Antonio Canosa

Cognitive correlates in amyotrophic lateral sclerosis: a population-based study in Italy

Background There is less data available regarding the characteristics of cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) in a population-based series. Methodology Patients with ALS incident in Piemonte, Italy, between 2009 and 2011 underwent an extensive neuropsychological battery. Cognitive status was classified as follows: normal cognition, frontotemporal dementia (ALS-FTD), executive cognitive impairment (ALS-ECI), non-executive cognitive impairment (ALS-NECI), behavioural impairment (ALS-Bi), non-classifiable cognitive impairment. We also assessed 127 age-matched and gender-matched controls identified through patients’ general practitioners. Results Out of the 281 incident patients, 207 (71.9%) underwent the neuropsychological testing; of these, 19 were excluded from the analysis due previous conditions affecting cognition. Ninety-one (49.7%) patients were cognitively normal, 23 (12.6%) had ALS-FTD, 36 (19.7%) ALS-ECI, 10 (5.5%) ALS-NECI, 11 (6.0%) ALS-Bi and 11 (6.0%) non-classifiable cognitive impairment, 1 had comorbid Alzheimers disease. Patients with ALS-FTD were older, had a lower education level, and had a shorter survival than any other cognitive group. Of the nine cases with C9ORF72 mutation, six had ALS-FTD, two ALS-ECI and one was cognitively normal; one of the five patients with SOD1 mutations and one of the five patients with TARBDP mutations had ALS-Bi. Conclusions About 50% of Italian patients with ALS had some degree of cognitive impairment, in keeping with a previous Irish study, despite the largely different genetic background of the two populations. The lower educational attainment in patients with ALS-FTD indicated a possible role of cognitive reserve in ALS-related cognitive impairment. ALS-ECI and ALS-NECI may represent discrete cognitive syndromes in the continuum of ALS and FTD.

Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels

Summary Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.

Pain in amyotrophic lateral sclerosis: a population-based controlled study

Background and purpose:  To assess the prevalence and characteristics of pain in an epidemiological series of patients with amyotrophic lateral sclerosis (ALS) compared to population‐based controls.

ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations

Background In the isolated population of Sardinia, a Mediterranean island, ∼25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene. Objective To describe the co-presence of two genetic mutations in two Sardinian ALS patients. Methods We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene. Results The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus. Conclusions Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.

UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: A population-based study

The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.

Genetic architecture of ALS in Sardinia

Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors.

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

18F-FDG-PET correlates of cognitive impairment in ALS

Objective: To identify the metabolic signature of the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET). Methods: A total of 170 ALS cases consecutively enrolled at the ALS Center of Turin underwent brain 18F-FDG-PET and were classified as displaying normal cognition (ALS-Cn; n = 94), full-blown frontotemporal dementia (ALS-FTD; n = 20), executive or nonexecutive cognitive impairment not fulfilling FTD criteria (ALS-Ci; n = 37), prevalent behavioral changes (n = 9), or nonclassifiable impairment (n = 10) according to neuropsychological testing. Group comparisons of 18F-FDG-PET pattern were carried out among the cognitive subgroups. Results: We found a significantly reduced frontal and prefrontal metabolism in ALS-FTD as compared to ALS-Cn, while ALS-Ci showed an intermediate metabolic behavior in frontal cortex, being hypometabolic as compared to ALS-Cn, and relatively hypermetabolic as compared to ALS-FTD. Hypometabolism in frontal regions was associated in all comparisons to hypermetabolism in cerebellum, midbrain, and corticospinal tracts: the more severe the cognitive decline, the larger the size of the cluster and the statistical significance of 18F-FDG uptake differences. Conclusions: This study demonstrated in a large cohort of patients with ALS a continuum of frontal lobe metabolic impairment reflecting the clinical and anatomic continuum ranging from pure ALS, through ALS with intermediate cognitive deficits, to ALS-FTD, and showing that patients with intermediate cognitive impairment display a characteristic metabolic pattern. Since 18F-FDG-PET allows us to estimate the cerebral lesion load in vivo in neurodegenerative diseases, it might be helpful to investigate in ALS its association with neuropsychological testing along the disease course to disclose the early metabolic signature of possible cognitive impairment.

A de novo nonsense mutation of the FUS gene in an apparently familial amyotrophic lateral sclerosis case

Mutations in C9ORF72, SOD1, TARDBP, and FUS genes account for approximately two-third of familial cases and 5% of sporadic amyotrophic lateral sclerosis (ALS) cases. We present the first case of an ALS patient carrying a de novo nonsense mutation in exon 14 of the FUS gene (c.1483c>t; p.R495X) with an apparently familial ALS. This mutation causes a phenotype characterized by a young age at onset, a rapid course (<24 months), and a bulbar onset with early respiratory involvement with a predominant lower motor neuron disease. De novo mutations could account for a sizable number of apparently sporadic ALS patients carrying mutations of ALS-related genes.

Metabolic spatial connectivity in amyotrophic lateral sclerosis as revealed by independent component analysis.

Positron emission tomography (PET) and volume of interest (VOI) analysis have recently shown in amyotrophic lateral sclerosis (ALS) an accuracy of 93% in differentiating patients from controls. The aim of this study was to disclose by spatial independent component analysis (ICA) the brain networks involved in ALS pathological processes and evaluate their discriminative value in separating patients from controls. Experimental design: Two hundred fifty‐nine ALS patients and 40 age‐ and sex‐matched control subjects underwent brain 18F‐2‐fluoro‐2‐deoxy‐D‐glucose PET (FDG‐PET). Spatial ICA of the preprocessed FDG‐PET images was performed. Intensity values were converted to z‐scores and binary masks were used as data‐driven VOIs. The accuracy of this classifier was tested versus a validated system processing intensity signals in 27 brain meta‐VOIs. A support vector machine was independently applied to both datasets and the ‘leave‐one‐out’ technique verified the general validity of results. Principal observations: The 8 components selected as pathophysiologically meaningful discriminated patients from controls with 99.0% accuracy, the discriminating value of bilateral cerebellum/midbrain alone representing 96.3%. Among the meta‐VOIs, right temporal lobe alone reached an accuracy of 93.7%. Conclusions: Spatial ICA identified in a very large cohort of ALS patients distinct spatial networks showing a high discriminatory value, improving substantially on the previously obtained accuracy. The cerebellar/midbrain component accounted for the highest accuracy in separating ALS patients from controls. Spatial ICA and multivariate analysis perform better than univariate semi‐quantification methods in identifying the neurodegenerative features of ALS and pave the way for inclusion of PET in clinical trials and early diagnosis. Hum Brain Mapp 37:942–953, 2016.