Marta Manes

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

Frontotemporal dementia (FTD) shows substantial phenotypic variability. In a multicentre study, Premi et al. explore the effect of cognitive reserve and TMEM106B genotype in modulating grey matter volume in presymptomatic FTD. Environmental as well as genetic factors affect rates of brain atrophy, suggesting a possible strategy for delaying disease onset.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation

Performance on gambling tasks in Parkinsons disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD.

Natural history and predictors of survival in progressive supranuclear palsy

BACKGROUND Progressive supranuclear palsy is a neurodegenerative disorder characterized by high functional disability and rapidly progressive dependency. The predictors of survival are still unclear. METHODS The predictors of survival were evaluated in a group of clinically diagnosed PSP patients, focusing primarily on extensive cognitive assessment. RESULTS The mean survival time from symptom onset was 8.25±3.0years. Sex, age at onset, education, occupation and severity of extrapyramidal symptoms did not correlate with survival. The only factor associated with a shorter life expectancy in our cohort was the presence of dementia at diagnosis. Impairment of executive functions was the best predictor of an unfavorable outcome. CONCLUSIONS Our findings suggest that dementia and executive functions need to be evaluated in order to define survival probability in PSP patients.

Anti-AMPA GluA3 antibodies in Frontotemporal dementia: A new molecular target

Frontotemporal Dementia (FTD) is a neurodegenerative disorder mainly characterised by Tau or TDP43 inclusions. A co-autoimmune aetiology has been hypothesised. In this study, we aimed at defining the pathogenetic role of anti-AMPA GluA3 antibodies in FTD. Serum and cerebrospinal fluid (CSF) anti-GluA3 antibody dosage was carried out and the effect of CSF with and without anti-GluA3 antibodies was tested in rat hippocampal neuronal primary cultures and in differentiated neurons from human induced pluripotent stem cells (hiPSCs). TDP43 and Tau expression in hiPSCs exposed to CSF was assayed. Forty-one out of 175 screened FTD sera were positive for the presence of anti-GluA3 antibodies (23.4%). FTD patients with anti-GluA3 antibodies more often presented presenile onset, behavioural variant FTD with bitemporal atrophy. Incubation of rat hippocampal neuronal primary cultures with CSF with anti-GluA3 antibodies led to a decrease of GluA3 subunit synaptic localization of the AMPA receptor (AMPAR) and loss of dendritic spines. These results were confirmed in differentiated neurons from hiPSCs, with a significant reduction of the GluA3 subunit in the postsynaptic fraction along with increased levels of neuronal Tau. In conclusion, autoimmune mechanism might represent a new potentially treatable target in FTD and might open new lights in the disease underpinnings.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.

Frontotemporal dementia and language networks: cortical thickness reduction is driven by dyslexia susceptibility genes.

Variations within genes associated with dyslexia result in a language network vulnerability, and in patients with Frontotemporal Dementia (FTD), language disturbances represent a disease core feature. Here we explored whether variations within three related-dyslexia genes, namely KIAA0319, DCDC2, and CNTNAP, might affect cortical thickness measures in FTD patients. 112 FTD patients underwent clinical and neuropsychological examination, genetic analyses and brain Magnetic Resonance Imaging (MRI). KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G and CNTNAP2 rs17236239 A/G genetic variations were assessed. Cortical thickness was analysed by Freesurfer. Patients carrying KIAA0319 A*(AG or AA) carriers showed greater cortical thickness atrophy in the left fusiform and inferior temporal gyri, compared to KIAA0319 GG (p ≤ 0.001). Patients carrying CNTNAP2 G*(GA or GG) showed reduced cortical thickness in the left insula thenCNTNAP2 AA carriers (p≤0.001). When patients with both at-risk polymorphisms were considered (KIAA0319 A* and CNTNAP2 G*), greater and addictive cortical thickness atrophy of the left insula and the inferior temporal gyrus was demonstrated (p ≤ 0.001). No significant effect of DCDC2 was found. In FTD, variations of KIAA0319 and CNTNAP2 genes were related to cortical thickness abnormalities in those brain areas involved in language abilities. These findings shed light on genetic predisposition in defining phenotypic variability in FTD.

Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38)

Introduction SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified. Objective The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38. Methods We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation. Results Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease. Conclusions SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions.

Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies

Abstract Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo‐controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease‐modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease‐modifying therapies.

Docosahexaenoic acid (DHA) is a beneficial replacement treatment for Spinocerebellar Ataxia 38 (SCA38)

Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.

Autoimmune Frontotemporal Dementia: A New Nosological Entity?

