Impairment In Amyotrophic Lateral Sclerosis Research Articles

Clinical usefulness of scales for evaluating cognitive impairment in patients with amyotrophic lateral sclerosis

Cognitive impairment is a common non-motor symptom of amyotrophic lateral sclerosis (ALS); however, scales suitable for detecting cognitive impairment in ALS patients in clinical practice are unclear. In this study, the Mini-Mental State Examination, Frontal Assessment Battery, and Montreal Cognitive Assessment (MoCA) were evaluated in 68 patients with ALS. The patients were classified into 3 groups based on the results of these clinical scales: group N, patients with scores higher than the cut-offs in all clinical scales; group M, patients with a score lower than the cut-off in one clinical scale; and group D, patients with scores lower than the cut-offs in two or three clinical scales. Clinical data were compared among the groups. Age at onset was significantly lower, and educational period was longer in group N than in group D. MoCA test reported the highest number of patients with a score lower than the cut-off value. The evaluation item of language in MoCA showed the lowest correct answer rate in group N, and evaluation items of executive function and memory in MoCA showed the lowest correct answer rates in group D. MoCA is the most sensitive clinical scale for evaluating cognitive impairment in ALS among the three scales.

The Calcium-Activated Chloride Channel TMEM16F Acts at C-Bouton to Modulate Motor Resistance and Contributes to ALS Pathogenesis

Neuronal Ca2+ entry elicited by electrical activity contributes to information coding via activation of K+ and Cl- channels. While Ca2+-dependent K+ channels have been extensively studied, the molecular identity and role of Ca2+-activated Cl- channels (CaCC) remains however unclear. Here, we show the CaCC encoded by Tmem16f is specifically expressed as clusters in α-motoneurons of the ventral spinal cord facing the pre-synaptic cholinergic C-boutons. Tmem16f-deficient mice display decreased motor performance under high-task exercise attributable to an increase of recruitment threshold of fast α-motoneurons. Remarkably, the deletion of TMEM16F in a mouse model of the amyotrophic lateral sclerosis (ALS) significantly reduces activity-dependent early stress marker expression, muscle denervation, preserves muscular force and delays disease progression. Thus, as a novel component of C-bouton, TMEM16F controls motoneuron excitability and impacts motor resistance as well as motor deterioration in ALS.

C9orf72 and intracerebral hemorrhage

The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

Longitudinal analysis of sniff nasal inspiratory pressure assessed using occluded and un-occluded measurement techniques in amyotrophic lateral sclerosis and primary lateral sclerosis

Objective: Sniff nasal inspiratory pressure (SNIP) is a commonly used clinical measure of respiratory impairment in amyotrophic lateral sclerosis (ALS), which is used to guide the initiation of noninvasive ventilation (NIV). SNIP can be completed with either an occluded or an un-occluded contralateral nostril. The aim of this study was to compare occluded and un-occluded SNIP measurements and to examine the decline in occluded SNIP over time compared to the ALSFRS-R respiratory subscore. Methods: This was a prospective longitudinal study examining occluded and un-occluded SNIP scores in ALS and PLS patients recorded between 2001 and 2018. Bland and Altman graphs were plotted for occluded vs. un-occluded SNIP measurements taking account of the repeated measures nature of the data. Longitudinal models were constructed as linear mixed effects multi-level models with follow-up in ALS limited to 6 years. Results: SNIP measured with an occluded contralateral nostril was systematically higher than with an un-occluded nostril. SNIP measured using both methods declined non-linearly, particularly after 2–3 years. The best fit model for decline in occluded SNIP included a main effect and interaction between site of onset and time, with age and diagnostic delay as independent variables. This showed a linear decline in spinal onset with a floor effect in bulbar-onset ALS. Conclusion: SNIP measured with an occluded and un-occluded contralateral nostril is not interchangeable, which is relevant in interpreting thresholds for initiation of NIV. SNIP declines non-linearly, which is explained in spinal onset ALS by age and diagnostic delay, but an apparent floor effect remains in bulbar onset.

