Small-vessel disease in patients with Parkinson's disease: A clinicopathological study

Mov Disord. 2012 Sep 26. doi: 10.1002/mds.25112. [Epub ahead of print]

Schwartz RS, Halliday GM, Cordato DJ, Kril JJ.

Source

Discipline of Pathology, University of Sydney, Sydney, New South Wales, Australia; Southern Neurology, Kogarah, New South Wales, Australia.

Abstract

Few studies have examined the relationship between cerebrovascular disease, vascular risk factors, and Parkinson's disease (PD), although 1 study found small-vessel disease (SVD) to be the main subtype of cerebrovascular disease. In this study we compared the extent and topography of SVD and assessed associated vascular risk factors in autopsy-proven PD cases and community-dwelling controls. Seventy-seven PD and 32 control brains from the Sydney Brain Bank were assessed microscopically by a single examiner blinded to the diagnosis. SVD was assessed by grading perivascular pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces in the white matter underlying the superior frontal and primary motor cortices, basal ganglia, and white matter tracts. A history of vascular risk factors (hypertension, heart disease, diabetes, and cigarette smoking) was obtained. Groups were compared using stepwise multiple regression analysis. There was significantly greater frontal pallor (P = .004) and widening of perivascular spaces in the globus pallidus interna (P = .007) in controls compared with PD. Hyaline thickening and widening of perivascular spaces in the frontal white matter, hyaline thickening in the motor white matter, and widening of perivascular spaces in the caudate nucleus were more common in the control group, but did not reach significance. The prevalence of vascular risk factors and SVD pathology was significantly lower in autopsy-proven PD compared with controls (P = .03) living in the same community. The results of this study support the need for further research in this area.

Evaluation of olfactory dysfunction in neurodegenerative diseases

J Neurol Sci. 2012 Sep 22. pii: S0022-510X(12)00480-7. doi: 10.1016/j.jns.2012.08.028. [Epub ahead of print]

Barresi M, Ciurleo R, Giacoppo S, Foti Cuzzola V, Celi D, Bramanti P, Marino S.

Source

IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.

Abstract

It is known that the olfactory dysfunction is involved in various neurological diseases, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, Huntington's disease and motor neuron disease. In particular, the ability to identify and discriminate the odors, as well as the odor threshold, can be altered in these disorders. These changes often occur as early manifestation of the pathology and they are not always diagnosed on time. The aim of this review is to summarize the major neurological diseases which are preceded or accompanied by olfactory dysfunction. In addition, new instrumental approaches, such as psychophysical testing, olfactory event-related potentials (OERPs) and functional magnetic resonance imaging (fMRI) measurements, supported by olfactometer for the stimuli delivery, and their combination in evaluation of olfactory function will be discussed. In particular, OERPs and fMRI might to be good candidates to become useful additional tools in clinical protocols for early diagnosis of neurological diseases.

Combined assessment of midbrain hyperechogenicity, hyposmia and motor asymmetry improves diagnostic accuracy in early Parkinson's disease

Expert Rev Neurother. 2012 Aug;12(8):911-4.

Poewe W, Mahlknecht P.

Source

Department of Neurology, University of Innsbruck, A-6020 Innsbruck, Anichstrasse 35, Austria.

Abstract

Evaluation of: Busse K, Heilmann R, Kleinschmidt S et al. Value of combined midbrain sonography, olfactory and motor function assessment in the differential diagnosis of early Parkinson's disease. J. Neurol. Neurosurg. Psychiatr. 83(4), 441-447 (2012). The differential diagnosis of Parkinsonian syndromes can be challenging, particularly in early disease stages, when overlapping clinical signs and symptoms may lead to erroneous classification. However, an early differentiation between Parkinson's disease (PD) and other diseases causing Parkinsonism is crucial for prognostic and therapeutic reasons and is essential for clinical research. In a recent study, Busse et al. investigated the diagnostic utility of a set of tests to improve diagnostic differentiation between PD, essential tremor and other Parkinsonian disorders. The authors studied a total of 632 patients divided into a retrospective (n = 517) and a prospective (n = 115) group. Diagnostic anchors were based on clinical criteria. Combining midbrain hyperechogenicity, hyposmia and motor asymmetry increased specificity and positive predictive value for diagnosis of PD up to 98% at the expense of sensitivity, whereas two features provided 91% sensitivity with 77% specificity. The results of this study further support the diagnostic utility of transcranial sonography in diagnosing PD.

Duration of L-dopa and dopamine agonist monotherapy in Parkinson's disease

Scott Med J. 2012 Sep 21. [Epub ahead of print]

Nissen T, Newman EJ, Grosset KA, Daghem M, Pal G, Stewart M, Odin P, Macphee GJ, Grosset DG.

Source

Department of Neurology, Klinikum Bremerhaven, Bremerhaven, Germany.

Abstract

The expected duration of initial antiparkinson monotherapy before the need for supplementation is not clearly defined for routine practice. The aim of this study was to define the length of l-dopa (L-3, 4-dihydrophenylalanine) and dopamine agonist monotherapy. The duration of monotherapy and discontinuation rates were investigated in a natural observational setting by plotting Kaplan-Meier survival curves. Out of 345 patients, 180 (52.2%) received l-dopa and 165 (47.8%) received a dopamine agonist as initial monotherapy. Half of the patients starting l-dopa received supplementary therapy with- in 3.6 years (95% confidence interval, 3.2-4.6), significantly longer than for dopamine agonist monotherapy (half required a second agent at 2.3 years [2.0-2.9]; P = 0.00017). Discontinuation of l-dopa therapy was 1%. Dopamine agonists were stopped (due to side-effects like impulse control disorders [6%], somnolence [4%] and light-headedness [3%]) in 20% over four years. The duration and tolerability of l-dopa and dopamine agonists as initial Parkinson's disease monotherapy are defined in this study; this may form part of the information exchange with patients.

Serum and cerebrospinal fluid urate levels in synucleinopathies versus tauopathies

Acta Neurol Scand. 2012 Sep 23. doi: 10.1111/ane.12012. [Epub ahead of print]

Constantinescu R, Andreasson U, Holmberg B, Zetterberg H.

Source

Department of Neurology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Abstract

BACKGROUND:

Low levels of serum urate are associated with a higher risk of Parkinson's disease (PD). Higher serum and cerebrospinal fluid (CSF) urate levels are associated with slower rates of clinical decline in PD and in multiple system atrophy (MSA).

AIMS:

To compare CSF and blood urate levels in healthy controls, patients with synucleinopathies and with tauopathies.

METHODS:

We investigated urate levels in serum and CSF from 18 healthy controls, 19 patients with synucleinopathies (six patients with PD and 13 with MSA), and 24 patients with tauopathies (18 with progressive supranuclear palsy and six with corticobasal degeneration). None of the patients were treated with dopaminergic medications.

RESULTS:

No significant differences were seen when comparing serum and CSF urate levels from controls across the parkinsonian diagnostic groups. However, in men, serum urate levels were significantly lower in the synucleinopathy group compared with the tauopathy group (P = 0.046), although with a broad overlap.

CONCLUSION:

Our study suggests that urate levels might provide new insights into the potential pathophysiological mechanisms underlying Parkinsonism and thereby contribute to the future management of these disorders.

Verbal fluency in Parkinson's disease patients on/off dopamine medication

Neuropsychologia. 2012 Sep 17. pii: S0028-3932(12)00388-0. doi: 10.1016/j.neuropsychologia.2012.09.016. [Epub ahead of print]

Herrera E, Cuetos F, Ribacoba R.

Source

University of Oviedo (Spain).

Abstract

INTRODUCTION:

Parkinson´s disease (PD) is associated with dopamine depletion in the fronto-striatal network which affects some language aspects such as verb processing. Some experiments have demonstrated that dopamine deficiency plays a role in the normal functioning of the lexico-semantic system. As a result, the verbal fluency task could be a useful tool to assess the function of the semantic system, by examining both the number of words generated and the frequency of use of those words.

OBJECTIVE:

The aim of this study was to find out how dopamine affects the performance of PD patients using a verbal fluency task, focussing on action-word fluency.

METHOD:

A group of 20 PD patients and 20 controls participated in the study. Participants were assessed with 4 different verbal fluency tasks: phonological, semantic (animal and supermarket words) and action fluency. PD patients were tested twice (on/off medication) and controls only once.

