Abstract Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing ...future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials.
•In ALS, no prominent cognitive deterioration seems to occur with disease progression.•Progressive cognitive decline occur with disease progression only in some ALS phenotypes.•Bulbar dysfunction may ...be correlated with progressive cognitive decline in ALS.•The slope of cognitive/behavioural decline is not related to the slope of motor disability.•Attrition rate and practice effect may affect the reliability of the cognitive assessment over time.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease marked by progressive loss of motor abilities. Approximately half of patents with ALS experience cognitive (ALSci) or behavioural impairment (ALSbi) during the course of the disease, with a small percentage developing overt frontotemporal dementia (FTD). ALSci and/or ALSbi can occur simultaneously with motor neuron degeneration or develop in advanced stages of the disease, but it can even precede motor involvement in some cases, namely in ALS patients meeting criteria for FTD. Despite clear evidence that cognitive/behavioural impairment may appear early in the course of ALS, no prominent deterioration seems to occur with disease progression. Longitudinal studies have failed to reach conclusive results on the progression of cognitive and behavioural involvement in ALS. This may be due to some structural limitations of the studies, such as attrition rate, practice effect, short-time interval between neuropsychological assessments, but it can also be due to the heterogeneity of ALS phenotypes. The objective of this review is to provide a comprehensive and critical analysis of results of longitudinal studies highlighting cognitive and behavioural domains mainly affected by neurodegeneration pointing out the determinants that might be associate with the development and worsening of frontotemporal symptoms in ALS. At this regard, older age, rapidly progressing ALS, bulbar-onset, advanced disease stages are among factors mainly associated with cognitive and behavioural involvement. Moreover, the progression of cognitive and behavioural deficits seems to be not directly related to the slope of motor disability, thus suggesting the independence of neuropsychological and motor functional decline in ALS. Cognitive and motor involvement may indeed present with distinct trajectories suggesting a differential vulnerability of motor and non-motor cortical networks. In this scenario, determining the progression of extra-motor involvement in ALS may help refine understanding of the clinical implications of cognitive and behavioural abnormalities, and provide clues to the aetiology of the disease.
variants in patients with amyotrophic lateral sclerosis (ALS) have been associated with peculiar clinical features and disease progression but rarely with cognitive and behavioral impairment. This ...study aims at describing the features of frontotemporal syndromes in patients with ALS carrying
variants.
Italian patients with ALS were consecutively enrolled between 2012 and 2020 at our Motor Neuron Disease Center. All underwent clinical assessment, extensive neurophysiologic test battery for the evaluation of cognitive functions and behavior, and targeted next-generation sequencing of
,
,
,
,
,
,
,
,
, and
genes. Neuropsychological profiles of
+ patients (SOD1+) were compared with those with no gene variants (SOD1-). To this aim, the occurrence of cognitive and behavioral impairment defined according to the current guidelines, the number of pathologic test performances based on Italian normative values, and scores of the Frontal Behavioral Inventory were collected.
Among 288 patients consecutively examined, we identified 8 known pathogenic
variants and one variant of uncertain significance (p.Ser26Asn) not previously described in 14 patients with ALS belonging to 11 families. The clinical phenotypes were mainly characterized by predominant lower motor neuron involvement with onset at the lower limbs, and one patient had bulbar onset. SOD1+ patients (n = 14) were compared with SOD1- patients (N = 274). SOD1+ patients were younger than SOD1-, and both groups had similar functional motor disabilities and disease duration. Based on the overall neuropsychological findings, the percentage of SOD1+ and SOD1- patients with altered profiles were approximately 60%. However, behavioral impairment defined by the Strong criteria, and most commonly featuring with irritability and mental rigidity, was more frequent in SOD1+ than SOD1- patients and mainly associated with variants in exon 5. Conversely, cognitive impairment was mainly found in SOD1- patients.
Our findings from a large cohort of deeply phenotyped patients with ALS demonstrated that behavioral involvement is more common than previously thought among patients harboring
variants and that it is independent from patients' age and disease stage. These findings could be relevant for the assessment of clinical trial outcomes and disease management.
Cortical neuron degenerative process underlying upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) spreads to extra-motor regions as disease progresses. This is associated with ...cognitive and behavioural worsening in more severe disease stages. However, the clinical variability of ALS patients might reflect different cortical involvement in extra-motor areas.
To investigate cortical thinning across disease stages in ALS patients accounting for their cognitive/behavioural impairment.
