Astrid Thomas

Peripheral cytokines profile in Parkinson's disease

Higher levels of proinflammatory cytokines are found in Parkinsons disease (PD) patients brains and inflammation is thought to be a major contributor to the neurodegeneration. During the inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood-brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines [Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinsons disease, Br. J. Pharmacol. 50, 963-976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo, Ann. Neurol. 57, 176-179]. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain. Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of MCP-1, RANTES, MIP-1alpha, IL-8, IFNgamma, IL-1beta and TNFalpha were significantly higher in PD patients than in HC subjects (p<0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage (p<0.001). The Pearsons correlation coefficient (R) was also used to assess the strength of the relationship between NF-kappaBp65 levels and all studied cyto/chemokines and between NF-kappaBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.

ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease

Objective: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). Methods: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. Results: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. Conclusions: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

Pathological gambling in Parkinson disease is reduced by amantadine

To investigate the possible efficacy of amantadine in the control of pathological gambling (PG) associated with Parkinson disease (PD), 17 PD patients with PG were randomly selected for a double‐blind crossover study with amantadine 200mg/day versus placebo and an open follow‐up. Assessments included PG‐specific scales (Yale‐Brown Obsessive‐Compulsive Scale for PG, Gambling‐Symptom Assessment Scale, South Oaks Gambling Screen) and assessment of expenditures and time spent gambling. Amantadine abolished or reduced PG in all treated patients, as confirmed by scale score and daily expenditure reduction. Amantadine might be useful to treat PG. The effect of amantadine, acting as an antiglutamatergic agent, also opens new insights into the pathogenesis of PG. ANN NEUROL 2010

Incidence of RBD and hallucination in patients affected by Parkinson's disease: 8-year follow-up

Abstract. We describe the 8-years follow-up of 80 patients affected by idiopathic, L-dopa-responsive Parkinsons disease. All patients were evaluated at baseline and during the follow-up with visual evoked potential, P300 event related potentials and polysomnography. The patients and their relatives compiled sleep and hallucination questionnaires. Statistical analysis was performed to evaluate if visual abnormalities, abnormal P300 recordings or sleep disturbances were linked to the development and hallucinations. Our results show that abnormal vision and abnormal P300 did not correlate with the incidence of hallucinations. However, the presence of REM sleep behavioral disorder (RBD) was significantly related to the development of hallucinations,independently of age, gender or duration of disease but dependent on the amount of dopaminoagonist treatment.

Botulinum Toxin Treatment of Lateral Axial Dystonia in Parkinsonism

Lateral axial dystonia (LAD) has been described in patients with Parkinsons disease (PD), but treatment might be more controversial than treatment of LAD in other neurological conditions. Our study was designed as a blinded cross‐over with botulinum toxin (BTX) and placebo in order to investigate the efficacy of BTX in PD LAD. Nine patients with LAD who failed to experience benefit from oral medications were randomly assigned to 2 groups, 4 patients received BTX and 5 placebo as a first treatment, and were switched‐over to BTX or placebo in the following treatment session, performed 3 months after the first session. Each patient was evaluated at baseline, 2 and 4 weeks after injection and after 3 months follow‐up with the Trunk Dystonia Disability Scale (TDDS), a Visual Analogue Scale (VAS) and a goniometric measurement of the lateral displacement. Patients were videotaped at each visit. None of the patients of the placebo group experienced benefit from treatment. BTX treatment was effective in 6 patients. One patient reported subjective benefit, with improvement of VAS score and mild improvement of TDDS score, but with no improvement of flexion degree. Two patients did not report any benefit. Four patients opted to continue to receive BTX treatment for 2 years after the cross‐over study. Our study shows that BTX could be considered a possible treatment for LAD in parkinsonism.

Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months.

The latency of P300 “cognitive” event-related potentials changes if cholinergic activities of the central nervous system are pharmacologically manipulated. We tested the hypothesis that the new cholinesterase inhibitors donepezil (DPZ) and rivastigmine (Riv) may have an effect on the frequently abnormal P300 component in patients with Alzheimer disease (AD), thereby allowing a significant evaluation of cholinesterase inhibitors. We evaluated 60 patients with mild to moderately severe probable AD, in comparison with 60 age-matched control subjects, with P300 recordings and neuropsychologic examinations. Forty patients were randomly assigned in a double-blinded trial to 5–10 mg/d DPZ versus 2,000 IU/d vitamin E, and 20 patients were instead treated in an open trial with 1.5 to 12 mg/d Riv. In patients treated with vitamin E, we observed latency increments (7.4 ± 3.5 msec) correlated with worsening neuropsychologic test scores. In patients treated with DPZ and Riv, we found significant P300 latency reductions (15.3 ± 3.2 msec and 22.0 ± 3.3 msec). Shorter P300 latencies were associated with higher Wechsler Adult Intelligence Scale scores and with lower AD Assessment Scale–cognitive subscale (ADAS-cog) scores (R = 0.72). Correlations between ADAS-cog changes and P300 changes significantly separated patients treated with DPZ and Riv from those treated with vitamin E. Administration of DPZ and Riv reduced the latencies of P300 components proportionately to neuropsychologic test improvements. Combined P300 and neuropsychologic test evaluation significantly separated DPZ-treated patients and Riv-treated patients from vitamin E-treated patients.