RESULTS:

For the number of words, there were significant differences between PD patients on and off medication in the phonological and action fluency tasks. Compared to controls, PD off medication produced significantly fewer words in phonological, animals and actions. Regarding frequency, differences were found between PD patients off medication and controls for the action-word category.

DISCUSSION:

Our data showed a specific deficit in PD patients off medication in categories mainly depending on frontal lobe function (phonological and actions) while these differences were restored with dopamine treatment. Moreover, PD patients off medication produced higher frequency verbs than controls, suggesting that dopamine affects the normal functioning within the lexico-semantic network of verbs.

Psychiatric syndromes in Parkinson's disease

Curr Opin Psychiatry. 2012 Sep 18. [Epub ahead of print]

Starkstein SE, Brockman S, Hayhow BD.

Source

School of Psychiatry and Neurosciences, University of Western Australia, Western Australia, Australia.

Abstract

PURPOSE OF REVIEW:

To examine progress about relevant behavioural and psychiatric disorders in Parkinson's disease, such as depression, apathy, psychosis, and impulse control disorder.

RECENT FINDINGS:

Several recent studies have characterized the phenomenology of depression in Parkinson's disease, and randomized controlled trials have demonstrated the efficacy of tricyclics, selective serotonin reuptake inhibitors and psychotherapy for depression in Parkinson's disease. Apathy is a valid behavioural syndrome in Parkinson's disease and is associated with depression and cognitive deficits. Psychosis is highly prevalent in the late stages of the disease, but there are few effective therapeutic modalities for this psychiatric condition. Impulse control disorders are also relatively frequent in Parkinson's disease, and are associated with comorbid psychiatric disorders.

SUMMARY:

Standardized criteria should be used to diagnose depression and apathy in Parkinson's disease. Psychotherapy and pharmacotherapy are useful treatment modalities for affective disorders in Parkinson's disease. Clozapine is still the most effective, albeit rarely used, treatment for psychosis in Parkinson's disease. Impulse control disorders are relatively frequent in Parkinson's disease and all patients should be screened for this complex disorder.

Cognitive Profile of the Earliest Stage of Dementia in Parkinson's Disease.

Am J Alzheimers Dis Other Demen. 2012 Sep 19. [Epub ahead of print]

Petrova M, Raycheva M, Traykov L.

Abstract

Recently, a strong interest has emerged in recognizing Parkinson's disease dementia (PDD) at a very early stage. However, the specific profile of the earliest stages of PDD is still unclear and a matter of considerable controversy. The objective of this study was to find out early neuropsychological markers for progression of dementia in this population. Fifty-eight patients with PDD were divided into 2 subgroups on the basis of the Mini-Mental State Examination: very mild and mild. The comparison with 26 normal controls shows that very mild PDD had deficits on attention/executive functions, naming, visuospatial/constructional abilities and retrieval of the episodic memory. Patients with mild PDD showed additional deficits on coding of episodic memory. Moreover, we found that in this early stage of PDD, the progression of dementia is mainly related to deterioration of attention/executive functions as well as retrieval and coding of episodic memory.

Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients

J Neurol Neurosurg Psychiatry. 2012 Sep 19. [Epub ahead of print]

Erro R, Picillo M, Vitale C, Amboni M, Moccia M, Longo K, Cozzolino A, Giordano F, De Rosa A, De Michele G, Pellecchia MT, Barone P.

Source

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

Abstract

BACKGROUND:

Non-motor symptoms are very common among patients with Parkinson's disease since the earliest stage, but little is known about their progression and their relationship with dopaminergic replacement therapy.

METHODS:

We studied non-motor symptoms before and after 2 years from dopaminergic therapy introduction in ninety-one newly diagnosed previously untreated PD patients.

RESULTS:

At baseline, nearly all patients (97.8%) referred at least one non-motor symptom. At follow-up, only few non-motor symptoms significantly changed. Particularly, depression and concentration became less frequent, while weight change significantly increased after introduction of dopamine agonists.

CONCLUSIONS:

We reported for the first time a 2-year prospective study on non-motor symptoms before and after starting therapy in newly diagnosed PD patients. Even if non-motor symptoms are very frequent in early stage, they tend to remain stable during the early phase of disease, being only few non-motor symptoms affected from dopaminergic therapy and, specifically, by the use of dopamine agonists.

No association between neuropathy and restless legs in Parkinson's disease

Acta Neurol Scand. 2012 Sep 18. doi: 10.1111/ane.12011. [Epub ahead of print]

Rajabally YA, Martey J.

Source

Department of Neurology, University Hospitals of Leicester, Leicester, UK.

Abstract

BACKGROUND:

The prevalence of restless legs syndrome (RLS) has been studied extensively in Parkinson's disease (PD), with conflicting findings. More recently, both neuropathy and leg motor restlessness (LMR) have been found to be significantly more prevalent in PD patients than in controls.

AIMS:

Our objective was to determine whether RLS or LMR may be secondary to neuropathy, or its currently postulated determinants, cumulative levodopa usage and vitamin B(12) metabolism, in patients with PD.

MATERIALS AND METHODS:

We compared prevalence of RLS, LMR and neuropathy in 37 PD patients and 37 age- and gender-matched controls. Correlations between RLS/LMR and neuropathy and symptomatic neuropathy, cumulative levodopa usage and vitamin B(12) levels were ascertained.

RESULTS:

RLS prevalence was comparable in PD patients and controls (16.2% vs 10.8%; P = 0.30). LMR was significantly more common in PD patients than in controls (40.5% vs 16.2%; P = 0.038), as was neuropathy (37.8% vs 8.1%; P = 0.005). Neither RLS, nor LMR correlated with neuropathy or symptomatic neuropathy, cumulative levodopa exposure or serum vitamin B(12) levels in patients with PD. There was a non-significant trend for a correlation between LMR and earlier age of onset of PD (P = 0.069).

CONCLUSIONS:

RLS and LMR appear unrelated to neuropathy or symptomatic neuropathy, cumulative levodopa usage, or serum vitamin B(12) levels in patients with PD. The occurrence of LMR may relate to the earlier onset of PD, raising the possibility of common pathophysiological mechanisms for PD and RLS, of which LMR may be an early manifestation in some patients.

Idiopathic Parkinson's disease: vocal and quality of life analysis

Arq Neuropsiquiatr. 2012 Sep;70(9):674-9.

Silva LF, Gama AC, Cardoso FE, Reis CA, Bassi IB.

Source

UFMG, Belo Horizonte, MG, Brazil.

Abstract

OBJECTIVE:

To compare voice and life quality of male patients with idiopathic Parkinson's disease, with individuals without disease (Control Group).

METHODS:

A cross-sectional study that evaluated the voice of individuals with Parkinson's disease, the group was composed of 27 subjects, aged from 39 to 79 years-old (average 59.96). The Control Group was matched on sex and age. Participants underwent voice recording. Perceptual evaluation was made using GRBASI scale, which considers G as the overall degree of dysphonia, R as roughness, B as breathiness, A as asthenia, S as strain and I as instability. The acoustic parameters analyzed were: fundamental frequency, jitter, shimmer, and harmonic to noise ratio (NHR). For vocal self-perception analysis, we used the Voice Related Quality of Life protocol.

RESULTS:

Fundamental frequency and jitter presented higher values in the Parkinson's group. NHR values were higher in the Control Group. Perceptual analysis showed a deviation ranging. The vocal disorder self-perception demonstrated a worse impact on quality of life.

CONCLUSIONS:

Individuals with Parkinson's disease have an altered voice quality and a negative impact on quality of life.

LRRK2 and vesicle trafficking

Biochem Soc Trans. 2012 Oct 1;40(5):1117-22.

Sanna G, Del Giudice MG, Crosio C, Iaccarino C.

Source

Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

Abstract

Mutations in LRRK2 (leucine-rich repeat kinase 2) (also known as PARK8 or dardarin) are responsible for the autosomal-dominant form of PD (Parkinson's disease). LRRK2 mutations were found in approximately 3-5% of familial and 1-3% of sporadic PD cases with the highest prevalence (up to 40%) in North Africans and Ashkenazi Jews. To date, mutations in LRRK2 are a major genetic risk factor for familial and sporadic PD. Despite the fact that 8 years have passed from the establishment of the first link between PD and dardarin in 2004, the pathophysiological role of LRRK2 in PD onset and progression is far from clearly defined. Also the generation of different LRRK2 transgenic or knockout animals has not provided new hints on the function of LRRK2 in the brain. The present paper reviews recent evidence regarding a potential role of LRRK2 in the regulation of membrane trafficking from vesicle generation to the movement along cytoskeleton and finally to vesicle fusion with cell membrane.

