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Background: Given that the pathogenetic process of ALS begins many years prior to its clinical onset, examining patients' residential histories may offer insights on the disease risk factors. Here, we analyzed the spatial distribution of a large ALS cohort in the 50 years preceding the disease onset. Methods: Data from the PARALS register were used. A spatial cluster analysis was performed at the time of disease onset and at 1-year intervals up to 50 years prior to that. Results: A total of 1124 patients were included. The analysis revealed a higher-incidence cluster in a large area (435,000 inhabitants) west of Turin. From 9 to 2 years before their onset, 105 cases were expected and 150 were observed, resulting in a relative risk of 1.49 (P = 0.04). We also found a surprising high number of patients pairs (51) and trios (3) who lived in the same dwelling while not being related. Noticeably, these occurrences were not observed in large dwellings as we would have expected. The probability of this occurring in smaller buildings only by chance was very low (P = 0.01 and P = 0.04 for pairs and trios, respectively). Conclusions: We identified a higher-incidence ALS cluster in the years preceding the disease onset. The cluster area being densely populated, many exposures could have contributed to the high incidence ALS cluster, while we could not find a shared exposure among the dwellings where multiple patients had lived. However, these findings support that exogenous factors are likely involved in the ALS pathogenesis. [ABSTRACT FROM AUTHOR]

TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis human mutation. 20 Geronimo AM, Martin A, Simmons Z. Inertial sensing of step kinematics in ambulatory patients with ALS and related motor neuron diseases. Arterial blood gas analysis: base excess and carbonate are predictive of noninvasive ventilation adaptation and survival in amyotrophic lateral sclerosis. [Extracted from the article]

Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis. 1996; 47 (2): 535 - 40. 33 Okada Y, Yamazaki H, Sekine-Aizawa Y, Hirokawa N. The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. [Extracted from the article]

Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. [Extracted from the article]

Background and purpose: The aim was to assess the frequency of plateaus in amyotrophic lateral sclerosis (ALS) progression using a large population‐based cohort. Methods: Data from the Piemonte and Valle d'Aosta ALS register were used. Patients who were diagnosed between 2007 and 2014 were considered. The follow‐up period was extended until 31 December 2018. Visits after tracheostomy were excluded. A plateau was defined as a stable Amyotrophic Lateral Sclerosis Functional Rating Scale revised (ALSFRSr) score lasting at least 6, 12 or 18 months. Results: Out of 1214 patients, 200 (16.5%), 93 (7.7%) and 52 (4.3%) showed at least one plateau lasting a minimum of 6, 12 and 18 months, respectively. Plateaus occurred mostly at high ALSFRSr scores and were more frequent during the initial phases of the disease course. Spinal onset [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.16–2.95, P value 0.01) and predominant upper motor neuron phenotype (OR 2.18, 95% CI 1.36–3.48, P value 0.001) conferred a higher risk for the subsequent appearance of plateaus; conversely, older age at diagnosis (OR 0.25, 95% CI 0.11–0.54, P value 0.002 for >75 year age class) reduced this risk. Conclusions: Plateaus in ALS progression lasting at least 6 months appear in about one out of six patients and could last even 12, 18 months or more in a smaller subgroup of patients. Plateau occurrence should not lead the neurologist to automatically reconsider ALS diagnosis and should be considered for future clinical trial design. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim of the study was to evaluate the metabolic correlates of Apolipoprotein E (APOE) genotype in amyotrophic lateral sclerosis (ALS) and to investigate the role of ε2 as a risk factor for cognitive impairment. Methods: A total of 159 ALS cases underwent APOE and ALS‐related genes analysis, neuropsychological assessment and cerebral 18F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography. The APOE genotype was regressed against whole brain metabolism as assessed by 18F‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography, with age, sex, education, type of onset and C9orf72 status as covariates. Results: Brain metabolism was significantly positively correlated with APOE genotype from ε2/ε2 to ε3/ε4 in the left prefrontal [Brodmann area (BA) 10], orbitofrontal (BAs 11, 45, 47) and anterior cingulate (BA 32) cortices. There was a tendency to a relative hypometabolism going towards the ε2/ε2 extreme. Conclusions: We found a highly significant, relatively lower metabolism in association with the ε2 allele in extra‐motor areas typically affected in frontotemporal dementia (left prefrontal, orbitofrontal and anterior cingulate cortices), strengthening the finding of a role of ε2 as a risk factor for cognitive impairment in ALS. Our data suggested a link between cholesterol homeostasis and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background and purpose: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. Methods: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow‐up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. Results: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well‐known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. Conclusions: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management. [ABSTRACT FROM AUTHOR]

