Cristina Moglia

Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study

Background Different amyotrophic lateral sclerosis (ALS) phenotypes have been recognised, marked by a varying involvement of spinal and bulbar upper and lower motor neurons. However, the differential characteristics of these phenotypes are still largely unknown. Objective To define the epidemiology and outcome of ALS phenotypes in a population based setting. Methods All ALS cases incident in two Italian regions were prospectively collected from 1995 to 2004 in an epidemiological register. Cases were classified according to established ALS phenotypes: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron (PLMN) and pure upper motor neuron (PUMN). Results ALS phenotype were determined in 1332 out of 1351 incident patients (98.6%). Classic and bulbar phenotypes had similar mean annual incidence rates. Gender specific incidence rates showed a male preponderance in respiratory, flail arm, classic and PLMN phenotypes; in all other phenotypes, men and women had similar incidence rates. Age at onset was significantly lower in pyramidal, PLMN and PUMN phenotypes and higher in the bulbar phenotype. The best outcomes were observed in PUMN, pyramidal, PLMN and flail arm phenotypes and the worst in respiratory and bulbar phenotypes. Conclusions Our epidemiological findings suggest that ALS phenotypes carry distinctive and easily distinguishable clinical and prognostic characteristics, strongly related to a complex interplay between gender and age. The categorisation of ALS patients according to more homogenous clinical groups is relevant in identifying biological markers for ALS and should be considered for the design of clinical trials.

A longitudinal study on quality of life and depression in ALS patient–caregiver couples

Objectives: To evaluate the modification of quality of life (QoL) and depression in a series of amyotrophic lateral sclerosis (ALS) patient–caregiver couples during a period of 9 months and compare them to patients’ ALS Functional Rating Scale (ALS-FRS). Methods: Depression was assessed with Zung Depression Scale (ZDS) and QoL with McGill Quality of Life Questionnaire (MQoL). Caregivers’ burden was assessed with Caregiver Burden Inventory (CBI), and patients’ feeling to be a burden with the Self-Perceived Burden Scale (SPBS). Results: Thirty-one ALS patient–caregiver couples were interviewed at baseline and after 9 months. The mean ALS-FRS score was 28.7 (SD 7) at baseline and 24.1 (6.9) at the second interview (p = 0.0001). Patients’ mean MQoL score slightly increased from 6.8 (1.6) to 7 (1.1) (p = 0.07); their ZDS score slightly increased (43.2 [8.7] at baseline and 45.7 [9.3] at the second interview) but they remained in the not depressed range. Caregivers’ mean MQoL score slightly decreased, and their mean ZDS increased from 38.9 (8.1) to 42.2 (8.7) (p = 0.02). The mean CBI score increased from 50.3 (17.6) to 55.8 (16.4) (p = 0.03). Conclusions: We found a substantial steadiness of quality of life and depression in patients with amyotrophic lateral sclerosis over a 9-month period, vs a significant increase of burden and depression of their caregivers.

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.

Extensive genetics of ALS: a population-based study in Italy.

Objective: To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases. Methods: The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed. Results: Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012). Conclusions: We have found that ∼11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease.

Neurobehavioral symptoms in ALS are negatively related to caregivers’ burden and quality of life

Objective:  To evaluate the frequency of neurobehavioral symptoms related to FTLD in a consecutive series of amyotrophic lateral sclerosis (ALS) patients and to assess their influence on patients’ and caregivers’ mood, burden, and quality of life.

Large proportion of amyotrophic lateral sclerosis cases in sardinia due to a single founder mutation of the TARDBP gene

OBJECTIVE To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations. DESIGN Population-based, prospective cohort study. PATIENTS A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients. INTERVENTION Patients underwent mutational analysis for SOD1, FUS, and TARDBP. RESULTS Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G>A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness. CONCLUSIONS The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.

Lower serum lipid levels are related to respiratory impairment in patients with ALS.

Background: Recently hyperlipidemia was reported to be related to a significantly better outcome in amyotrophic lateral sclerosis (ALS). To investigate this, we evaluated the status of blood lipids in a large Italian series of patients with ALS, and assessed the effect of hyperlipidemia on patients’ survival. Methods: The study population included 658 patients with ALS consecutively observed in 2 Italian ALS centers between 2000 and 2006. They were compared to a series of 658 healthy subjects, matched by age and gender. Results: The mean levels of total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the LDL/HDL ratio were similar in patients with ALS and controls. Total cholesterol, HDL, triglyceride, and LDL/HDL ratio levels showed a significant decrease in patients with forced vital capacity <70% compared to those with FVC ≥90%. For each level of ALS-FRS, poorer respiratory function was related to a lower LDL/HDL ratio. Univariate survival analysis did not find any significant effect of LDL/HDL ratio on survival, either when comparing patients with ratios ≤2.99 vs >2.99 or patients in the first quartile of LDL/HDL ratio (≤1.67) vs those in the fourth quartile (>2.79). No dose-response was found for LDL/HDL ratio subdividing patients into 5 quintiles. Conclusion: Our findings do not support the observation that patients with amyotrophic lateral sclerosis have hyperlipidemia or that hyperlipidemia in this population is related to longer survival. However, some evidence emerged that respiratory impairment, but not a worse clinical status or a lower body mass index, is related to a decrease in blood lipids and LDL/HDL ratio.

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.

Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset

PurposeTo identify the neurobiological traits of amyotrophic lateral sclerosis (ALS) and to elucidate functional differences between ALS of spinal and bulbar onset. We hypothesized that glucose metabolism distribution might vary between groups.MethodsThe study groups comprised 32 patients with ALS of either bulbar (n = 13) or spinal (n = 19) onset and 22 subjects as controls. They were investigated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (FDG PET), comparing the patient groups with each other and with the controls by statistical parametric mapping.ResultsHighly significant relative increases in glucose metabolism distribution were found in the group comprising all 32 ALS patients as compared with the controls in the bilateral amygdalae, midbrain, pons and cerebellum. Relative hypermetabolism was also found in patients with spinal onset as compared with the controls in the right midbrain. In patients with bulbar onset compared with the controls and with patients with spinal onset, large relatively hypometabolic areas were found in the bilateral frontal cortex, right insula, anterior cingulate, precuneus and inferior parietal lobe. Patients with spinal onset had significantly higher scores in a neuropsychological test assessing verbal fluency compared with patients with bulbar onset.ConclusionThis large FDG PET investigation provided unprecedented evidence of relatively increased metabolism in the amygdalae, midbrain and pons in ALS patients as compared with control subjects, possibly due to local activation of astrocytes and microglia. Highly significant relative decreases in metabolism were found in large frontal and parietal regions in the bulbar onset patients as compared with the spinal onset patients and the controls, suggesting a differential metabolic and neuropsychological state between the two conditions.

C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population.

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.