Bariatric surgery and dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis.

INTRODUCTION: Lymphopenia is a known side effect of dimethyl fumarate (DMF), a disease-modifying therapy (DMT) for patients with multiple sclerosis (pwMS). A body mass index ≥ 30 kg/m2 has been identified as a protective factor; however, no data are available on lymphopenia in pwMS undergoing to weight loss due to bariatric surgery. METHODS: We described two pwMS with history of bariatric surgery who started DMF as DMT. RESULTS: The two pwMS experienced persistent lymphopenia during DMF-treatment, which was resolved after its discontinuation. CONCLUSIONS: Several mechanisms might modify DMF pharmacokinetic profiles after bariatric surgery and its bioavailability. Absolute lymphocyte count should be monitored in pwMS treated with DMF and history of bariatric surgery and weight loss.

Starting eculizumab as rescue therapy in refractory myasthenic crisis.

INTRODUCTION: Myasthenia gravis is a long-lasting autoimmune neuromuscular disease caused by antibodies attacking the neuromuscular junction, which can result in muscle weakness, fatigue, and respiratory failure in severe cases. Myasthenic crisis is a life-threatening event that requires hospitalization and treatments with intravenous immunoglobulin or plasma exchange. We reported the case of an AChR-Ab-positive myasthenia gravis patient with refractory myasthenic crisis, in which starting eculizumab as rescue therapy led to a complete resolution of the acute neuromuscular condition. CASE PRESENTATION: A 74-year-old man diagnosed with myasthenia gravis. ACh-receptor antibodies positivity comes to our observation for a recrudescence of symptoms, unresponsive to conventional rescue therapies. Due to the clinical worsening over the following weeks, the patient was admitted to intensive care unit, where he underwent therapy with eculizumab. About 5 days after the treatment, there was a significant and complete recovery of clinical condition with weaning-off from invasive ventilation and discharge to outpatient regimen, with reduction of steroid intake and biweekly maintenance with eculizumab. DISCUSSION: Eculizumab, a humanized monoclonal antibody that inhibits complement activation, is now approved as treatment for refractory generalized myasthenia gravis with anti-AChR antibodies. The use of eculizumab in myasthenic crisis is still investigational, but this case report suggests that it may be a promising treatment option for patients with severe clinical condition. Ongoing clinical trials will be needed to further evaluate the safety and efficacy of eculizumab in myasthenic crisis.

Anterior lumbosacral polyradiculoneuropathy following intrathecal methotrexate administration: a case report and literature update.

INTRODUCTION: We describe a case of intrathecal methotrexate toxicity and perform a literature review of existing cases. CASE PRESENTATION: A 23-year-old man who received diagnosis of acute lymphoblastic leukemia and started chemotherapy according to the LAL1913 protocol underwent CNS prophylaxis with intrathecal methotrexate. About 1 month after, he developed a flaccid paraparesis. CSF analysis showed albumin/cytological dissociation. Spinal MRI showed thickening of the ventral roots of the cauda equina with contrast enhancement. Nerve conduction studies showed severe lower limb motor axonal neuropathy. Needle examination showed acute denervation involving L3-S1 roots. Methotrexate was stopped, and the patient was treated with intravenous immunoglobulins, followed by high-dose intravenous methylprednisolone, with a gradual improvement. Three months later, the spine MRI was normal. Electrophysiological and imaging findings were indicative of pure motor L3-S1 polyradiculopathy. DISCUSSION: Literature review of existing cases confirm the relatively selective involvement of lumbosacral ventral roots in intrathecal methotrexate toxicity. Pathophysiologic mechanisms suggest either a direct toxicity with localized folate deficiency or an immune-mediated mechanism, the latter consistent, in our patient, with the albumin/cytological dissociation and response to immunomodulatory treatments. Pure motor polyradiculopathy of the lower limbs is rare but predictable complication of intrathecal methotrexate, which can benefit from early withdrawal and immunomodulatory treatments.