Background and purpose: The analysis of the spatial distribution of cases could give important cues on putative environmental causes of a disease. Our aim was to perform a spatial analysis of an amyotrophic lateral sclerosis (ALS) cohort from the Piedmont and Aosta Valley ALS register (PARALS) over a 20‐year period. Methods: The address at the moment of diagnosis was considered for each ALS case. Municipalities’ and census divisions’ resident populations during the 1995–2014 period were obtained. A cluster analysis was performed adopting both Moran's index and the Kulldorff spatial scan statistic. Results: A total of 2702 ALS patients were identified. An address was retrieved for 2671 (99%) patients. Moran's index was −0.01 (P value 0.83), thus revealing no clusters. SaTScan identified no statistically significant clusters. When census divisions were considered, Moran's index was 0.13 (P value 0.45); SaTScan revealed one statistically significant small cluster in the province of Alessandria. Here, 0.0099 cases were expected and three cases were observed (relative risk 304.60; 95% confidence interval 109.83–845.88, P value 0.03). Discussion: Our study showed a substantial homogeneous distribution of ALS cases in Piedmont and Aosta Valley. The population‐based setting and the adoption of proper statistical analyses strengthen the validity of our results. Such a finding further suggests the involvement of multiple environmental and genetic factors in ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Aims Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes. Methods TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls ( n = 10), patients with mutant TARDBP ( n = 4, 1 homozygous), valosin-containing protein ( VCP; n = 2), fused in sarcoma/translocated in liposarcoma ( FUS; n = 2), Cu/Zn superoxide dismutase 1 ( SOD1; n = 6), chromosome 9 open reading frame 72 ( C9ORF72; n = 4), without mutations ( n = 5) and neurologically unaffected subjects with mutant TARDBP ( n = 2). Results TDP-43 cytoplasmic accumulation was found ( P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes. Conclusions In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments. [ABSTRACT FROM AUTHOR]

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. Methods: Of the 183 patients with ALS resident in the province of Torino, Italy, 160 accepted to be interviewed. Controls were randomly selected from the lists of general practitioners. Pain was assessed using the Brief Pain Inventory. Results: Patients with ALS reported pain more frequently than controls [91 (56.9%) vs. 53 (33.1%); P = 0.001]. Pain frequency and intensity were correlated with a worse functional score and a longer disease duration. In patients with ALS, pain was more frequently located at the extremities ( P = 0.006). Pain interfered with all areas of daily function, but patients reported a greater interference than controls in the domains of enjoyment of life and relation with other people. Sixty-four patients (70.3% of those with pain) and 24 controls (45.3% of those with pain) ( P = 0.003) were treated for pain, most frequently with non-steroidal anti-inflammatory drugs. ALS cases were also more frequently prescribed non-opioid analgesics and opioids than controls. Conclusions: Our study indicates that pain is frequent in all stages of ALS, but that it often goes underrecognized and undertreated. It is significantly more frequent in patients with ALS than in population-based controls. Future studies need to clarify the mechanisms of pain in ALS and determine the most effective treatment strategy. [ABSTRACT FROM AUTHOR]