LRRK2 and autophagy: a common pathway for disease.

Biochem Soc Trans. 2012 Oct 1;40(5):1147-51.

Manzoni C.

Source

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, U.K.

Abstract

LRRK2 (leucine-rich repeat kinase 2) is an enzyme implicated in human disease, containing kinase and GTPase functions within the same multidomain open reading frame. Dominant mutations in the LRRK2 gene are the most common cause of familial PD (Parkinson's disease). Additionally, in genome-wide association studies, the LRRK2 locus has been linked to risk of PD, Crohn's disease and leprosy, and LRRK2 has also been linked with cancer. Despite its association with human disease, very little is known about its pathophysiology. Recent reports suggest a functional association between LRRK2 and autophagy. Implications of this set of data for our understanding of LRRK2's role in physiology and disease are discussed in the present paper.

When does Parkinson's disease begin? From prodromal disease to motor signs

Rev Neurol (Paris). 2012 Sep 12. pii: S0035-3787(12)00883-1. doi: 10.1016/j.neurol.2012.07.004. [Epub ahead of print]

Meissner WG.

Source

Service de neurologie et centre de référence atrophie multisystématisée, CHU de Bordeaux, avenue Magellan, 33604 Pessac cedex, France; Université de Bordeaux, institut des maladies neurodégénératives, UMR 5293, 33000 Bordeaux, France; CNRS, institut des maladies neurodégénératives, UMR 5293, 33000 Bordeaux, France. 

Abstract

Cardinal motor features of Parkinson's disease (PD) appear when about half of the nigral dopamine neurons have disappeared. Based on extrapolations from post-mortem and imaging studies, the delay between the onset of dopamine denervation and the appearance of motor signs ranges from 5 to 20years. According to Braak and co-workers, motor symptoms only appear at stage III of PD, while the neurodegenerative process begins earlier in the olfactory bulb and lower brain stem. In addition to the cardinal motor features, non-motor signs are increasingly being recognized in PD. Some of them, mainly olfactory disturbances, rapid-eye-movement sleep behaviour disorder and autonomic dysfunction, are already present in the early disease stages and may precede the onset of motor signs by up to four decades. These non-motor signs are related to widespread extranigral and even extracerebral degeneration, and have been considered risk factors for many years. Indeed, recent evidence suggests that they may be prodromal manifestations of PD. From the perspective of future disease-modifying or neuroprotective treatments, combining prodromal non-motor signs and paraclinical investigations may help to further develop reliable tools for early diagnosis of PD before the onset of its cardinal motor features.

Charity warns of 'retreat' from dementia research

http://www.bbc.co.uk/news/health-19653707

Prescribing in Parkinson's disease: a story of hope and adverse events

Pract Neurol. 2012 Oct;12(5):335-40.

Morrish P.

Abstract

A review of National Health Service spending in England on prescription drugs used in Parkinsonism over the last 10 years shows that spending has risen rapidly and that newly introduced drugs are quickly and expensively adopted. This paper explores the gains and costs of such prescribing.

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Increased risk of parkinsonism associated with welding exposure

Neurotoxicology. 2012 Sep 3. pii: S0161-813X(12)00207-0. doi: 10.1016/j.neuro.2012.08.011. [Epub ahead of print]

Racette BA, Criswell SR, Lundin JI, Hobson A, Seixas N, Kotzbauer PT, Evanoff BA, Perlmutter JS, Zhang J, Sheppard L, Checkoway H.

Source

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110, USA.

Abstract

OBJECTIVE:

Manganese (Mn), an established neurotoxicant, is a common component of welding fume. The neurological phenotype associated with welding exposures has not been well described. Prior epidemiologic evidence linking occupational welding to parkinsonism is mixed, and remains controversial.

METHODS:

This was a cross-sectional and nested case-control study to investigate the prevalence and phenotype of parkinsonism among 811 shipyard and fabrication welders recruited from trade unions. Two reference groups included 59 non-welder trade workers and 118 newly diagnosed, untreated idiopathic PD patients. Study subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism cases were defined as welders with UPDRS3 score ≥15. Normal was defined as UPDRS3<6. Exposure was classified as intensity adjusted, cumulative hours of welding. Adjusted prevalence ratios for parkinsonism were calculated in relation to quartiles of welding hours.

RESULTS:

The overall prevalence estimate of parkinsonism was 15.6% in welding exposed workers compared to 0% in the reference group. Among welders, we observed a U-shaped dose-response relation between weighted welding exposure-years and parkinsonism. UPDRS3 scores for most domains were similar between welders and newly diagnosed idiopathic Parkinson disease (PD) patients, except for greater frequency of rest tremor and asymmetry in PD patients.

CONCLUSION:

This work-site based study among welders demonstrates a high prevalence of parkinsonism compared to nonwelding-exposed workers and a clinical phenotype that overlaps substantially with PD.

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This a couple of years old but given the current interest in this topic...

PLoS One. 2010 Sep 14;5(9):e12728.

Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms.

Lebouvier T, Neunlist M, Bruley des Varannes S, Coron E, Drouard A, N'Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, Galmiche JP, Damier P, Derkinderen P.

Source

UMR 913, Inserm, Nantes, France.

Abstract

BACKGROUND:

The presence of Lewy bodies and Lewy neurites (LN) has been demonstrated in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. The aims of the present research were to use routine colonoscopy biopsies (1) to analyze, in depth, enteric pathology throughout the colonic submucosal plexus (SMP), and (2) to correlate the pathological burden with neurological and gastrointestinal (GI) symptoms.

METHODOLOGY/PRINCIPAL FINDINGS:

A total of 10 control and 29 PD patients divided into 3 groups according to disease duration were included. PD and GI symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively. Four biopsies were taken from the ascending and descending colon during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein, neurofilaments NF 220 kDa (NF) and tyrosine hydroxylase (TH). The density of LN, labeled by anti-phosphorylated alpha-synuclein antibodies, was evaluated using a quantitative rating score. Lewy pathology was apparent in the colonic biopsies from 21 patients and in none of the controls. A decreased number of NF-immunoreactive neurons per ganglion was observed in the SMP of PD patients compared to controls. The amount of LN in the ENS was inversely correlated with neuronal count and positively correlated with levodopa-unresponsive features and constipation.

CONCLUSION/SIGNIFICANCE:

Analysis of the ENS by routine colonoscopy biopsies is a useful tool for pre-mortem neuropathological diagnosis of PD, and also provides insight into the progression of motor and non-motor symptoms.

Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson's disease

Eur J Neurol. 2012 Sep 12. doi: 10.1111/j.1468-1331.2012.03840.x. [Epub ahead of print]

Schapira AH, Stocchi F, Borgohain R, Onofrj M, Bhatt M, Lorenzana P, Lucini V, Giuliani R, Anand R.

Source

Department of Clinical Neurosciences, University College London, Institute of Neurology, London, UK.

Abstract

BACKGROUND AND PURPOSE:

Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD).

METHODS:

Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to 'intervention', defined as: increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post-hoc analyses were performed on each separate dose group.

RESULTS:

Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post-hoc analyses, patients receiving safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis).

CONCLUSIONS:

The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post-hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD.

Neuropsychiatric symptoms in Parkinson's disease with mild cognitive impairment and dementia

Parkinsons Dis. 2012;2012:308097. Epub 2012 Aug 30.

Leroi I, Pantula H, McDonald K, Harbishettar V.

Source

Institute of Brain, Behavior and Mental Health, School of Community-Based Medicine, University of Manchester, Jean McFarlane Building, Oxford Road, Manchester M13 9PL, UK.

Abstract

Neuropsychiatric symptoms commonly complicate Parkinson's disease (PD), however the presence of such symptoms in mild cognitive impairment (PD-MCI) specifically has not yet been well described. The objective of this study was to examine and compare the prevalence and profile of neuropsychiatric symptoms in patients with PD-MCI (n = 48) to those with PD and no cognitive impairment (PD-NC, n = 54) and to those with dementia in PD (PDD, n = 25). PD-MCI and PDD were defined using specific consensus criteria, and neuropsychiatric symptoms were assessed with the 12-item Neuropsychiatric Inventory (NPI). Self-rated apathy, depression, and anxiety rating scales were also administered. Over 79% of all participants reported at least one neuropsychiatric symptom in the past month. The proportion in each group who had total NPI scores of ≥4 ("clinically significant") was as follows: PD-NC, 64.8%; PD-MCI, 62%; PDD 76%. Apathy was reported in almost 50% of those with PD-MCI and PDD, and it was an important neuropsychiatric symptom differentiating PD-MCI from PD-NC. Psychosis (hallucinations and delusions) increased from 12.9% in PD-NC group; 16.7% in PD-MCI group; and 48% in PDD group. Identifying neuropsychiatric symptoms in PD-MCI may have implications for ascertaining conversion to dementia in PD.

