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Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Hypertrophic cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are inherited diseases characterized by a wide genetic heterogeneity. Based on the separate incidence of these pathologies and on the absence of linkage, the occurrence of both diseases in the same individual has an incidence of about 1/250000. We describe a rare case report of a 24 years-old patient with maternal familiarity for type 1 LQTS (mother carrier of KCNQ1 c.1781G>A) and paternal familiarity for HCM (father carrier of TNNI3 c.592C>G mutation) who inherited both gene mutations and was diagnosed with HCM and LQTS later in adolescence, after clinical and genetic evaluations.

Objective The main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism. Methods Intermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers. Results We found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype. Conclusions Enhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects. Significance Since γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.

Parkinson disease (PD) is a complex neurodegenerative disorder, usually with multifactorial etiology. It is characterized by prominent movement disorders and non-motor symptoms. Movement disorders commonly include bradykinesia, rigidity, and resting tremor. Non-motor symptoms can include behavior disorders, sleep disturbances, hyposmia, cognitive impairment, and depression. A fraction of PD cases instead is due to Parkinsonian conditions with Mendelian inheritance. The study of the genetic causes of these phenotypes has shed light onto common pathogenetic mechanisms underlying Parkinsonian conditions. Monogenic Parkinsonisms can present autosomal dominant, autosomal recessive, or even X-linked inheritance patterns. Clinical presentations vary from forms indistinguishable from idiopathic PD to severe childhood-onset conditions with other neurological signs. We provided a comprehensive description of each condition, discussing current knowledge on genotype-phenotype correlations. Despite the broad clinical spectrum and the many genes involved, the phenotype appears to be related to the disrupted cell function and inheritance pattern, and several assumptions about genotype-phenotype correlations can be made. The interest in these assumptions is not merely speculative, in the light of novel promising targeted therapies currently under development.

The 5&ndash, 10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10&ndash, 20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.

Parkin/PINK1 deficiency impairs mitophagy in mice, leading to the release of mitochondrial DNA (mtDNA) and triggering inflammation. Borsche et al. now demonstrate elevated serum Interleukin 6 and circulating cell-free mtDNA also in patients with Parkin/PINK1 mutations, further implicating inflammation in Parkinson’s disease., There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

Young-onset Parkinson's disease (YOPD) is a relevant condition whose neurobiology is questioned if different from those of typical late-onset Parkinson's disease (LOPD). Here, we explored whether the clinical-biochemical profile of Parkinson's disease (PD) could be affected by the age-of-onset (AO), as a possible result of a distinct neurodegenerative process. A panel of fluid biomarkers (CSF lactate, 42-amyloid-b peptide, total and 181-phosphorylated tau; serum uric acid) and the standard scores for motor and nonmotor signs were assessed in 76 idiopathic PD patients (genetic cases excluded; YOPD, AO_ 50, n ¼ 44; LOPD, AO > 50, n ¼ 32) and 75 sex/age-matched controls, adjusting the models for the main confounding factors. In PD, AO directly correlated to either CSF lactate and tau proteins or the nonmotor symptoms scale score. Specifically, a younger AO was associated with lower levels of biomarkers and minor burden of nonmotor symptoms. Our findings indicate that clinical-biochemical features of idiopathic PD may vary depending on the AO, accounting for different profiles in YOPD and LOPD whose recognition is fundamental for further pathophysiological implications and clinical applications.

QTc prolongation is reported in patients with hypertrophic cardiomyopathy (HCM). However, the causes of the QTc interval increase remain unclear. The main contribution to QTc prolongation in HCM is attributed to the myocardial hypertrophy and related structural damage. In a 24-year-old male proband, affected by HCM and long QTc, we identified by Next Generation Sequencing a pathogenic variant in gene TNNI3 co-inherited with a damaging variant in KCNQ1 gene. This evidence suggests the possibility that QTc interval prolongation and its dispersion in HCM could be associated not only to the severity of left ventricular hypertrophy but also to the co-inheritance of pathogenic variants related to both long QT Syndrome (LQTS) and HCM. Although the simultaneous presence of pathogenic variants in genes related to different heart diseases is extremely rare, counseling and genetic testing appear crucial for the clinical diagnosis. Screening of LQTS genes should be considered in HCM patients to clarify the origin of long QTc, to provide more information about the clinical presentation and to evaluate the incidence of the co-existence of LQTS/HCM gene variants that could occur more frequently than so far reported.

Background Mutations in HPCA , a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term "DYT2 dystonia". Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood. Methods 73 patients with isolated dystonia of various distribution, manifesting within 21 years of age, were enrolled in this Italian study and underwent a mutational screening of HPCA gene by means of Sanger sequencing. Results/conclusions Mean age at onset was 10.2 (±5.1) years and mean age at the time of genetic testing was 33 (±14.2) years. Mean disease duration at the time of enrollment was 22.7 (±12.8) years. None of the patients enrolled was found to carry HPCA mutations, rising suspicion that these probably represent a very rare cause of dystonia in childhood-adolescence. Larger studies will help determining the real mutational frequency of this gene also in different ethnic groups.

To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p

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 Parkinson9s 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.

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.

