Davide Bertuzzo

Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis

Objective: We investigated a large sample of patients with amyotrophic lateral sclerosis (ALS) at rest in order to assess the value of 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) PET as a biomarker to discriminate patients from controls. Methods: A total of 195 patients with ALS and 40 controls underwent brain 18F-FDG-PET, most within 5 months of diagnosis. Spinal and bulbar subgroups of ALS were also investigated. Twenty-five bilateral cortical and subcortical volumes of interest and cerebellum were taken into account, and 18F-FDG uptakes were individually normalized by whole-brain values. Group analyses investigated the ALS-related metabolic changes. Discriminant analysis investigating sensitivity and specificity was performed using the 51 volumes of interest as well as age and sex. Metabolic connectivity was explored by voxel-wise interregional correlation analysis. Results: Hypometabolism was found in frontal, motor, and occipital cortex and hypermetabolism in midbrain, temporal pole, and hippocampus in patients with ALS compared to controls. A similar metabolic pattern was also found in the 2 subgroups. Discriminant analysis showed a sensitivity of 95% and a specificity of 83% in separating patients from controls. Connectivity analysis found a highly significant positive correlation between midbrain and white matter in corticospinal tracts in patients with ALS. Conclusions: 18F-FDG distribution changes in ALS showed a clear pattern of hypometabolism in frontal and occipital cortex and hypermetabolism in midbrain. The latter might be interpreted as the neurobiological correlate of diffuse subcortical gliosis. Discriminant analysis resulted in high sensitivity and specificity in differentiating patients with ALS from controls. Once validated by diseased-control studies, the present methodology might represent a potentially useful biomarker for ALS diagnosis. Classificaton of evidence: This study provides Class III evidence that 18F-FDG-PET accurately distinguishes patients with ALS from normal controls (sensitivity 95.4%, specificity 82.5%).

Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving upper and lower motor neurons. Up to 50 % of ALS cases have cognitive and/or behavioral impairment falling into the spectrum of frontotemporal dementia (FTD) [1]. Approximately 10 % of cases are familial (FALS), while the others are considered sporadic, as their occurrence seems to be random throughout the population. Recently, a GGGGCC hexanucleotide repeat expansion in the first intron of c9orf72 gene on chromosome 9p21 has been related to familial and sporadic cases with ALS, ALS-FTD, or FTD. [2–4]. We describe a 52-year-old man carrying the GGGGCC expansion in the c9orf72 gene. At 50, he developed muscle weakness and wasting at the right hand. Soon after he developed intrusive thoughts of urine loss, not supported by clinical evidence. After a pantoclastic episode characterized by aggressiveness towards objects and auditory hallucinations due to an obsessive impulse to urinary stimuli, he was admitted to our hospital. He had muscle weakness and atrophy of upper limbs (predominantly right) and spasticity of upper and lower limbs, hyperactive deep tendon reflexes, hyperactive jaw jerk, and fasciculations at limbs and trunk muscles. Bulbar and respiratory muscles were spared. Needle EMG showed a diffuse pattern of chronic and active denervation, with normal nerve conduction studies. Motor-evoked potentials demonstrated increased central motor conduction time. Psychiatric evaluation was consistent with obsessive–compulsive disorder (OCD) with predominantly Obsessional Thoughts or Rumination (ICD-10 code F42.0), with psychotic manifestations. The patient’s father died at 42 years old from spinal amyotrophic lateral sclerosis (ALS); he had no cognitive or behavioral impairment. The patient’s sister and a paternal uncle had a depressive disorder. The patient was found to carry a hexanucleotide repeat expansion in c9orf72 gene ([50 repeats); no other mutations of major ALS-FTD related genes were found. Magnetic resonance imaging (MRI) revealed bilateral reduction of fractional anisotropy along the corticospinal tract (predominantly right). Brain positron emission tomography (PET) with FDG presented reduced hypometabolism in the motor cortex bilaterally, in the fronto-mesial cortex bilaterally between the anterior and the middle cingulate gyrus (predominantly right) and in the postero-lateral occipital cortex bilaterally (Fig. 1). The neuropsychological assessment was consistent with a diagnosis of behavioral FTD, associated to OCD, hallucinations, and depressive mood disorder. In the following months, the patient developed dysarthria, dysphagia, tongue atrophy with fasciculations, lower limb weakness and hypotrophy, and worsening of spasticity at the upper and lower limbs. A. Calvo (&) C. Moglia A. Canosa A. Ilardi E. Bersano D. Bertuzzo A. Chio Department of Neuroscience, University of Turin, via Cherasco 15, 10126 Turin, Italy e-mail: andreacalvo@hotmail.com

Secular Trends of Amyotrophic Lateral Sclerosis: The Piemonte and Valle d’Aosta Register

Importance This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register. Objective To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d’Aosta regions of Italy. Design, Setting, and Participants The Piemonte and Valle d’Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model. Main Outcomes and Measures The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants. Results During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07; P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553; P = .03) and in women (change in deviance, 3.8821; P = .05) but not in men (change in deviance, 0.77215; P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day (December 31, 2014), corresponding to a crude prevalence rate of 10.54 per 100 000 population (95% CI, 9.64-11.52). Conclusions and Relevance During the 1995 to 2014 period, the crude and adjusted incidences of ALS increased in Piemonte and Valle d’Aosta, mostly in women. The APC model revealed that the increase of ALS incidence is attributable to a birth cohort effect in women, with a peak in the 1930 cohort. The different increase of ALS incidence in men and women points to an effect of exogenous factors with a differential effect on the 2 sexes, acting on a genetic background.

Common polymorphisms of chemokine (C-X3-C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population-based study: CX3CR1 Gene and ALS Outcome

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018

Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018

Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study

Abstract Objective: To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. Methods: A total of 650 ALS patients from the Piemonte/Valle d’Aosta Register for ALS, incident in the 2007–2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients’ CV risk profile was calculated according to the Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice (JBS2). Results: At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. Conclusions: This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.

Common polymorphisms of CX3CR1 gene modify ALS outcome: A population-based study.

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212–216, 2018

Persistent idiopathic hypoglossal nerve palsy: A motor neuron disease-mimic syndrome?

Unilateral isolated hypoglossal nerve palsy (IHNP) is a condition (1 – 7) usually symptomatic of a pathology of the skull base (6,8). In rare cases, IHNP remains of unknown aetiology and is classifi ed as idiopathic IHNP; its course is usually benign with a spontaneous remission (1,6). To our knowledge, only very few cases of persistent, idiopathic IHNP have been described (1,4,5,9,10). We report the case of a young patient with a persistent idiopathic IHNP, along with a brief review of the literature.