Parasomnias: An Updated Review

Neurotherapeutics. 2012 Sep 11. [Epub ahead of print]

Howell MJ.

Source

Department of Neurology, University of Minnesota Medical Center, Sleep Disorders Center, University of Minnesota, Minnesota, MN, USA

Abstract

Parasomnias are abnormal behaviors emanating from or associated with sleep. Sleepwalking and related disorders result from an incomplete dissociation of wakefulness from nonrapid eye movement (NREM) sleep. Conditions that provoke repeated cortical arousals, or promote sleep inertia lead to NREM parasomnias by impairing normal arousal mechanisms. Changes in the cyclic alternating pattern, a biomarker of arousal instability in NREM sleep, are noted in sleepwalking disorders. Sleep-related eating disorder (SRED) is characterized by a disruption of the nocturnal fast with episodes of feeding after an arousal from sleep. SRED is often associated with the use of sedative-hypnotic medications; in particular, the widely prescribed benzodiazepine receptor agonists. Recently, compelling evidence suggests that nocturnal eating may in some cases be a nonmotor manifestation of Restless Legs Syndrome (RLS). rapid eye movement (REM) Sleep Behavior Disorder (RBD) is characterized by a loss of REM paralysis leading to potentially injurious dream enactment. The loss of atonia in RBD often predates the development of Parkinson's disease and other disorders of synuclein pathology. Parasomnia behaviors are related to an activation (in NREM parasomnias) or a disinhibition (in RBD) of central pattern generators (CPGs). Initial management should focus on decreasing the potential for sleep-related injury followed by treating comorbid sleep disorders. Clonazepam and melatonin appear to be effective therapies in RBD, whereas paroxetine has been reported effective in some cases of sleep terrors. At this point, pharmacotherapy for other parasomnias is less certain, and further investigations are necessary.

Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis

Neurology. 2012 Sep 11;79(11):1174-80.

Mortimer JA, Borenstein AR, Nelson LM.

Abstract

OBJECTIVE:

To examine associations of welding and manganese exposure with Parkinson disease (PD) using meta-analyses of data from cohort, case-control, and mortality studies.

METHODS:

Epidemiologic studies related to welding or manganese exposure and PD were identified in a PubMed search, article references, published reviews, and abstracts. Inclusion criteria were 1) cohort, case-control, or mortality study with relative risk (RR), odds ratio (OR), or mortality OR (MOR) and 95 confidence intervals (95% CI); 2) RR, OR, and MOR matched or adjusted for age and sex; 3) valid study design and analysis. When participants of a study were a subgroup of those in a larger study, only results of the larger study were included to assure independence of datasets. Pooled RR/OR estimates and 95% CIs were obtained using random effects models; heterogeneity of study effects were evaluated using the Q statistic and I(2) index in fixed effect models.

RESULTS:

Thirteen studies met inclusion criteria for the welding meta-analysis and 3 studies for the manganese exposure meta-analysis. The pooled RR for the association between welding and PD for all study designs was 0.86 (95% CI 0.80-0.92), with absence of between-study heterogeneity (I(2) = 0.0). Effect measures for cohort, case-control, and mortality studies were similar (0.91, 0.82, 0.87). For the association between manganese exposure and PD, the pooled OR was 0.76 (95% CI 0.41-1.42).

CONCLUSIONS:

Welding and manganese exposure are not associated with increased PD risk. Possible explanations for the inverse association between welding and PD include confounding by smoking, healthy worker effect, and hormesis.

Neuropathological correlates of dopaminergic imaging in Alzheimer's disease and Lewy body dementias

Brain. 2012 Sep;135(Pt 9):2798-808.

Colloby SJ, McParland S, O'Brien JT, Attems J.

Source

Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. s.j.colloby@ncl.ac.uk.

Abstract

Investigation of dopaminergic transporter loss in vivo using (123)I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane single photon emission computed tomography has been widely used as a diagnostic aid in Lewy body disease. However, it is not clear whether the pathological basis for the imaging changes observed reflects loss of dopaminergic transporter expressing neurons because of cell death or dysfunctional neurons due to possible nigral and/or striatal neurodegenerative pathology. We aimed to investigate the influence of nigral neuronal loss as well as nigral (α-synuclein, tau) and striatal (α-synuclein, tau, amyloid β) pathology on striatal uptake in a cohort of autopsy-confirmed Alzheimer's disease (n = 4), dementia with Lewy bodies (n = 7) and Parkinson's disease dementia (n = 12) cases. Subjects underwent ante-mortem dopaminergic scanning and post-mortem assessments (mean interval 3.7 years). Striatal binding (caudate, anterior and posterior putamen) was estimated using region of interest procedures while quantitative neuropathological measurements of α-synuclein, tau and amyloid β were carried out. Similarly, nigral neuronal density was assessed quantitatively. Stepwise linear regression was performed to identify significant pathological predictors of striatal binding. In all striatal regions, image uptake was associated with nigral dopaminergic neuronal density (P ≤ 0.04) but not α-synuclein (P ≥ 0.46), tau (P ≥ 0.18) or amyloid β (P ≥ 0.22) burden. The results suggest that reduced uptake in vivo may be influenced considerably by neuronal loss rather than the presence of pathological lesions, in particular those related to Alzheimer's disease and Lewy body dementias. However, dysfunctional nigral neurons may have an additional effect on striatal uptake in vivo but their respective role remains to be elucidated.

The clinical features of pathologically confirmed vascular Parkinsonism

J Neurol Neurosurg Psychiatry. 2012 Oct;83(10):1027-9.

Glass PG, Lees AJ, Bacellar A, Zijlmans J, Katzenschlager R, Silveira-Moriyama L.


Source

Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, 1 Wakefield St, London, WC1N 1PJ, UK; l.moriyama@ion.ucl.ac.uk.

Abstract

OBJECTIVE:

To evaluate in detail the clinical features in a large series of pathologically confirmed cases of vascular Parkinsonism (VP).

BACKGROUND:

In the absence of widely accepted diagnostic criteria for VP pathological confirmation of diagnosis is necessary to ensure diagnostic reliability, and has only been reported in a few small series.

DESIGN/METHODS:

The archival records of the Queen Square Brain Bank (QSBB) have been used to identify cases of Parkinsonism where cerebrovascular disease was the only pathological finding. Clinical notes were scrutinised and milestones of disease progression were compared with other atypical Parkinsonian syndromes from previous QSBB studies.

RESULTS:

Twenty-eight cases were included. Mean age of onset and disease duration were 70.6 (SD± 6.42) and 10.5 (SD± 66.1) years respectively. Bradykinesia was present in all cases, rigidity in 96%, falls in 76%, pyramidal signs in 54%, urinary incontinence in 50% and dementia in 39%.Visual hallucinations in 0%. Two-thirds had an insidious onset and a relentless rather than stepwise progression of disability. When compared with other Parkinsonian syndromes, VP had an older age of onset.

CONCLUSIONS:

In comparison with other Parkinsonian syndromes the patients were older and had an extremely low frequency of visual hallucinations compared with Parkinson's disease.

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Roles of Education and IQ in Cognitive Reserve in Parkinson's Disease-Mild Cognitive Impairment

Dement Geriatr Cogn Dis Extra. 2012 Jan;2(1):343-52. Epub 2012 Aug 22.

Armstrong MJ, Naglie G, Duff-Canning S, Meaney C, Gill D, Eslinger PJ, Zadikoff C, Mapstone M, Chou KL, Persad C, Litvan I, Mast BT, Fox S, Tang-Wai DF, Marras C.

Source

Toronto Western Hospital Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, Ont., Canada.

Abstract

BACKGROUND/AIMS:

The role of cognitive reserve in Parkinson's disease (PD)-mild cognitive impairment (MCI) is incompletely understood.

METHODS:

The relationships between PD-MCI, years of education, and estimated premorbid IQ were examined in 119 consecutive non-demented PD patients using logistic regression models.