Sex Differences in Parkinson's Disease: From Bench to Bedside.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and gender differences have been described on several aspects of PD. In the present commentary, we aimed to collect and discuss the currently available evidence on gender differences in PD regarding biomarkers, genetic factors, motor and non-motor symptoms, therapeutic management (including pharmacological and surgical treatment) as well as preclinical studies. METHODS: A systematic literature review was performed by searching the Pubmed and Scopus databases with the search strings "biomarkers", "deep brain stimulation", "female", "gender", "genetic", "levodopa", "men", "male", "motor symptoms", "non-motor symptoms", "Parkinson disease", "sex", "surgery", and "women". RESULTS: The present review confirms the existence of differences between men and women in Parkinson Disease, pointing out new information regarding evidence from animal models, genetic factors, biomarkers, clinical features and pharmacological and surgical treatment. CONCLUSIONS: The overall goal is to acquire new informations about sex and gender differences in Parkinson Disease, in order to develop tailored intervetions.

Temporal muscle thickness and survival in patients with amyotrophic lateral sclerosis.

Temporal muscle thickness (TMT) is a new potential MRI biomarker, which has shown prognostic relevance in neuro-oncology. We aim at investigating the potential prognostic value of TMT in patients with Amyotrophic Lateral Sclerosis (ALS). We retrospectively evaluated 30 ALS patients, whose clinical, Magnetic Resonance Imaging (MRI) and Electrodiagnostic testing (EDX) data were available, in comparison to age-matched 30 healthy subjects. TMT calculated on T1-weighted MR images was significantly lower in ALS patients than in healthy subjects (p < 0.001), correlating with the ALS Functional Rating Scale (FRS) (p:0.018) and compound motor action potential (CMAP) (p:0.012) in the patients group. Multivariate analysis of overall survival (OS) showed that the only parameters that remained significant were TMT (p:0.002, OR 0.45, 95%vCI: 0.28-0.75) and ALS FRS-R (p:0.023, OR: 0.80, 95%CI: 0.67-0.92). TMT seems to be a promising surrogate biomarker of survival and functional status in ALS. Our data deserve further investigations in multicenter and prospective trials.

Does an association between cigarette smoking and Parkinson's Disease-related psychosis exist? Insights from a large non-demented cohort.

BACKGROUND: Parkinson's Disease-related Psychosis (PDP) encompasses a spectrum of symptoms ranging from "minor" hallucinations to formed hallucinations and delusions. Notably, cognitive impairment has been recognized as the strongest risk factor for PDP. Several evidences suggest a possible role of cigarette smoking in both cognition and psychotic syndromes. OBJECTIVES: To evaluate the possible independent association between cigarette smoking and PDP in a large cohort of non-demented PD patients. METHODS: A cohort of non-demented PD patients was selected from the FRAGAMP study population. All participants underwent a standardised structured questionnaire to assess demographic, clinical and environmental exposure data. Clinical features were assessed using UPDRS, HY stage, AIMS, MMSE and Hamilton Rating Scale for Depression. Presence of psychotic symptoms was assessed using UPDRS-I.2 score. Diagnosis of PDP was made according to NINDS/NIMH criteria. RESULTS: Four hundred eighty-five non-demented PD patients were enrolled [292 men (60.2%); mean age ± SD 65.6 ± 9.8]. Among them, 28 (5.8%) had PDP. Multivariate analysis, adjusting by HY stage, MMSE and LED, shown an independent association between PDP and "nightmares-abnormal movements during sleep" and current smoking [adjOR 7.39 (95%CI 1.45-37.69; P-value 0.016)]. CONCLUSIONS: Our findings provide interesting insights about the possible role of current smoking in facilitating the occurrence of psychotic symptoms in PD.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

AIM: Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS: We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS: PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p < 0.05). CONCLUSION: We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.

The role of disease duration and severity on novel clinical subtypes of Parkinson disease.

