study inclusion followed by a structured telephone interview focusing on early Parkinsonian symptoms at the time point of second PET study and 3.5 years later. The [18Fluoro] Dopa uptake remained unchanged in eight of ten participants. In the other two subjects marked unilateral reduction of putaminal [18Fluoro] Dopa uptake ratios appeared over the time, followed by complaints of a clinically manifest PD in one. We suggest that the progressive pathological PET findings in 20 % and PD conversion in 10 % of our cohort may be in accordance with the presumed proportion of SN+ individuals eventually developing PD based on SN+ prevalence of 10 % within the healthy population, being ten times higher than PD prevalence in the age of over 60 years. Our findings hint towards a significance of SN+ indicating a high risk for PD in some extrapyramidally healthy SN+ individuals.

Prodromal autonomic symptoms and signs in Parkinson's disease and dementia with Lewy bodies.

Mov Disord. 2013 Mar 28. doi: 10.1002/mds.25445. [Epub ahead of print]

Postuma RB, Gagnon JF, Pelletier A, Montplaisir J.

Source

Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada; Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.

Abstract

Pathologic staging systems suggest that autonomic dysfunction may be an early manifestation of Parkinson's disease and dementia with Lewy bodies. However, direct evidence is limited, and no prospective studies have measured when autonomic dysfunction starts before disease. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder are at very high risk of developing neurodegenerative synucleinopathy, providing an opportunity to directly observe the development of autonomic dysfunction from prodromal stages of neurodegeneration. Patients with idiopathic REM sleep behavior disorder were followed annually in a prospective cohort that was established in 2004. Urinary, orthostatic, erectile, and constipation symptoms and systolic blood pressure drop from lying to standing were assessed annually. Patients who eventually developed defined synucleinopathy were compared with age-matched controls. The evolution of autonomic measures was assessed with regression analysis to determine when markers first deviated from control values. Sensitivity and specificity of autonomic markers for identification of prodromal disease were calculated. Of 91 patients, 32 developed disease. In prodromal stages, there was substantial autonomic dysfunction observable at least 5 years before diagnosis. On regression analysis, autonomic dysfunction appeared to progress slowly over prodromal periods. The estimated onset of autonomic dysfunction ranged from 11 years to 20 years, and systolic drop (20.4 years) and constipation (15.3 years) had the earliest estimates. Systolic drop, erectile dysfunction, and constipation could identify disease up to 5 years before diagnosis with sensitivity ranging from 50% to 90%. By directly observing development of neurodegenerative synucleinopathy, we confirmed that autonomic dysfunction can occur early in neurodegenerative synucleinopathy, even as long as 20 years before defined disease.

The relationship between balance control and vitamin D in Parkinson's disease-a pilot study

Mov Disord. 2013 Apr 2. doi: 10.1002/mds.25405. [Epub ahead of print]

Peterson AL, Mancini M, Horak FB.

Source

Parkinson's Center of Oregon, Oregon Health and Science University, Portland, Oregon, USA; Parkinson's Disease Research and Education Center, Portland Veterans Affairs Hospital, Portland, Oregon, USA.

Abstract

BACKGROUND:

Balance problems and falls are a major source of morbidity and mortality in patients with Parkinson's disease. Vitamin D supplementation reduces falls and sway in neurologically intact elderly fallers, but effects in Parkinson's disease are not established.

METHODS:

To study this relationship and select outcome measures for a vitamin D intervention study, balance function and vitamin D concentration were quantified in a series of Parkinson's patients in a cross-sectional, observational study. Participants underwent a battery of 5 balance tests.

RESULTS:

Serum vitamin D concentrations were correlated inversely with Parkinson's severity, as measured by the motor Unified Parkinson's Disease Rating Scale. Among the balance measures, vitamin D concentrations were correlated with automatic posture responses to backwards translation, specifically with response strength and stance weight asymmetry.

CONCLUSIONS:

These findings support the hypothesis that vitamin D plays a role in balance among patients with Parkinson's disease and identify specific outcome measures for detecting effects of vitamin D upon balance.

Cognitive Change in Newly-Diagnosed Patients with Parkinson's Disease: A 5-Year Follow-up Study

J Int Neuropsychol Soc. 2013 Apr 2:1-14. [Epub ahead of print]

Broeders M, Velseboer DC, de Bie R, Speelman JD, Muslimovic D, Post B, de Haan R, Schmand B.

Source

1 Department of Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.

Abstract

Cognitive change is frequently observed in patients with Parkinson's disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here.