RESULTS:

Higher education and IQ were associated with reduced odds of PD-MCI in univariate analysis. In multivariable analysis, a higher IQ was associated with a significantly decreased odds of PD-MCI, but education was not.

CONCLUSION:

The association of higher IQ and decreased odds of PD-MCI supports a role for cognitive reserve in PD, but further studies are needed to clarify the interaction of IQ and education and the impact of other contributors such as employment and hobbies.

 

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Caffeine drinking, cigarette smoking, and dopaminergic replacement therapy dose in Parkinson's disease

Neurol Sci. 2012 Sep 7. [Epub ahead of print]

Ojeda-López C, Cervantes-Arriaga A, Rodríguez-Violante M, Corona T.

Source

Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, Col. La Fama, Tlalpan, 14269, Mexico, DF, Mexico

Abstract

The objective of this study is to assess the effect of smoking and caffeine intake in the dosage of dopaminergic replacement therapy. Patients were recruited from the movement disorders clinic of the National Institute of Neurology and Neurosurgery in Mexico City. An interviewer-administered structured questionnaire was given to all subjects regarding their smoking and caffeine drinking habits. Dopaminergic replacement therapy information was collected and levodopa, dopamine agonists, and levodopa equivalent daily doses were calculated. 146 Parkinson's disease patients (50 % female) were included. All patients were on antiparkinsonian treatment, with a mean levodopa equivalent daily dose (LEDD) of 550.2 ± 408. Patients were stratified according to smoking and caffeine drinking status. 104 (71.2 %) of the patients were "never smokers", 33 (22.6 %) were "former smokers" and 9 (6.2 %) were "current smokers". 40 (27.4 %) patients reported no history of caffeine intake, 36 (24.7 %) were former consumers and 70 (47.9 %) were current caffeine drinkers. No association between LEDD and smoking or caffeine intake was found. A weak positive correlation (r = 0.22, p < 0.04) was found between the daily dose of pramipexole and the daily intake of caffeine. LEDD, levodopa daily dose and dopamine agonist daily dose were not related to smoking or caffeine intake status. We found a weak correlation between caffeine daily intake and pramipexole dose. Further prospective exploration is needed to address the interaction of concomitant A2A antagonism induced by caffeine intake and dopaminergic replacement therapy.

Neurodegenerative causes of death among retired National Football League players

Neurology. 2012 Sep 5. [Epub ahead of print]

Lehman EJ, Hein MJ, Baron SL, Gersic CM.

Source

From the Centers for Disease Control and Prevention, The National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Cincinnati, OH.

Abstract

OBJECTIVE:

To analyze neurodegenerative causes of death, specifically Alzheimer disease (AD), Parkinson disease, and amyotrophic lateral sclerosis (ALS), among a cohort of professional football players.

METHODS:

This was a cohort mortality study of 3,439 National Football League players with at least 5 pension-credited playing seasons from 1959 to 1988. Vital status was ascertained through 2007. For analysis purposes, players were placed into 2 strata based on characteristics of position played: nonspeed players (linemen) and speed players (all other positions except punter/kicker). External comparisons with the US population used standardized mortality ratios (SMRs); internal comparisons between speed and nonspeed player positions used standardized rate ratios (SRRs).

RESULTS:

Overall player mortality compared with that of the US population was reduced (SMR 0.53, 95% confidence interval [CI] 0.48-0.59). Neurodegenerative mortality was increased using both underlying cause of death rate files (SMR 2.83, 95% CI 1.36-5.21) and multiple cause of death (MCOD) rate files (SMR 3.26, 95% CI 1.90-5.22). Of the neurodegenerative causes, results were elevated (using MCOD rates) for both ALS (SMR 4.31, 95% CI 1.73-8.87) and AD (SMR 3.86, 95% CI 1.55-7.95). In internal analysis (using MCOD rates), higher neurodegenerative mortality was observed among players in speed positions compared with players in nonspeed positions (SRR 3.29, 95% CI 0.92-11.7).

CONCLUSIONS:

The neurodegenerative mortality of this cohort is 3 times higher than that of the general US population; that for 2 of the major neurodegenerative subcategories, AD and ALS, is 4 times higher. These results are consistent with recent studies that suggest an increased risk of neurodegenerative disease among football players.

Treatment of patients with early and advanced Parkinson's disease with rotigotine transdermal system: Age-relationship to safety and tolerability

Parkinsonism Relat Disord. 2012 Sep 3. [Epub ahead of print]

Oertel W, Lewitt P, Giladi N, Ghys L, Grieger F, Boroojerdi B.

Source

Department of Neurology, Philipps-Universität, Baldingerstrasse, D 35043 Marburg, Germany.

Abstract

Although dopamine agonists (DAs) are sometimes perceived as poorly tolerated by the elderly, there is little clinical evidence to support these concerns. Safety and tolerability of rotigotine have been demonstrated in four 6-month randomized placebo-controlled studies: two in early Parkinson's disease (PD) and two in advanced PD. A post hoc analysis of data from these pivotal trials was carried out to compare the adverse event (AE) profiles of younger and older patient populations. Data from early and advanced PD trials were separately pooled and evaluated using two age cut-offs (<65 vs. ≥65 years; <75 vs. ≥75 years). For most AEs, no age-related differences in incidence were observed. In the early PD pool, nausea (38% vs. 30%) and headache (15% vs. 9%) were more frequent in younger (<65 years) compared with older (≥65 years) patients using the 65-year age cut-off. Using the 75-year cut-off, nausea (36% vs. 21%) was more frequent in younger patients (<75 years) and dizziness (15% vs. 28%) was more frequent in older patients (≥75 years). In the advanced PD pool, nausea was more frequent in younger patients using the 65-year age cut-off (24% vs. 19%) and falls were more frequent in older patients using the 75-year age cut-off (8% vs. 13%). In this relatively healthy population which included only few patients aged 75 years or older, rotigotine was generally well tolerated regardless of age. Data from more representative PD populations are required to fully assess potential risks of DA therapy in elderly patients.

Willingness of Parkinson's Disease Patients to Participate in Research Using Internet-Based Technology

Telemed J E Health. 2012 Sep 6. [Epub ahead of print]

Shprecher D, Noyes K, Biglan K, Wang D, Dorsey ER, Kurlan R, Adams MJ.

Source

1 Department of Neurology, University of Utah , Salt Lake City, Utah.

Abstract

Abstract Background: Motor impairment and travel time have been shown to be important barriers to recruitment for Parkinson's disease (PD) clinical trials. This study determined whether use of Internet-based video communication for study visits would improve likelihood of participating in PD clinical trials. Subjects and Methods: University of Utah PD clinic patients were invited to complete a survey asking if they would be willing to participate in a hypothetical research study under four different scenarios. McNemar's test was used to test the hypothesis that remote assessments would improve willingness to participate. Results: Willingness to participate was 101/113 (87%) in the standard scenario. Willingness to participate was highest (93%; p=0.046) with most visits occurring via telemedicine at a local clinic, followed by some visits occurring via telemedicine at a local clinic (91%; p=0.157). Willingness to participate was lower with some (80%; p=0.008) or most (82%; p=0.071) visits occurring by home telemonitoring. Conclusions: Use of telemedicine may be an acceptable means to improve participation in clinical trials. This would need to be confirmed with the use of a larger-scale inquiry involving rural populations. Future research should assess subject or caregiver comfort and trainability with respect to computer-based technology in the home and systems barriers for wider implementation of telemedicine in neurology.

Othello syndrome secondary to ropinirole: a case study

Case Rep Psychiatry. 2012;2012:353021. Epub 2012 Jun 24.

Pal K, Smith A, Hayes J, Chakraborty A.

Source

Highgate Mental Health Centre, Camden and Islington NHS Foundation, Dartmouth Park Hill, London N19 5NX, UK.

Abstract

This case report describes a forty-two-year-old man with no previous psychiatric history who developed delusional jealousy (Othello Syndrome) associated with ropinirole treatment. Ropinirole is a commonly used dopamine receptor agonist, which was being used to treat his Parkinson's disease, and his delusional symptoms resolved entirely with ropinirole dose reduction.

Biosignatures for Parkinson's disease and atypical parkinsonian disorders patients

PLoS One. 2012;7(8):e43595. Epub 2012 Aug 27.

Potashkin JA, Santiago JA, Ravina BM, Watts A, Leontovich AA.

Source

The Cellular and Molecular Pharmacology Department, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, Illinois, United States of America.