INTRODUCTION: One of the latest subtyping systems of Parkinson disease (PD) identifies motor severity, cognitive dysfunction, dysautonomia, and rapid eye movement behavior disorder as key features for phenotyping patients into three different subtypes (i.e., mild motor-predominant, diffuse-malignant and intermediate). Since PD subtypes are clinically most relevant if they are mutually exclusive and consistent over-time, we explored the impact of disease stage and duration on these novel subtypes. METHODS: One-hundred-twenty-two consecutive patients, with a disease duration ranging from 0 to 20 years, were allocated as suggested into these three subtypes. The relationship between either disease duration or stage, as measured by the Hoehn and Yahr staging, and subtype allocation was explored. RESULTS: Significant differences in subtype distribution were observed across patients stratified according to either disease duration or staging, with the diffuse-malignant subtypes increasing in prevalence as the disease advanced. Both disease duration and staging were independent predictors of subtype allocation. CONCLUSIONS: These novel PD subtypes are significantly influenced by disease duration and staging, which might suggest that they do not represent mutually exclusive disease pathways. This should be taken into account when attempting correlations with putative biomarkers of disease progression.

Screening for Aphasia in NeuroDegeneration for the Diagnosis of Patients with Primary Progressive Aphasia: Clinical Validity and Psychometric Properties.

BACKGROUND: We evaluated the psychometric proprieties of the Screening for Aphasia in NeuroDegeneration (SAND) battery in Italian primary progressive aphasia (PPA) and movement disorder (MD) patients. METHODS: The sample included 30 consecutive PPA and 45 MD patients who completed the SAND battery together with a clinical interview and a neurological/neuropsychological examination and 130 healthy controls (HC). RESULTS: The SAND battery showed good internal consistency and good convergent and divergent validity. receiver operating characteristic analysis revealed an area under the curve of 0.978 for PPA versus HC and of 0.786 for PPA versus MD. A cutoff ≥3 gave a sensitivity of 0.933% and a specificity of 0.946% for discriminating PPA versus HC, whereas a cutoff ≥5 gave a sensitivity of 0.767% and a specificity of 0.667% for discriminating PPA versus MD. CONCLUSION: These results indicate that the SAND battery is an adequate, reliable, and valid diagnostic tool for PPA.

Head trauma and Parkinson's disease: results from an Italian case-control study.

We evaluated the possible association between head trauma and Parkinson's disease (PD). The FRAGAMP (Fattori di Rischio Ambientali e Genetici Associati alla Malattia di Parkinson) study is a large Italian multicenter case-control study carried out to evaluate the possible role of environmental and genetic factors in PD. Cases and controls were enrolled from six movement disorders centers located in the Central-Southern Italy. A standardized questionnaire was administered to record demographic, epidemiological, and clinical data. Positive history of head trauma was considered only if the head trauma preceded the onset of PD. All cases and controls underwent a standard neurological examination. Adjusted ORs and 95% CI were estimated using multivariate analysis (logistic regression). Four hundred ninety-two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. A positive history for head trauma was reported by 106 (21.5%) PD patients and by 62 (13.5%) healthy controls. Multivariate analysis (OR adjusted by age, sex, family history, coffee smoking, and alcohol consumption) showed a significant positive association between PD and head trauma with an adjusted OR of 1.50 (95%CI 1.04-2.17; p value 0.03). In agreement with literature data, our study supports the positive association between head trauma and PD.

SAND: a Screening for Aphasia in NeuroDegeneration. Development and normative data.

Language assessment has a critical role in the clinical diagnosis of neurodegenerative diseases, in particular, in the case of Primary Progressive Aphasia (PPA). The current diagnostic criteria (Gorno-Tempini et al., 2011) identify three main variants on the basis of clinical features and patterns of brain atrophy. Widely accepted tools to diagnose, clinically classify, and follow up the heterogeneous language profiles of PPA are still lacking. In this study, we develop a screening battery, composed of nine tests (picture naming, word and sentence comprehension, word and sentence repetition, reading, semantic association, writing and picture description), following the recommendations of current diagnostic guidelines and taking into account recent research on the topic. All tasks were developed with consideration of the psycholinguistic factors that can affect performance, with the aim of achieving sensitivity to the language deficit to which each task was relevant, and to allow identification of the selective characteristic impairments of each PPA variant. Normative data on 134 Italian subjects pooled across homogeneous subgroups for age, sex, and education are reported. Although further work is still needed, this battery represents a first step towards a concise multilingual standard language examination, a fast and simple tool to help clinicians and researchers in the diagnosis of PPA.