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. Methods: A total of 70 couples of ALS patients and their caregivers consecutively seen in our ALS clinic were separately interviewed using a battery of tests assessing frontotemporal-related neurobehavioral symptoms, emotional status, and quality of life. Patients’ behavioral abnormalities were assessed with the Frontal Systems Behavior Scale (FrSBe). Caregiver burden was assessed with the Caregiver Burden Inventory (CBI). Results: According to caregivers’ evaluations, 34 (48.6%) patients had FrSBe pathological scores at the time of the interview. According to patients’ evaluation, 9 (12.9%) patients had pathological scores at the time of the interview. In caregivers’ assessment, at the time of the interview the most commonly impaired neurobehavioral domain was apathy (39 patients, 55.7%), followed by executive dysfunction (32, 45.7%) and disinhibition (18, 25.7%). Neurobehavioral symptoms were related to the presence of bulbar symptoms at the time of the interview, but not to patients’ age, gender, or physical status (ALS-FRS score). Patients’ neurobehavioral symptoms were significantly related to lower caregivers’ quality of life, highest depression, and highest burden, both in univariate and in multivariable analyses. Conclusions: Neurobehavioral symptoms were present in 50% of our ALS patients and were related to bulbar symptoms. They have a profound negative impact on caregivers’ psychological status and were highly related with caregivers’ burden. [ABSTRACT FROM AUTHOR]

Background: Although depression has been widely studied in amyotrophic lateral sclerosis (ALS), there is little information on anxiety. Objective: To detect anxiety in patients with ALS and their caregivers, comparing the diagnostic and the follow-up phases of the disease and assessing its impact on quality of life (QoL). Methods: Anxiety has been evaluated with the State and Trait Anxiety Inventory in a series of 75 consecutive ALS patients and their primary caregivers. Anxiety has been related to depression, QoL, and satisfaction with life. Results: In patients, state anxiety was significantly higher during the diagnostic phase, whilst in caregivers it was similar in the two phases. Patients’ state anxiety was related to depression, shorter disease duration and lower satisfaction with life. Caregivers’ state anxiety was related to their trait anxiety. Whilst in patients QoL and satisfaction with life were similar in the two phases, in caregivers there was a significant decrease of satisfaction with life in the follow-up phase. Conclusions: Treating neurologists should recognize that the diagnostic phase and the earlier period after the diagnosis is characterized by a high level of anxiety both in ALS patients and in their caregivers, and should propose pharmacological and psychological interventions to relieve this highly distressing disturbance. [ABSTRACT FROM AUTHOR]

The "voluntary" control of pupillary constriction during accommodative tasks (PAR) has been recently tested in healthy subjects and proposed as a communication tool for paralyzed patients (Ponzio et al, 2019). Whether pupil functionality and PAR is preserved in a progressively paralyzing disease such as amyotrophic lateral sclerosis (ALS) is not known and is here addressed with a longitudinal and a cross sectional study. The pupil light reflex and PAR have been investigated in a group of 19 ALS patients, consecutively enrolled at the time of diagnosis and followed for 15 months, and in 10 ALS patients, in an advanced stage of the disease (all artificially ventilated). The PAR was tested by asking the patient to shift the gaze from a far (>3m) to a near (40 cm) visual target. In 4 patients of the latter group, a communication protocol was tested, requiring a PAR as input to answer "YES/NO" to a series of 10 questions with known answers. Pupil size was bilaterally monitored (EyeTribe). Pupil functionality appeared to be stable in the follow-up and still present in (9 out of 10) advanced stage patients (constriction magnitude: PAR: 19 ± 8 %; light reflex: 40 ±8 %). The accommodative task was easily understood and could effectively be used to answer the posed questions (accuracy 87.5 %). For the first time, the PAR is shown to be well preserved in advanced ALS patients and suitable to be employed as a binary communication, without requiring any previous learning or training session. [ABSTRACT FROM AUTHOR]