Abstract

Diagnosis of Parkinson' disease (PD) carries a high misdiagnosis rate due to failure to recognize atypical parkinsonian disorders (APD). Usually by the time of diagnosis greater than 60% of the neurons in the substantia nigra are dead. Therefore, early detection would be beneficial so that therapeutic intervention may be initiated early in the disease process. We used splice variant-specific microarrays to identify mRNAs whose expression is altered in peripheral blood of early-stage PD patients compared to healthy and neurodegenerative disease controls. Quantitative polymerase chain reaction assays were used to validate splice variant transcripts in independent sample sets. Here we report a PD signature used to classify blinded samples with 90% sensitivity and 94% specificity and an APD signature that resulted in a diagnosis with 95% sensitivity and 94% specificity. This study provides the first discriminant functions with coherent diagnostic signatures for PD and APD. Analysis of the PD biomarkers identified a regulatory network with nodes centered on the transcription factors HNF4A and TNF, which have been implicated in insulin regulation.

Parkinson's disease subtypes: lost in translation?

J Neurol Neurosurg Psychiatry. 2012 Sep 5. [Epub ahead of print]

Marras C, Lang A.

Source

Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Ontario, Canada.

Abstract

Like many neurodegenerative disorders, Parkinson's disease (PD) is clinically highly heterogeneous. A number of studies have proposed and defined subtypes of PD based on clinical features that tend to cluster together. These subtypes present an opportunity to refine studies of aetiology, course and treatment responsiveness in PD, as clinical variability must represent underlying biological or pathophysiological differences between individuals. In this paper, we review what subtypes have been identified in PD and the validation they have undergone. We then discuss what the subtypes could tell us about the disease and how they have been incorporated into studies of aetiology, progression and treatment. Finally, with the knowledge that they have been incorporated very little into PD clinical research, we make recommendations for how subtypes should be used and make some practical recommendations to address this lack of knowledge translation.

Abnormal network topographies and changes in global activity: Absence of a causal relationship

Neuroimage. 2012 Aug 19. [Epub ahead of print]

Dhawan V, Tang CC, Ma Y, Spetsieris P, Eidelberg D.

Abstract

Changes in regional brain activity can be observed following global normalization procedures to reduce variability in the data. In particular, spurious regional differences may appear when scans from patients with low global activity are compared to those from healthy subjects. It has thus been suggested that the consistent increases in subcortical activity that characterize the abnormal Parkinson's disease-related metabolic covariance pattern (PDRP) are artifacts of global normalization, and that similar topographies can be identified in scans from healthy subjects with varying global activity. To address this issue, we examined the effects of experimental reductions in global metabolic activity on PDRP expression. Ten healthy subjects underwent (18)F-fluorodeoxyglucose PET in wakefulness and following sleep induction. In all subjects, the global metabolic rate (GMR) declined with sleep (mean -34%, range: -17 to -56%), exceeding the test-retest differences of the measure (p<0.001). By contrast, sleep-wake differences in PDRP expression did not differ from test-retest differences, and did not correlate (R(2)=0.04) with concurrent declines in global metabolic activity. Indeed, despite significant GMR reductions in sleep, PDRP values remained within the normal range. Likewise, voxel weights on the principal component patterns resulting from combined analysis of the sleep and wake scans did not correlate (R(2)<0.07) with the corresponding regional loadings on the PDRP topography. In aggregate, the data demonstrate that abnormal PDRP expression is not induced by reductions in global activity. Moreover, significant declines in GMR are not associated with the appearance of PDRP-like spatial topographies.

Higher normal fasting plasma glucose is associated with hippocampal atrophy The PATH Study

Nicolas Cherbuin, PhD, Perminder Sachdev, MD, PhD, FRANZCP and Kaarin J. Anstey, PhD

Neurology September 4, 2012 vol. 79 no. 10 1019-1026

ABSTRACT

Objectives: Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60–64 years, taking part in a longitudinal study of aging.

Methods: Fasting plasma glucose was assessed at wave 1. Hippocampal and amygdala volumes were manually traced on 1.5 T MRI scans collected at wave 1 and at wave 2 4 years later. General linear model analyses were used to assess the relationship between plasma glucose and incident medial temporal lobe atrophy after controlling for a range of sociodemographic and health variables.

Results: Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%–10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking.

Conclusions: High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes.

Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease

Laura L. Kilarski PhD¹,  Justin P. Pearson MRCP¹,  Victoria Newsway BSc¹,  Elisa Majounie PhD¹,  M. Duleeka W. Knipe BSc, MPH²,  Anjum Misbahuddin PhD MRCP³, Patrick F. Chinnery PhD, FRCP⁴,  David J. Burn MD, FRCP⁴,  Carl E. Clarke MD, FRCP^5,6,  Marie-Helene Marion MD⁷, Alistair J. Lewthwaite MRCP^5,8,9,  David J. Nicholl PhD, FRCP^5,6,10,  Nicholas W. Wood PhD, FRCP⁹,  Karen E. Morrison DPhil, FRCP^5,8,  Caroline H. Williams-Gray PhD, MRCP¹¹,  Jonathan R. Evans PhD, MRCP¹¹,  Stephen J. Sawcer PhD FRCP¹¹, Roger A. Barker PhD, MRCP¹¹,  Mirdhu M. Wickremaratchi PhD, MRCP¹²,  Yoav Ben-Shlomo PhD, FFPH¹³,  Nigel M. Williams PhD¹,  Huw R. Morris PhD, FRCP^1,*

Movement Disorders Journal. 
DOI: 10.1002/mds.25132Article first published online: 6 SEP 2012

Abstract

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.

Alzheimer’s drugs take a new tack

Check out this NATURE News item

http://www.nature.com/news/alzheimer-s-drugs-take-a-new-tack-1.11343

Eli Lilly’s solanezumab faces grim prospects of attaining conditional FDA approval in mild Alzheimer’s

Check out this link to the Financial Times

http://www.ft.com/cms/s/2/cbc228be-f6d3-11e1-827f-00144feabdc0.html#axzz25j8NA1Vp

WiiPD - Objective Home Assessment of Parkinson's Disease using the Nintendo Wii Remote.

IEEE Trans Inf Technol Biomed. 2012 Aug 28. [Epub ahead of print]

Synnott J, Chen L, Nugent C, Moore G.

Abstract

Current clinical methods for the assessment of Parkinson's disease suffer from inconvenience, infrequency and subjectivity. WiiPD is an approach for the objective home based assessment of Parkinson's disease which utilizes the intuitive and sensor rich Nintendo Wii Remote. Combined with an electronic patient diary, a suite of mini-games, a metric analyzer, and a visualization engine, we propose that this system can complement existing clinical practice by providing objective metrics gathered frequently over extended periods of time. In this paper we detail the approach and introduce a series of metrics deemed capable of quantifying the severity of tremor and bradykinesia in those with Parkinson's disease. The system has been tested on a 71 year old participant with Parkinson's disease over a period of 15 days, a 72 year old control user without Parkinson's disease, and a group of 8 young adults. Results indicate a clear correlation between patient self rating scores of tremor severity and metric values obtained, in addition to clear differences in metrics obtained from each user group. These results suggest that this approach is capable of indicating the presence and severity of the motor symptoms of Parkinson's disease that affect arm motor control.

Can a Screening Questionnaire Accurately Identify Mild Parkinsonian Signs?

Neuroepidemiology. 2012 Aug 29;39(3):171-175. [Epub ahead of print]

Dahodwala N, Kubersky L, Siderowf A.

Source

Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of Pennsylvania, Philadelphia, Pa., USA.

Abstract

Background: Mild parkinsonian signs (MPS) are early features that, when present, increase the risk of neurodegenerative disease and mortality. Current methods to identify MPS are limited to neurological examination. Our objective was to assess the ability of a 9-item Parkinson's Disease Screening Questionnaire (PDSQ), which has high sensitivity in the detection of overt Parkinson's disease (PD), to detect MPS. Methods: Measures including the PDSQ, Unified Parkinson's Disease Rating Scale and University of Pennsylvania Smell Identification Test were administered to 267 participants without neurodegenerative disease. Two published definitions of MPS were used to classify cases. Results: PDSQ scores were higher for cases compared to controls (p < 0.001 for the first case definition and 0.07 for the second). However, the questionnaire had low sensitivity (47 and 59%) and specificity (62 and 63%) in the detection of MPS. Adding factors such as age, gender and smell test score to the questionnaire in a predictive model only marginally improved the test characteristics. Conclusion: The results show the screening questionnaire does not accurately identify MPS. More accurate tests are needed to improve the detection of this early syndrome which can lead to motor disability, neurodegenerative disease and mortality.