The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals.

Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2-binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell-derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic-specific autophagy defects to Parkinson's disease.

The relevance of gender in Parkinson's disease: a review.

Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.

Caffeine consumption and the 4-year progression of de novo Parkinson's disease.

INTRODUCTION: Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD. METHODS: 79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models. RESULTS: The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00). CONCLUSION: Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.

Impulsive-compulsive behaviors in parkin-associated Parkinson disease.

OBJECTIVE: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin-associated Parkinson disease (PD) compared to a group of patients without the mutation. METHODS: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin, PINK1, DJ-1, and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose. A semistructured interview was used to diagnose each of the following ICBs: compulsive sexual behavior, compulsive buying, binge eating, punding, hobbyism, and compulsive medication use. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was adopted to rate ICB severity. RESULTS: Frequency of patients with at least one ICB was comparable between parkin-PD and PD-NM. Nevertheless, when analyzing the distribution of specific ICBs, a higher frequency of compulsive shopping, binge eating, and punding/hobbyism was found in the parkin-PD group. Compared to PD-NM, parkin-PD patients with ICB had younger onset age and higher frequency of smokers; in 5 patients, ICB had predated PD onset. Total and partial (compulsive buying, compulsive sexual behavior, binge eating, hobbyism/punding) QUIP-RS scores were higher in patients with parkin-PD compared to patients with PD-NM. Logistic regression analysis showed that the presence of parkin mutations was associated with smoking status and higher QUIP-RS total score. CONCLUSIONS: Our data expand the parkin-associated phenotypic spectrum demonstrating higher frequency and severity of specific ICBs, and suggesting an association between the parkin genotype, smoking status, and ICB severity.

Non-Motor Correlates of Smoking Habits in de Novo Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) subjects are less likely to ever smoke and are more prone to quit smoking, as compared to controls. Therefore, smoking habits can be considered part of the non-motor phenotype, preceding the onset of motor PD by several years. OBJECTIVE: To explore non-motor symptom (NMS) correlates of smoking habits in de novo PD. METHODS: This cross-sectional study included 281 newly diagnosed, drug-naïve PD subjects, recruited in Naples (Italy) and in Kassel (Germany). All subjects completed the NMS Questionnaire (NMSQ), and were investigated for smoking status (never, current and former smokers) and intensity (pack-years). RESULTS: 140 PD subjects never smoked, 20 currently smoked, and 121 had quit smoking before PD diagnosis. NMSQ total score did not associate with smoking status, but with smoking intensity (p = 0.028; coefficient = 0.088). A multinomial logistic regression stepwise model presenting never smoking as reference, selected as NMSQ correlates of current smoking: sex difficulties (p = 0.002; OR = 5.254), daytime sleepiness (p = 0.046; OR = 0.085), insomnia (p = 0.025; OR = 0.135), and vivid dreams (p = 0.040; OR = 3.110); and of former smoking: swallowing (p = 0.013; OR = 0.311), nausea (p = 0.027; OR = 7.157), unexplained pains (p = 0.002; OR = 3.409), forgetfulness (p = 0.005; OR = 2.592), sex interest (p = 0.007; OR = 0.221), sex difficulties (p = 0.038; OR = 4.215), and daytime sleepiness (p = 0.05; OR = 0.372). An ordinal logistic regression stepwise model selected as NMSQ correlates of smoking intensity: nocturnal restlessness (p = 0.027; coefficient = 0.974), and leg swelling (p = 0.004; coefficient = 1.305). CONCLUSIONS: Certain NMSs are associated with different smoking status and intensity, suggesting a variety of adaptive mechanisms to cigarette smoking.

