Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population

Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (N = 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in GTF2H2 (5q13; alternative T allele: OR [CI] = 8.16[1.08; 61.52], FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- [\u3b2(SE) = -0.039(0.013); FDR = 0.039] and caudate-PRS [0.043(0.013); 0.028] with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R2 = 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (~20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

Neuroimaging advances in Parkinson's disease with freezing of gait: A systematic review

Freezing of gait (FOG) is a paroxysmal gait disorder that often occurs at advanced stages of Parkinson's disease (PD). FOG consists of abrupt walking interruption and severe difficulty in locomotion with an increased risk of falling. Pathophysiological mechanisms underpinning FOG in PD are still unclear. However, advanced MRI and nuclear medicine studies have gained relevant insights into the pathophysiology of FOG in PD. Neuroimaging studies have demonstrated structural and functional abnormalities in a number of cortical and subcortical brain regions in PD patients with FOG. In this paper, we systematically review existing neuroimaging literature on the structural and functional brain changes described in PD patients with FOG, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluate previous studies using various MRI techniques to estimate grey matter loss and white matter degeneration. Moreover, we review functional brain changes by examining functional MRI and nuclear medicine imaging studies. The current review provides up-to-date knowledge in this field and summarizes the possible mechanisms responsible for FOG in PD

Clinical Trials for Neuroprotection in ALS

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies

Functional disconnection of the dentate nucleus in essential tremor

Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of disconnection of the dentate nucleus (DN), the main output cerebellar pathway, still needs clarification. In this study, we evaluated DN functional connectivity (FC) changes and their relationship with motor and non-motor symptoms in ET. We studied 25 ET patients and 26 healthy controls. Tremor severity was assessed using the Fahn–Tolosa–Marin tremor rating scale (FTM-TRS) and tremor amplitude and frequency were evaluated using kinematic techniques. Cognitive profile was assessed by montreal cognitive assessment (MoCA) and frontal assessment battery (FAB). All participants underwent a 3 T MRI protocol including resting-state blood oxygenation level dependent and diffusion tensor sequences. We used a seed-based approach to investigate DN FC and to explore the diffusion properties of cerebellar peduncles. There was significantly decreased DN FC with cortical, subcortical, and cerebellar areas in ET patients compared with healthy controls. Correlation analysis showed that: (1) the DN FC with the supplementary motor area, pre and postcentral gyri, and prefrontal cortex negatively correlated with FTM-TRS score and disease duration; (2) DN FC changes in the thalamus and caudate negatively correlated with peak tremor frequency, changes in the cerebellum positively correlated with tremor amplitude, and changes in the bilateral thalamus negatively correlated with tremor amplitude, and (3) DN FC with the associative prefrontal and parietal cortices, basal ganglia, and thalamus positively correlated with the MoCA score. Diffusion abnormalities were found in the three cerebellar peduncles, which did not correlate with clinical scores

The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by loss of motor neurons both in the brain and spinal cord, which dramatically reduces life expectancy. ALS occurs either in familial ALS or, more frequently, in sporadic ALS forms. Several mechanisms have been postulated to underlie motor neuron death. In the present paper, starting from some of the genes related to familial ALS, we overview and discuss their potential role in modifying of the physiological clearance of altered proteins and organelles in motor neurons. Special emphasis is placed on the role of autophagy, which seems to prevail as a protein clearing system over other multienzymatic pathways such as the proteasome within motor neurons. The evidence which links an altered autophagy to the onset of motor neuron death proposes that this biochemical pathway might represent a final common mechanism underlying both inherited and sporadic forms of ALS. In light of these findings we also analyze the potential significance of a novel association between ALS, altered autophagy, and mutations of nuclear proteins such as TAR-DNA-Binding Protein 43 and fused in sarcoma/translated in liposarcoma. Such an association appears to be critical since it is now well demonstrated that all sporadic and most familiar forms of ALS are characterized by altered deposition and mislocalization of TAR-DNA-Binding Protein 43. These novel insights into the pathogenesis of ALS may lead to the identification of novel strategies to promote motor neuron survival

No evidence of iron deposition in essential tremor: a susceptibility-weighted imaging study

Objective: To evaluate the role of iron deposition in subcortical nuclei of patients with essential tremor (ET). Methods: Twenty-three patients with ET underwent a standardized 3T-MRI protocol. We specifically assessed iron deposition using susceptibility-weighted angiography (SWAN) images in seven specific regions of interest (ROIs): the thalamus, putamen, globus pallidus, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus. Tremor in ET patients was clinically assessed using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). ET patient data were compared with data obtained from 23 Parkinson’s disease (PD) patients and 14 healthy subjects (HS). Results: No differences in iron deposition in the seven ROIs were found between ET patients and HS. Conversely, PD patients showed increased iron deposition in the substantia nigra in comparison with both ET patients and HS. Conclusions: Our results indicate the absence of iron deposition in subcortical nuclei of ET patients, which is generally considered a marker of neurodegeneration

Neuromelanin-sensitive resonance imaging as a Parkinson's disease biomarker

Introduction: Neuromelanin-sensitive (NM) magnetic resonance imaging visualizes dopaminergic neuronal loss in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD), and may be a useful diagnostic marker Methods: Fifty-five patients with early stage PD and 12 age-matched healthy volunteers (HV) underwent 3T MR scanning. SNc volumes were determined according to the threshold of background signal intensity+3SD. SNc volumes were also compared between HV and three PD sub-groups as divided by UPDRS 3 scores with tertile calculations, using analysis of covariance (ANCOVA), adjusting by regional volumes and age. Results: PD patients showed marked reductions of SNc volumes compared to HV (p<0.001). Within the PD group, nigral volume reductions were consistent for clinical laterality (p<0.05). Nigral volumes inversely correlated with UPDRS 3 (p<0.01), and were lowest in PD patients in the worst tertile for motor severity, compared to the more mildly affected PD cases (p<0.05) and HV groups (p<0.001). Discussion: Our results confirm that NM-sensitive MR imaging helps distinguish early PD from healthy volunteers. In addition, the significant relationship between nigral volume and motor severity suggests that the method could be developed as a disease biomarker

d-Aspartate activates mGlu receptors coupled to polyphosphoinositide hydrolysis in neonate rat brain slices

The D-amino acid, D-aspartate, is abundant in the developing brain, yet its function is unknown. Addition of d-aspartate to hippocampal or cortical slices prepared from 8- to 9-day-old rats stimulated polyphosphoinositide (PI) hydrolysis to a slightly greater extent than L-glutamate. The action of D-aspartate was concentration-dependent with an apparent EC(50) value of 1 mM and a maximal stimulation of 6- and 20-fold in cortical and hippocampal slices, respectively. Stimulation of PI hydrolysis by D-aspartate was largely reduced by pharmacological blockade of mGlu5 metabotropic glutamate receptors with 2-methyl-6-(phenylethynyl)pyridine. These findings suggest that D-aspartate behaves as an endogenous agonist of mGlu5 receptors during early postnatal life