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a deficit in executive functions, language impairment, behavioral abnormalities and social misconduct. Current clinical criteria for FTD have been proved to be accurate, mostly when supported by frontotemporal atrophy upon neuroimaging examination.1 In most cases, either TDP43 or tau inclusions may be found at autopsy. An autosomal dominant inherited trait is reported in almost 40% of patients, in particular in those with a positive family history or early disease onset2; for a proportion of these patients, mutations in granulin (GRN), microtubule-associated protein tau (MAPT) or C9ORF72 genes may be recognized as causative for the disease. The large efforts devoted to genetic investigations argue that other genes will be found to be associated to the disease in familial cases. However, for the majority of sporadic FTD patients the determination of susceptibility or causative factors remains largely unknown. Interesting hints have been provided by studies on language variants of FTD, namely primary progressive aphasias (PPAs), in which for some cases, specifically those who have undergone vasectomy, the authors hypothesized that an immune response may have triggered the neurodegenerative process.3 In this work, we described a patient who developed a clinical syndrome that met FTD criteria in which an autoimmune antibody was detected. CASE REPORT A 41-year-old man was admitted to the Neurology Unit, University of Brescia, Italy, as he had developed progressive language disturbances, binge eating, personal neglect, and irritability over the past 6 months. He was right-handed and had 18 years of education, working as a lawyer in a company. In the past 2 years, he had complained of social withdrawal, apathy and emotional flatness, which were attributed to job problems; during these 2 years antidepressant medications of duloxetine 60mg/die and amisulpiride 50mg/die had been taken for 6 months, without benefit. His past medical history was unremarkable. No family history of neurodegenerative disorder was reported (see pedigree in the Supplementary Data, Supplemental Digital Content 1, http:// links.lww.com/WAD/A152). Neurological examination was unremarkable, but frontal release signs were appreciated (glabellar reflex, snout reflex, and bilateral palmar grasp). Neither pyramidal, extrapyramidal nor cerebellar signs were detected. The patient underwent an extensive neuropsychological assessment (Table 1). Spontaneous speech was insufficient in content and it consisted of short phrases characterized by the presence of brief disfluencies, pauses, latencies, anomia (mainly for nouns), frequent word-finding pauses, passe-partout words, and circumlocutions, with intact grammar. Ecolalia and verbal perseverations were present, but not dysarthria or speech apraxia. The patient was markedly impaired in naming and comprehension tasks, mostly for the syntactic structures. Verbal fluency for both phonological prompts and semantic categories was severely decreased. Repetition was normal, with exception of sentences and phrases due to working memory impairment. His reading abilities were preserved, whereas dysgraphia was present. In addition to language disturbances, the patient was impaired in executive functions of working memory, visuospatial planning, selective attention, and shifting abilities. Overall, he had relatively preserved orientation and ideomotor praxis. Independence in instrumental activities of daily living was impaired. Regarding behavior, he revealed apathy, lessened social interaction and personal neglect, initial loss of empathy, irritability, poor judgment and disorganization, binge eating with sweets as a preference. Loss of insight was reported. Brain magnetic resonance imaging (MRI) revealed marked frontotemporal cortical and subcortical atrophy, slightly prevalent on the left side, and increased T2-fluid attenuation inversion recovery signal in white matter in frontal and temporal lobes, sparing U-fibers and partially involving the corpus callosum (Figs. 1A, B). Brain positron emission tomographyfluorodeoxyglucose demonstrated severe hypometabolism in the left frontal lobe and in the temporal-occipital cortex (Fig. 1C). Upon hospitalization, cerebrospinal fluid (CSF) analysis was within the normal range for chemical-physical parameters (protein=42mg/dL, cell=0cells/mL, glucose=62mg/dL, no oligoclonal bands) and ruled out Alzheimer disease [Ab42=759pg/mL (reference value, pathologic<650pg/mL), t=157pg/mL (<400pg/ mL), p-t=33pg/mL (<30pg/mL)]. Received for publication July 18, 2016; accepted October 17, 2016. From the *Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, Neurology Unit, University of Brescia; zIII Laboratory of Analysis, Biotechnology Unit, Spedali Civili Hospital; yNeuroradiology Unit, University of Brescia, Brescia; and wNeurology IV—Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute Carlo Besta, Milan, Italy. The authors declare no conflicts of interest. Reprints: Barbara Borroni, MD, Department of Clinical and Experimental Sciences, University of Brescia, Piazza Spedali Civili 1, Brescia 25100, Italy (e-mail: bborroni@inwind.it). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved. BRIEF REPORT