Fattouch J, Di Bonaventura C, Casciato S, Bonini F, Petrucci S, Lapenta L, Manfredi M, Prencipe M, Giallonardo AT. Intravenous Levtiracetam as first-line treatment of status epilepticus in the elderly. Acta Neurol Scand: 2010: 121: 418–421. © 2010 John Wiley & Sons A/S. Background – Status epilepticus is a condition of prolonged/repetitive seizures that often occurs in the elderly. Treatment in the elderly can be complicated by serious side effects associated with traditional drugs. Objective – The aim of this pilot study was to evaluate the short-term efficacy/safety of intravenously administered LEV (IVLEV) as the treatment of choice for SE in the elderly. Methods – We enrolled nine elderly patients (five female/four male; median age 78 years) with SE. Two patients had a previous diagnosis of epilepsy; in the remaining seven, SE was symptomatic. SE was convulsive in five and non-convulsive in four. All the patients presented concomitant medical conditions (arrhythmias/respiratory distress/hepatic diseases). As the traditional therapy for SE was considered unsafe, IVLEV was used as first-line therapy (loading dose of 1500 mg/100 ml/15 min, mean maintenance daily dose of 2500 mg/24 h) administered during video-EEG monitoring. Results/conclusions – In all the patients but one, IVLEV was effective in the treatment of SE and determined either the disappearance of (7/8), or significant reduction in (1/8), epileptic activity; no patient relapsed in the subsequent 24 h. No adverse events or changes in the ECG/laboratory parameters were observed. These data suggest that IVLEV may be an effective/safe treatment for SE in the elderly.

Summary Purpose: Diffusion-weighted magnetic resonanceimaging(DWI)isusedtodetectchangesinthedis-tribution of water molecules in regions affected byvarious pathologies. Like other conditions, ictalepileptic activity, such as status epilepticus (SE),can cause regional vasogenic/cytotoxic edemathat reflects hemodynamic and metabolicchanges. This study describes the electroclinicaland neuroimaging findings in 10 patients with par-tial SE whose DWI evaluation disclosed periictalchangesrelatedtosustainedepilepticactivity.Patients and Methods: In this retrospective studywe selected 10 patients with partial SE of differentetiologies (six acute symptomatic SE; four withprevious epilepsy and concomitant precipitatingfactors) who underwent video-EEG (electroen-cephalography) monitoring and a DWI studyduring the periictal phase. We analyzed ictal elec-troclinical features and DWI changes in the acutephaseandduringthefollow-upperiod.Results: DWI images revealed significant signalalterations in different brain regions depending onthe location of ictal activity. DWI changes werehighly concordant with the electroclinical findingsin all 10 patients. As the SE resolved and the clini-cal conditions improved, DWI follow-up showedthat the signal alterations gradually disappeared,thereby documenting their close relationship withictalactivity.Conclusions: This study confirms the usefulness ofDWI imaging in clinical practice for a more accu-rate definition of the hemodynamic/metabolicchanges occurring during sustained epilepticactivity.KEY WORDS: DWI, Status epilepticus, Epilepsy,Neuroimaging.Many neuroimaging techniques disclose in vivochangesintheregion involvedbyepilepticactivityduringprolonged seizures or status epilepticus (SE). Thesechangesare caused by factorssuch as increased metabolicactivity, the consequent ictal hyperperfusion (often fol-lowed by postictal hypoperfusion), and some transientultrastructural pathologic alterations, all of which reflectthesustainedelectricalactivityofepilepticneurons.Sinceictalfunctionalchangeswerefirstdocumentedbyangiography(Penfield,1933),theyhavebeeninvestigatedby means of other neuroimaging techniques that explorehemodynamics perfusion computed tomography (CT),perfusion magnetic resonance imaging (PWI), functionalMRI (fMRI), single-proton emission computed tomogra-phy (SPECT)] and brain metabolism [positron emissiontomography(PET)andspectroscopy-MRI].By measuring the apparent diffusion coefficient(ADC), diffusion-weighted MRI (DWI) detects changesin the distribution of water molecules in regions affectedby various forms of epileptic activity, such as partial SE(Cole, 2004). DWI is used to investigate many brain dis-eases (namely, acute ischemic stroke, brain tumors, infec-tions, etc.), as it is sensitive to the molecular motion ofwater,ordiffusivity,anintrinsicpropertyoftissues(Grantet al., 2001). Changes in water diffusion in the epileptic

Objective This work investigated the molecular cause responsible for a late-onset parkinsonism–dystonia phenotype in three Italian siblings, and clinically characterize this condition. Methods Extensive neurophysiological and neuroradiological exams were performed on the three sibs. Most frequent late-onset metabolic diseases were ruled out through laboratory and biochemical analyses. A whole exome sequencing (WES) approach was used to identify the molecular cause underlying this condition. Results and conclusions Peculiar neurologic phenotype was characterized by dystonia–parkinsonism, cognitive impairment, gait ataxia and apraxia, pyramidal signs. WES analysis allowed the identification of a compound heterozygosity for two nucleotide substitutions (c.1340G>A, p.R447H; c.790C>T, p.Q264X) affecting the TPP1 gene in the three affected siblings. Biochemical analyses demonstrated abrogated TPP1 catalytic activity in primary skin fibroblasts, but revealed residual activity in leukocytes. Our findings document that late infantile neuronal ceroid lipofuscinosis (CLN2), which is caused by TPP1 gene mutations, should be considered in the differential diagnosis of autosomal recessive dystonia–parkinsonism syndromes. The availability of enzyme replacement therapy and other therapeutic approaches for ceroid lipofuscinoses emphasizes the value of reaching an early diagnosis in patients with atypical and milder presentation of these disorders.

Hypoglycaemia, common in diabetic patients treated with insulin, can induce various neurological disturbances. Of these, seizures are the most common acute symptom, mainly of the generalised tonic-clonic type, with focal events only exceptionally being reported and documented. Hypoglycaemia can modify cortical excitability by determining an imbalance between excitation and inhibition; some brain structures, such as the temporal lobe and hippocampus, appear to be particularly susceptible to this insult. We describe a case of a 61-year-old diabetic patient in whom insulin-induced transient hypoglycaemia triggered a focal seizure of temporal origin that was well documented by EEG during 24-hour ambulatory monitoring. This is, to our knowledge, one of the few, well-documented cases of this type of seizure.