Semantic Deficits in ALS Related to Right Lingual/Fusiform Gyrus Network Involvement: A Case-Control Study

Background: The clinicopathological continuity between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is well known. Although patients with ALS demonstrate similar language symptoms to patients with FTLD, including semantic dementia, word reading impairments in ALS have not been well studied. are kanji-written with irregular pronunciation that applies to exception words and are useful for detecting semantic deficits in Japan. We investigated Jukujikun reading impairments and related changes in resting-state networks in patients with ALS. Methods: We enrolled 140 participants, including 71 ALS patients and 69 healthy controls. We examined demographic and comprehensive neuropsychological factors, including Jukujikun. We also performed resting-state functional magnetic resonance imaging with voxel-based graph analysis on a subset of participants who agreed to participate in the imaging study to investigate the regions and related networks associated with Jukujikun impairments in ALS. Findings: Fifty-two percent of ALS patients (N=37) exhibited a significantly reduced score in Jukujikun reading compared with controls. We classified those patients as ALS with positive Jukujikun deficit (ALS-JD+) and the other patients as ALS with negative deficit (ALS-JD-). Resting-state network analysis showed significantly decreased degree centrality in the right fusiform/lingual gyrus and increased degree centrality in the left inferior/middle temporal gyrus in ALS-JD+ compared with ALS-JD- and controls. Seed-based analysis also revealed that the dysfunction in the right fusiform/lingual gyrus depended on decreased connectivity with regions associated with visual word perception, semantic processing, and speech. On the other hand, the observed increased degree centrality in the left inferior/middle temporal gyrus was derived from regions related to semantic processing. Interpretation Dysfunction of the hub in the right fusiform/lingual gyrus can affect semantic deficit in ALS. Considering neuropsychological symptoms as network impairments is vital for understanding various diseases. Funding MHLW and MEXT, Japan. Funding Statement: MHLW and MEXT, Japan. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study conformed to the Ethical Guidelines for Medical and Health Research Involving Human Subjects endorsed by the Japanese government. The study protocol was approved by the Ethics Review Committee of the Nagoya University Graduate School of Medicine, and written informed consent was obtained from all participants.

Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS) in Norway: Protocol for validation and a prospective cohort study.

In amyotrophic lateral sclerosis (ALS) cognitive impairment may occur. This could detrimentally influence communication between patient and health-care professionals and make clinical assessment difficult. Given the short life expectancy after diagnosis, it is crucial to accurately identify ALS patients early. Although suitable cognitive screening tools for patients with ALS are available, they have not been evaluated in a Norwegian population. Interpretation of scores for available tests and practical application of scoring is also not well established. The protocol described here involves two related studies that aim to improve the quality of ALS clinical testing instruments used in the Norwegian population. The first is a validation study that evaluates the psychometric properties of the ECAS-Norwegian. The second is a prospective cohort study that evaluates the ECAS-Norwegian as a tool to predict early changes in ability to work, drive a car and the need for advanced therapy. Study 1 is a multicenter study using international quality criteria. Patients with ALS, healthy control subjects, and control subjects with dementia will be included. Primary outcome is ECAS-Norwegian scores. In study 2, patients with ALS will be included. ECAS-Norwegian compared to Clinical Dementia Rating score and Montreal Cognitive Assessment scores will be used as a prognostic tool for working, driving, and initiating advanced life-prolonging therapy. Before clinical implementation, the ECAS-Norwegian needs to be evaluated and validated. Successful validation and implementation of the ECAS-Norwegian may provide early identification of cognitive impairment in ALS, leading to more proactive, individualized treatment.

Excitability in somatosensory cortex correlates with motoric impairment in amyotrophic lateral sclerosis

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motoneuron disease. As previous studies reported alterations in motor cortex excitability, we evaluate excitability changes in somatosensory system. Methods: We examined 15 ALS patients and 15 healthy controls. Cortical excitability was assessed using paired somatosensory evoked potentials of median nerves. To determine disease severity and functional impairment, we assessed muscle strength and revised ALS-Functional Rating Scale (ALSFRS-R). Results: We found significantly reduced bilateral paired-stimulation inhibition in the ALS-group (both p < 0.05). Additionally, paired-stimulation ratios significantly correlated with ALSFRS-R (left somatosensory cortex: r= −orte; right somatosensory cortex: r= −ort4; both p < 0.05) and contralateral muscle strength (left somatosensory cortex: r= −orte, p = 0.007; right somatosensory cortex: r= −ortex p = 0.003). Conclusions: The results indicate disinhibition of the somatosensory cortex in ALS. It remains open if central somatosensory disinhibition is a primary characteristic of ALS as one element of a multisystem neurodegenerative disorder or a compensatory up-regulation due to functional motoric impairment. Longitudinal studies are necessary to categorize these findings.

Validation of the revised classification of cognitive and behavioural impairment in ALS

ObjectiveIn 2017, the diagnostic criteria for cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (ALSFTD-1) have been modified (ALSFTD-2) with the inclusion of a novel category...