Neuropsychological assessment of driving safety risk in older adults with and without neurologic disease

J Clin Exp Neuropsychol. 2012 Sep 3. [Epub ahead of print]

Anderson SW, Aksan N, Dawson JD, Uc EY, Johnson AM, Rizzo M.

Source

a Division of Neuroergonomics, Department of Neurology , University of Iowa , Iowa City , IA , USA.

Abstract

Decline in cognitive abilities can be an important contributor to the driving problems encountered by older adults, and neuropsychological assessment may provide a practical approach to evaluating this aspect of driving safety risk. The purpose of the present study was to evaluate several commonly used neuropsychological tests in the assessment of driving safety risk in older adults with and without neurological disease. A further goal of this study was to identify brief combinations of neuropsychological tests that sample performances in key functional domains and thus could be used to efficiently assess driving safety risk. A total of 345 legally licensed and active drivers over the age of 50, with no neurologic disease (N = 185), probable Alzheimer's disease (N = 40), Parkinson's disease (N = 91), or stroke (N = 29), completed vision testing, a battery of 10 neuropsychological tests, and an 18-mile drive on urban and rural roads in an instrumented vehicle. Performances on all neuropsychological tests were significantly correlated with driving safety errors. Confirmatory factor analysis was used to identify 3 key cognitive domains assessed by the tests (speed of processing, visuospatial abilities, and memory), and several brief batteries consisting of one test from each domain showed moderate corrected correlations with driving performance. These findings are consistent with the notion that driving places demands on multiple cognitive abilities that can be affected by aging and age-related neurological disease, and that neuropsychological assessment may provide a practical off-road window into the functional status of these cognitive systems.

Image from www.rospa.com

Shared Predispositions of Parkinsonism and Cancer: A Population-Based Pedigree-Linked Study

Arch Neurol. 2012 Sep 3:1-6. doi: 10.1001/archneurol.2012.2261. [Epub ahead of print]

Kareus SA, Figueroa KP, Cannon-Albright LA, Pulst SM.

Abstract

OBJECTIVE To use a statewide population-based genealogic database to evaluate the relationship between Parkinson disease (PD) and cancer subtypes. 

DESIGN Using a computerized genealogy for the Utah pioneers and their descendants linked to a statewide cancer registry and statewide death certificates, we estimated relative risks for cancer in individuals with PD listed on their death certificate, and in their first-degree, second-degree, and third-degree relatives. 

SETTING Utah Cancer Registry. 

PARTICIPANTS Approximately 2.3 million individuals in the Utah genealogic resource, including death certificates of 2998 individuals with PD listed as a cause of death from 1904 to 2008 and information on 100 817 individuals with a cancer diagnosis in the Utah Cancer Registry. 

RESULTS Melanoma and prostate cancer were the only cancers observed in significant excess among PD cases; colorectal, lung, pancreas, and stomach cancers were observed in deficit. A significantly increased risk for prostate cancer was observed in the PD population as well as among their relatives. A reciprocal significantly increased risk for PD was also found in the 22 147 prostate cancer cases and their relatives. A significantly elevated risk for melanoma was found in the Utah PD population as well as in their relatives. A reciprocal significantly increased relative risk for PD was found in 7841 Utah melanoma cases and their relatives. 

CONCLUSIONS Our study identified a novel association between PD and prostate cancer, which extended to first-degree, second-degree, and third-degree relatives. We also confirmed the reported risk association for melanoma in patients with PD; we extended the finding to include a significantly increased risk in relatives. These results strongly support a genetic link. This conclusion is further strengthened by observation of the reciprocal relationship, an increased risk for PD in relatives of individuals with melanoma or prostate cancer.

NFL Players May Be at Higher Risk of Death from Alzheimer’s and ALS

http://www.aan.com/press/index.cfm?fuseaction=release.view&release=1101

A golden age of discovery in neuroscience

http://www.bbc.co.uk/news/health-19367832

Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology.

J Neurol Neurosurg Psychiatry. 2012 Sep 1. [Epub ahead of print]

Asahina M, Vichayanrat E, Low DA, Iodice V, Mathias CJ.

Source

Department of Neurology, Chiba University School of Medicine, Chiba, Japan.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction (parkinsonism) and several non-motor features. Dysautonomia is a significant non-motor feature as well as a neuropsychiatric symptom. Autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD. The patterns of autonomic features in PD are different from other parkinsonian disorders. Detection of autonomic dysfunction may therefore be helpful in diagnosing PD in the early or pre-motor stages, and/or in differentiating it from other parkinsonian disorders, such as multiple system atrophy and progressive supuranuclear palsy. The aim of this review is to describe aspects of autonomic dysfunction, including symptoms, assessment and pathophysiology, resulting from autonomic impairment in PD and other parkinsonian syndromes.

Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss

Acta Neuropathol. 2012 Sep 2. [Epub ahead of print]

Annerino DM, Arshad S, Taylor GM, Adler CH, Beach TG, Greene JG.

Source

Department of Neurology and the Center for Neurodegenerative Disease, Emory University School of Medicine, 6009 Woodruff Memorial Research Bldg, 101 Woodruff Circle, Atlanta, GA, 30322, USA.

Abstract

Gastrointestinal dysfunction is a prominent non-motor feature of Parkinson's disease (PD) that contributes directly to the morbidity of patients, complicates management of motor symptoms, and may herald incipient PD in patients without motor disability. Although PD has traditionally been considered a disease of dopaminergic neurons in the substantia nigra, analyses of gastrointestinal samples from PD patients have consistently revealed pathology in the enteric nervous system. The relationship of PD pathology to GI dysmotility is poorly understood, and this lack of understanding has led to limited success in developing treatments for PD-related GI symptoms. We have quantitatively compared myenteric neuron density and relative abundance of NO, VIP, and catecholamine neurons between patients with PD and control individuals along the length of the GI tract. In addition, we have examined the frequency of GI α-synuclein neuritic pathology and its co-localization with the same neuronal markers. We have included a comparison with a small population of patients with incidental Lewy bodies found at autopsy. These data indicate that there is no neuronal loss in the myenteric plexus in PD. Lewy body pathology parallels parasympathetic autonomic input from the dorsal motor nucleus of the vagus, not the distribution of extrinsic sympathetic input or intrinsic enteric neurons, and is only rarely co-localized with tyrosine hydroxylase. These data provide a critical background to which further analyses of the effect of PD on the GI tract may be compared and suggest that neuropathology in myenteric neurons is unlikely to be a causative factor in PD-related GI dysmotility.

Fifth Sense UK Event on 23rd September in Norwich - money raised goes towards investigation and treatment of anosmia sufferers

Is transcranial sonography useful to distinguish scans without evidence of dopaminergic deficit patients from Parkinson's disease?

Mov Disord. 2012 Aug;27(9):1182-5. doi: 10.1002/mds.25102. Epub 2012 Jun 28.

Stockner H, Schwingenschuh P, Djamshidian A, Silveira-Moriyama L, Katschnig P, Seppi K, Dickson J, Edwards MJ, Lees AJ, Poewe W, Bhatia KP.

Source

Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.

Abstract

BACKGROUND:

Approximately 10% of patients clinically diagnosed with early Parkinson's disease (PD) subsequently have normal dopaminergic functional imaging. Transcranial sonography (TCS) has been shown to detect midbrain hyperechogenicity in approximately 90% of Parkinson's disease (PD) patients and 10% of the healthy population. The aim of this study was to investigate the prevalence of midbrain hyperechogenicity in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDD), in comparison to PD patients.

METHODS:

TCS was performed in 14 patients with SWEDD and 19 PD patients.

RESULTS:

There was a significantly increased area of echogenicity in the PD group (0.24 ± 0.06 cm(2) ), compared to the group of patients with SWEDD (0.13 ± 0.06 cm(2) ; P < 0.001). One (9.1%) of these patients, compared to 14 (82.5%) of the PD patients, was found to have hyperechogenicity (P < 0.001).

CONCLUSIONS:

We conclude that TCS is useful to distinguish PD patients from patients with suspected parkinsonism and SWEDD.

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Clinical differences among mild cognitive impairment subtypes in Parkinson's disease.

Mov Disord. 2012 Aug;27(9):1129-36. doi: 10.1002/mds.25062. Epub 2012 Jul 6.

Goldman JG, Weis H, Stebbins G, Bernard B, Goetz CG.