Acute akinesia in Parkinson disease

Objective: To assess acute akinesia in patients with Parkinson disease (PD) (“acute akinesia” defined as a sudden deterioration in motor performance that persists for ≥48 hours despite treatment). Methods: The study population was a cohort of 675 patients followed regularly for 12 years in the authors’ outpatient clinic. All patients were studied when acute akinesia led to hospitalization. Unified Parkinson’s Disease Rating Scale (UPDRS) scores were rated during the akinetic state and compared with ratings obtained 1.6 ± 0.9 months before the onset or after recovery. Results: Twenty-six patients developed acute akinesia; in 17 of the 26 patients, new akinetic symptoms first manifested at the onset of an infectious disease or after surgery and appeared unrelated to changes in treatment or altered levodopa kinetics. In nine patients, acute akinesia developed concurrently with gastrointestinal diseases or drug manipulations showed features of neuroleptic malignant syndrome. Acute akinesia severe enough to increase the UPDRS Motor Subscale score by 31.4 ± 12.8 appeared within 2 to 3 days and persisted for 11.2 ± 6.2 days despite attempts to increase the dopaminergic drug dose or administer continuous subcutaneous apomorphine infusion. Symptomatic recovery began 4 to 26 days after the onset of acute akinesia and appeared incomplete in 10 patients. Four patients of 26 died despite treatment. Levodopa kinetics were normal in all patients without gastrointestinal disease and in one patient with gastric stasis. Conclusions: Acute akinesia is a life-threatening complication of Parkinson disease (PD). It is unlike the “wearing-off” phenomenon that occurs when dopaminergic drug levels decline and responds to dopaminergic rescue drugs. Acute akinesia may be a clinical entity distinct from the previously described PD motor fluctuations.

Default network is not hypoactive in dementia with fluctuating cognition: an Alzheimer disease/dementia with Lewy bodies comparison.

Default mode network resting state activity in posterior cingulate cortex is abnormally reduced in Alzheimer disease (AD) patients. Fluctuating cognition and electroencephalogram abnormalities are established core and supportive elements respectively for the diagnosis of dementia with Lewy bodies (DLB). Our aim was to assess whether patients with DLB with both of these features have different default mode network patterns during resting state functional magnetic resonance imaging compared with AD. Eighteen patients with DLB, 18 AD patients without fluctuating cognition, and 15 control subjects were selected after appropriate matching and followed for 2-5 years to confirm diagnosis. Independent component analysis with functional connectivity (FC) and Granger causality approaches were applied to isolate and characterize resting state networks. FC was reduced in AD and DLB patients compared with control subjects. Posterior cingulate cortex activity was lower in AD than in control subjects and DLB patients (p < 0.05). Right hemisphere FC was reduced in DLB patients in comparison with control subjects but not in patients with AD, and was correlated with severity of fluctuations (ρ = -0.69; p < 0.01). Causal flow analysis showed differences between patients with DLB and AD and control subjects.

Cohort study on somatoform disorders in Parkinson disease and dementia with Lewy bodies

Objective: To assess somatoform disorder (SFMD) prevalence and impact in Parkinson disease (PD) and dementia with Lewy bodies (DLB). Methods: SFMD were assessed by direct observation of symptoms in the year coincident (±6 months) with definite diagnosis of PD, DLB, Alzheimer disease, multiple system atrophy, progressive supranuclear palsy, or frontotemporal dementia, and by interviews with patients, caregivers, and general practitioners, and reviews of prior hospital admissions, in a cohort of 942 patients with neurodegenerative disorders. Matched groups of patients with PD and patients with DLB without vs with SFMD were selected for comparisons and followed up over 4 years. Results: The frequency of SFMD was higher in DLB (15 patients, 12%) and PD (29 patients, 7%) than in other neurodegenerative diseases (0%–3%). SFMD consisted of conversion motor or sensory disorders, often accompanied by delusional thought content; in one patient catatonic symptoms were observed concomitantly with PD diagnosis. Evidence of SFMD symptoms, preceding diagnosis by 6 months–10 years, was obtained in 28 patients with PD and all patients with DLB. A total of 22 patients with PD and all patients with DLB could be followed for 4 years. SFMD symptoms recurred during follow-up, with catatonic signs developing in 9 patients with PD and 8 patients with DLB. Most baseline demographic and clinical features did not differ between subjects with or without SFMD. Decline of cognitive function was greater in PD-SFMD patients than in those without SFMD (p < 0.01); it was comparable to that observed in DLB. Conclusions: The frequency of somatoform disorder (SFMD) (with catatonic signs) in Parkinson disease and dementia with Lewy bodies suggests that SFMD are part of the spectrum of Lewy body diseases.

Visual hallucinations in Parkinson's disease: Clues to separate origins

Our paper discusses two experimental studies suggesting that Visual Hallucinations (VH) in Parkinsons Disease (PD) may have separate origins. The first is a prospective 8years study evaluating the appearance of VH, visual abnormalities assessed by Visual Evoked Potentials (VEPs) and REM sleep Behaviour Disorder (RBD), in 80 PD patients treated with l-Dopa and Dopaminoagonists (DA). In chronically treated, cognitively unimpaired, PD patients VH were statistically related (p=0.001) to RBD occurrence and high DA doses. Visual abnormalities were significantly reduced by l-Dopa or DA intake, and were statistically unrelated to VH. The second study involved PD patients placed in a Virtual Reality Environment, to decontextualize visual input. When motor symptoms worsened and VEP abnormalities developed patients consistently described hallucinatory dysperceptions of the virtual environment. The two studies therefore show that VH can occur in two seemingly distinct conditions, one is related to chronic treatment and to a sleep disorder frequently observed in PD, the other is probably related to a hypodopaminergic state. Our studies support a recently proposed integrative model of VH, and show that the neural circuits purported to explain VH must include the retinal dopaminergic system and the REM sleep regulatory system.