Dysfunction of attention switching networks in amyotrophic lateral sclerosis.

ObjectiveTo localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms.RationaleThe MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes.MethodsMMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography.ResultsCompared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10−6, right: p = 1.07 × 10−5) and left superior temporal gyri (p = 9.30 × 10−6). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95).InterpretationSource localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI).Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials.

Correlation between Apolipoprotein E genotype and brain metabolism in amyotrophic lateral sclerosis.

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. A total of 159 ALS cases underwent APOE and ALS-related genes analysis, neuropsychological assessment and cerebral 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography. The APOE genotype was regressed against whole brain metabolism as assessed by 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography, with age, sex, education, type of onset and C9orf72 status as covariates. 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. 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.

Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis.

Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King's clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p < .05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p < .05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment.

Age-related impairment in Addenbrooke’s cognitive examination revised scores in patients with amyotrophic lateral sclerosis

Objective: Older age is thought to be a risk factor for cognitive impairment in amyotrophic lateral sclerosis (ALS). However, very few clinical studies have investigated this relationship using sufficient numbers of healthy controls that correspond to each generation. The purpose of this study was to determine the age-related changes of Addenbrooke’s Cognitive Examination-Revised (ACE-R) score in ALS patients by comparing healthy controls of various ages.Methods: 131 ALS patients (86 males, 45 females; mean age: 64.8 ± 10.2; mean education: 12.5 ± 2.7) and 151 age-, gender-, and education-matched healthy controls were enrolled. We applied ACE-R, which could evaluate not only global cognition but five cognitive subdomains that included orientation/attention, memory, verbal fluency, language, and visuospatial ability.Results: ALS patients had significantly lower total and subdomain scores of ACE-R than healthy controls. Multiple regression analysis suggested that age at examination and age at onset had significant influence on ACE-R scores. When we divided ALS patients and healthy controls into 4 groups according to age at examination for ALS, total and each subdomain scores were significantly lower with age, particularly in the older-middle and the oldest group (66.31 years or more) of ALS compared with healthy controls. Locally weighted scatterplot smoothing analysis supported that these reductions of ACE-R total and subdomain scores in ALS patients were more accelerated by approximately 60 years as compared with healthy controls.Conclusion: ALS patients showed accelerated age-related ACE-R score reduction beyond normal ageing processes.

Amyotrophic lateral sclerosis in Nordland county, Norway, 2000–2015: prevalence, incidence, and clinical features

Objective: There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years. Methods: All patients with motor neuron disease (MND) living in Nordland County in the period 2000–2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015. Results: We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000–2004, 2.3 in 2005–2009, and 2.0 in 2010–2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD). Conclusion: The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients.

S150. Detection of upper motor neuron impairment in ALS with central motor conduction time

Detection of both upper and lower motor neuron impairments is essential for making a diagnosis of amyotrophic lateral sclerosis (ALS). Although electrophysiological findings identifying lower motor neuron damage have been established, there are few useful objective biomarkers for upper motor neuron impairment. Here, we retrospectively investigated the utility of the central motor conduction time (CMCT) for the detection of upper motor neuron impairment in patients with ALS. Fifty-five patients were diagnosed as ALS from 2007 to 2017 in our hospital. Forty-five ALS patients without any signal changes in the pyramidal tracts on magnetic resonance images and 10 healthy controls participated in this study. Electromyograms were recorded from the first dorsal interosseous and tibialis anterior muscles. Transcranial magnetic stimulation and magnetic motor root stimulation were performed to measure cortical and root latencies and obtained the CMCT. ALS patients were classified into two subgroups; positive and negative Babinski’s sign. The cortical and motor root latencies and CMCT were compared between two subgroups. Finally, we calculated the rates of ALS patients with abnormally prolonged CMCT (longer than mean +2 standard deviation of normal values). Cortical latency, motor root latency and CMCT were significantly longer in ALS group than the control group. There were no differences in the latencies and CMCT between the two subgroups of ALS patients. The CMCT was abnormally prolonged in 60% of ALS patients with positive Babinski’s sign and 50% of those with negative Babinski’s sign, respectively. The CMCT is useful for detecting upper motor neuron impairment in patients with ALS without any clinical pyramidal signs. CMCT can pave the way for finding upper motor neuron impairment masked by lower motor neuron damage in ALS patients.