Source

Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.

Abstract

Mild cognitive impairment is increasingly recognized as a construct in Parkinson's disease (PD) and occurs in about 25% of nondemented PD patients. Although executive dysfunction is the most frequent type of cognitive deficit in PD, the cognitive phenotype of PD mild cognitive impairment (PD-MCI) is broad. PD-MCI subtypes are represented by amnestic and nonamnestic domain impairment as well as single- and multiple-domain impairment. However, it is unclear whether patients with different PD-MCI subtypes also differ in other clinical characteristics in addition to cognitive profile. We studied 128 PD-MCI subjects at our Movement Disorders center, comparing clinical, motor, and behavioral characteristics across the PD-MCI subtypes. We found varying proportions of impairment subtypes: nonamnestic single domain, 47.7%; amnestic multiple domain, 24.2%; amnestic single domain, 18.8%; and nonamnestic multiple domain, 9.5%. Attentional/executive functioning and visuospatial abilities were the most frequently impaired domains. PD-MCI subtypes differed in their motor features, with nonamnestic multiple-domain PD-MCI subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in age, PD duration, medication use, mood or behavioral disturbances, and vascular disease were not significant. Thus, in addition to differing cognitive profiles, PD-MCI subtypes differed in motor phenotype and severity but not in mood, behavioral, or vascular comorbidities. Greater postural instability and gait disturbances in the nonamnestic multiple-domain subtype emphasize shared nondopaminergic neural substrates of gait and cognition in PD. Furthermore, increased burden of cognitive dysfunction, rather than type of cognitive deficit, may be associated with greater motor impairment in PD-MCI. © 2012 Movement Disorder Society.

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Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson's disease

J Neurol Sci. 2012 Aug 27. [Epub ahead of print]

Solla P, Cannas A, Ibba FC, Loi F, Corona M, Orofino G, Marrosu MG, Marrosu F.

Abstract

BACKGROUND:

Parkinson's disease (PD) occurs more frequently in men than in women and a higher risk for PD development in males compared with females has been hypothesized, suggesting gender may be a significant factor in the development and progression of parkinsonism. To date, gender differences in non-motor symptoms are under-reported.

OBJECTIVE:

To assess gender differences in motor and non-motor symptoms among Sardinian PD patients.

METHODS:

One hundred fifty-six (91 male and 65 female) consecutive Sardinian PD outpatients were included in this analysis. Modified Hoehn and Yahr scale and UPDRS were used to assess motor symptoms, while non-motor disturbances were evaluated with the non-motor symptoms scale (NMSS). Presence of depression, anxiety and other iatrogenic behavioral disorders was also investigated. In order to determine how gender differences could be specific to PD, 132 age-matched normal controls were assessed with the NMSS.

RESULTS:

Women were more likely than men to present with tremor as initial symptom (p<.025) and worse UPDRS instability score (p<.02). NMSS score in females was significantly higher than that in males (p<.018). A significantly higher severity in cardiovascular (p<0.002), sleep/fatigue (p<.018) and mood/apathy (p<.001) domains was observed in female PD patients, while the sexual dysfunction domain was reported with a significantly higher score in male patients (p<.017). Fatigue (p<.03), lack of motivation (p<.015) and sadness (p<.009) were observed significantly more frequent in females, while altered interest in sex was noted as more common in males (p<.001). Frequency of depression (p<.011) and anxiety (p<.001) was significantly higher in females, while male patients had increased frequency of compulsive sexual behaviors (p<.05). There was a significantly higher frequency of non-motor symptoms in eight domains in both male and female PD patients compared with controls (p<.001, for all comparisons, with the exception of urinary disturbances in females: p<.004). Only sexual dysfunctions were not significantly higher in male and female PD patients compared with controls.

DISCUSSION:

The present study highlights the role of gender differences associated with the occurrence of motor and non-motor disorders and our findings indicate that spectrum and severity of non-motor symptoms may present with different gender distribution in PD patients, suggesting a possible sex-related effect.

Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling

Genet Med. 2012 Aug 30. doi: 10.1038/gim.2012.107. [Epub ahead of print]

Rana HQ, Balwani M, Bier L, Alcalay RN.

Source

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

Abstract

Purpose: We sought to estimate age-specific risk of Parkinson disease in relatives of patients with Gaucher disease, who are obligate carriers of GBA mutations and who were not ascertained by family history of Parkinson disease.

Methods: A validated family history of Parkinson disease questionnaire was administered to 119 patients with Gaucher disease who were evaluated at the Mount Sinai School of Medicine from 2009 to 2012; the ages of their parents, siblings, and children, history of Parkinson disease, age at onset of Parkinson disease, and ethnic background were obtained. Kaplan-Meier survival curves were used to estimate age-specific Parkinson disease penetrance among parents of patients with Gaucher disease, who are obligatory GBA mutation carriers.

Results: Two participants with Gaucher disease were affected by Parkinson disease (5.4% of those who were 60 years or older). Of the 224 informative parents of patients with Gaucher disease, 11 had Parkinson disease (4.9%). Among the parents (obligatory carriers), cumulative risk of Parkinson disease by ages 65 and 85 was estimated to be 2.2% ±2.1% and 10.9% ±7.2%, respectively.

Conclusion: We provide useful age-specific estimates of Parkinson disease penetrance in patients with Gaucher disease and GBA heterozygous carriers for genetic counseling. Although GBA mutations may increase the risk for PD, the vast majority of patients with Gaucher disease and heterozygotes may not develop the disease. Further studies are needed to identify what modifies the risk of Parkinson disease in GBA mutation carriers.

α-Synuclein and Neuronal Cell Death

Mol Neurobiol. 2012 Aug 31. [Epub ahead of print]

Yasuda T, Nakata Y, Mochizuki H.

Source

Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ∼1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal αSyn. The extracellular αSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.

Agrochemicals, α-Synuclein, and Parkinson's Disease

Mol Neurobiol. 2012 Aug 30. [Epub ahead of print]

Silva BA, Breydo L, Fink AL, Uversky VN.

Source

Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064, USA.

Abstract

Epidemiological, population-based case-control, and experimental studies at the molecular, cellular, and organism levels revealed that exposure to various environmental agents, including a number of structurally different agrochemicals, may contribute to the pathogenesis of Parkinson's disease (PD) and several other neurodegenerative disorders. The role of genetic predisposition in PD has also been increasingly acknowledged, driven by the identification of a number of disease-related genes [e.g., α-synuclein, parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), and nuclear receptor-related factor 1]. Therefore, the etiology of this multifactorial disease is likely to involve both genetic and environmental factors. Various neurotoxicants, including agrochemicals, have been shown to elevate the levels of α-synuclein expression in neurons and to promote aggregation of this protein in vivo. Many agrochemicals physically interact with α-synuclein and accelerate the fibrillation and aggregation rates of this protein in vitro. This review analyzes some of the aspects linking α-synuclein to PD, provides brief structural and functional descriptions of this important protein, and represents some data connecting exposure to agrochemicals with α-synuclein aggregation and PD pathogenesis.

An extracellular mechanism that can explain the neurotoxic effects of α-synuclein aggregates in the brain

Front Physiol. 2012;3:297. Epub 2012 Jul 26.

Pacheco C, Aguayo LG, Opazo C.

Source

Laboratory of Neurobiometals, Department of Physiology, University of Concepción Concepción, Chile.

Abstract

Neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Dementia with Lewy bodies (DLB), display an accumulation of proteins including α-synuclein aggregates in cortical and subcortical regions of the brain. PD is a complex, progressive disease which involves damage of motor and cognitive brain regions, as well as autonomic and sensory areas. Since α-synuclein is a neuronal cytosolic protein, it is assumed that pathogenic changes induced by α-synuclein aggregates occur only at the cytoplasmic level. However, recent studies have identified the presence of extracellular α-synuclein, suggesting that the pathogenic action of this protein may also occur in the extracellular milieu through an unknown mechanism. One of the hypotheses is that extracellular α-synuclein aggregates or oligomers may directly disrupt the neuronal membrane by the formation of a pore reminiscent to the ones formed by β-amyloid aggregates. Here, we will review some evidence that support this mechanism, analyzing the interactions of α-synuclein with components of the plasma membrane, the formation of pore/perforated structures, and the implications on ionic dyshomeostasis. Furthermore, we will also discuss how this mechanism can be integrated into a general phenomenon that may explain the synaptotoxicity and neurotoxicity observed in different neurodegenerative diseases.