Olfaction in Homozygous and Heterozygous SYNJ1 Arg258Gln Mutation Carriers.

Hyposmia is a common nonmotor symptom in Parkinson's disease (PD) and has been variably detected in monogenic parkinsonism. SYNJ1 has been recently identified as the gene defective in a novel form of autosomal-recessive, early-onset atypical parkinsonism, designed as PARK20. To assess olfaction in PARK20, we administered the University of Pennsylvania Smell Identification Test (UPSIT) in four groups of subjects: SYNJ1 homozygous (HOM = 3) and heterozygous (HET = 4); sporadic PD (PD = 68); and healthy control subjects (CTR = 61). A linear regression model was constructed to assess the association between raw UPSIT score (outcome) and group (HOM, HET, PD, and CTR), adjusting for age, gender, and current smoking status. Likewise in PD patients, odor identification is impaired in homozygous SYNJ1 mutation carriers. Although the limited sample size precludes definite conclusions about olfaction in SYNJ1-related parkinsonism, our findings suggest new insights into PARK20 phenotype and pathophysiology.

Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features.

The cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is because of NOTCH3 mutations affecting the number of cysteine residues. In this view, the role of atypical NOTCH3 mutations is still debated. Therefore, we investigated a family carrying a NOTCH3 nonsense mutation, with dominantly inherited recurrent cerebrovascular disorders. Among 7 family members, 4 received a clinical diagnosis of CADASIL. A heterozygous truncating mutation in exon 3 (c.307C>T, p.Arg103X) was found in the 4 clinically affected subjects and in one 27-year old lady, only complaining of migraine with aura. Magnetic resonance imaging scans found typical signs of small-vessel disease in the 4 affected subjects, supporting the clinical diagnosis. Skin biopsies did not show the typical granular osmiophilic material, but only nonspecific signs of vascular damage, resembling those previously described in Notch3 knockout mice. Interestingly, messenger RNA (mRNA) analysis supports the hypothesis of an atypical NOTCH3 mutation, suggesting a nonsense-mediated mRNA decay. In conclusion, the present study broadens the spectrum of CADASIL mutations, and, therefore, opens new insights about Notch3 signaling.

Quitting smoking: an early non-motor feature of Parkinson's disease?

INTRODUCTION: Epidemiological studies report a 60-70% reduced risk of Parkinson's disease (PD) in smokers as compared to non-smokers. However, relationships between former smoking and PD have been poorly investigated. METHODS: We recruited 116 de novo PD subjects, and investigated current, former and never smoking, and reasons for smoking cessation among former smokers. Two hundred and thirty-two controls were matched by Propensity Score. RESULTS: PD subjects and controls were found to be current smokers (7.7 vs. 39.6%), former smokers (43.9 vs. 6.5%) and never smokers (48.2 vs. 53.9%). Logistic regression showed that current smokers were less likely to have PD (p < 0.001; OR: 0.22; 95% CI: 0.10-0.46), while former smokers were more likely to have PD (p < 0.001; OR: 7.6; 95% CI: 4.09-15.75), as compared to never smokers. Fifty-one PD patients reported quitting smoking before PD diagnosis (mean time since cessation 9.4 ± 7.3 years). Most important reasons to quit smoking in PD group were illness different from PD (26 subjects, 51.0%), knowledge of the harmful effects of smoking (24 subjects, 47.0%), and physician's advice (1 subject, 2.0%). CONCLUSION: The reduced prevalence of current smokers among PD subjects as compared to healthy controls is consistent with previous findings, suggesting a possible neuroprotective effect of smoking. However, it could be due, at least in part, to the increased prevalence of former smokers among PD patients, that were more prone to quit smoking as compared to healthy controls. We suggest that smoking cessation could be an early preclinical condition occurring in PD.