Thirty-six ALS patients (17 with cognitive/behavioural impairment, ALSimp) and 26 healthy controls underwent structural 3T magnetic resonance imaging. Cortical thickness was measured with a region-wise approach. The King's Clinical Staging System was used to determine disease stages. The Jonckheere-Terpstra test tested for trends in cortical thinning and cognitive involvement across disease stages.
Significant trends toward cortical atrophy across disease stages were found in bilateral frontal and cingular cortex, left temporal gyrus and right occipital gyrus of ALS patients, consistently with cognitive impairment in phonemic fluency, language, verbal episodic memory and social cognition. Sub-group analyses revealed that ALSimp had specific thinning in the right fronto-temporal insular cortex related to more pronounced cognitive involvement.
Looking at ALS patients irrespective of their cognitive phenotype, motor and extra-motor cortical involvement is consistent with neuropathological studies of disease dissemination. Segregating patients according to their cognitive status, a distinctive trajectory of cortical thinning emerged for ALSimp patients, suggesting a specific course distinct to that of the classic ALS phenotype.
•Cortical thinning trajectories across disease stages in ALS.•Identification of specific cortical thinning trajectories in ALS subgroups.•Right hemisphere involvement in the pathological course of cognitive ALS phenotypes.
Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account ...for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins.
We generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for
, and
genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene.
Of the 1,077 genetically tested cases, 74 (6.9%) carried
mutations, 20 (1.9%) had
mutations, 15 (1.4%) had
mutations, and 3 (0.3%) carried
mutations. In the whole population, there was a linear relationship between log incidence and log age (
= 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for
-mutated patients confirmed a linear relationship (
= 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for
and with a 4-step process for
.
The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS.
This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register.
To examine the 20-year epidemiologic trends of ALS in the Piemonte and ...Valle d'Aosta regions of Italy.
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.
The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants.
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).
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.
Objectives
Amyotrophic lateral sclerosis (ALS) is not only a motor disorder: More than 50% of patients have cognitive dysfunctions over the course of the disease. At the same time, mood disorders may ...also occur in ALS patients following diagnosis due to the fatal prognosis; however, little data are available on any depression beforehand. Starting from these considerations, the aim of our study was to investigate the occurrence of depression in Italian ALS patients prior to diagnosis, evaluating its prevalence in the subjects who have developed cognitive dysfunctions and in those who did not.
Materials and methods
We included 318 patients, establishing the presence of depression in the 5 years before ALS diagnosis. Patients underwent a complete battery of neuropsychological tests with the aim to evaluate the executive functions, behavior, language, and memory.
Results
Before diagnosis, 40 patients with ALS had been diagnosed with depression: Among them, 29 patients had cognitive impairment over the course of the disease and only 11 did not develop any cognitive alteration (OR 1.46; 95% CI: 1.26‐1.66, adjusted for sex, age, and disease phenotype, P: 0.038). Moreover, there is a significant difference in survival time between ALS patients with depression before ALS, compared to ALS patients without previous depression (P: 0.006).
Conclusions
We reported a high prevalence of depression in the past in patients with ALS and cognitive impairment, as compared to patients without cognitive deficits, showing also that patients with both had a shorter survival time. These aspects require multidisciplinary approach at disease onset.
Objective: Long-term life experiences, such as education, occupational attainment, leisure activities, and bilingualism, have been considered proxies of cognitive reserve (CR). In neurodegenerative ...disease, CR is considered as a modulator of a more favorable cognitive trajectory and motor functions. Our study investigated the role of CR on cognitive and motor involvement in a large cohort of incident patients with amyotrophic lateral sclerosis (ALS). Methods: Cognition assessment and clinical and demographic information were obtained in 101 incident ALS patients. CR was measured based on years of education, occupational attainment, amount of leisure activities, and bilingualism. Correlation and regression analyses were performed to test the association between CR and the clinical expression of ALS. Results: We found that all proxies of CR were positively associated with executive functions, verbal fluency, and memory domains. Motor impairment was inversely related to educational level and occupational attainment. Regression analysis documented the association between CR and cognitive performances in all patients and the predictive role of CR in modulating motor functional disability in patients with bulbar-onset. Conclusion: Our findings showed that CR mediates the extent of cognitive decline and that of functional bulbar impairment, suggesting that the concept of reserve applied to ALS should encompass cognitive and motor domains.
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