Platform Session – Electromyography: Neural correlates of cognitive set shifting in amyotrophic lateral sclerosis

Introduction Neurodegeneration in amyotrophic lateral sclerosis (ALS) has traditionally been thought to be restricted to motor pathways. Over the last decades, it became increasingly recognized that functional impairment in ALS also extends to the cognitive domain. For example, accumulating neuropsychological evidence suggests that up to 50% of patients with ALS show impairments in executive functioning. Executive dysfunctions impose a severe burden on both patients with ALS and their caregivers. The neuropsychological assessment of ALS-related changes in executive functioning can provide diagnostic information of high clinical importance. However, standard neuropsychological testing in ALS is often complicated by patients’ motor symptoms. The recording of event-related potential (ERP) correlates of executive functions offers an opportunity to overcome this limitation. Methods I will describe two ERP studies that focused on cognitive set shifting as a specific domain of executive functioning. In both studies, patients with ALS and healthy control participants completed computerized set-shifting tasks while their EEG was being measured. Participants were required to sort cards according to changing task rules. When the valid task rule changed, a cue informed participants that they should shift to another sorting criterion. On the level of ERPs, such shift cues typically elicit a sustained positivity over parietal electrode sites. This so-called posterior switch positivity (PSP) is commonly regarded as an ERP indicator of set-shifting processes. Our studies examined the utility of the PSP as an indicator of executive dysfunctions in patients with ALS. Results In Study 1, we found the amplitude of the PSP to be significantly attenuated in patients with ALS in comparison to healthy controls. In addition, the individual extent of PSP-amplitude attenuation was significantly associated with patients’ performance on neuropsychological tests of executive functioning. Study 2 replicated this pattern of reduced PSP amplitudes in an independent sample of patients with ALS while using a considerably simplified set-shifting task. Attenuated PSP amplitudes were also observed in patients who did not show any signs of cognitive impairment in neuropsychological assessment. Conclusion ALS seems to be associated with a robust attenuation of PSP amplitudes that is not bound to a particular set-shifting paradigm. This ERP change can be detected in the absence of overt executive dysfunctions. Attenuated PSP amplitudes in ALS may thus reflect subtle changes in cognitive set shifting before these changes can be detected with neuropsychological tests. If longitudinal studies can corroborate the prognostic value of PSP amplitudes in ALS patients, PSP recordings might complement the neuropsychological assessment of executive dysfunctions in ALS.

Bulbar impairment score and survival of stable amyotrophic lateral sclerosis patients after noninvasive ventilation initiation.

There is general agreement that noninvasive ventilation (NIV) prolongs survival in amyotrophic lateral sclerosis (ALS) and that the main cause of NIV failure is the severity of bulbar dysfunction. However, there is no evidence that bulbar impairment is a contraindication for NIV. The aim of this study was to determine the effect of bulbar impairment on survival in ALS patients with NIV.ALS patients for whom NIV was indicated were included. Those patients who refused NIV were taken as the control group.120 patients who underwent NIV and 20 who refused NIV were included. The NIV group presented longer survival (median 18.50 months, 95% CI 12.62–24.38 months) than the no-NIV group (3.00 months, 95% CI 0.82–5.18 months) (p<0.001) and also in those patients with severe bulbar dysfunction (13.00 months (95% CI 9.49–16.50 months) versus 3.00 months (95% CI 0.85–5.15 months), p<0.001). Prognostic factors for ALS using NIV, adjusted for NIV failure, were severity of bulbar dysfunction (hazard ratio (HR) 0.5, 95% CI 0.92–0.97; p=0.001) and time spent with oxygen saturation measured by pulse oximetry <90% (%sleepSpO2<90) using NIV (HR 1.12, 95% CI 1.01–1.24; p=0.02).Severe bulbar impairment in ALS does not always prevent NIV from being used, but the severity of bulbar dysfunction at NIV initiation and %sleepSpO2<90 while using NIV appear to be the main prognostic factors of NIV failure in ALS.

Impairment in Respiratory Function Contributes to Olfactory Impairment in Amyotrophic Lateral Sclerosis

Nonmotor symptoms are very common in neurodegenerative diseases. In patients suffering from amyotrophic lateral sclerosis (ALS), olfactory dysfunction was first reported more than 20 years ago; however, its pathophysiological correlates and further implications remain elusive. In this so far largest case-control study, we analyzed olfactory performance with the "Sniffin' Sticks," a validated olfactory testing kit used in clinical routine. This test kit was designed to investigate different qualities of olfaction including odor threshold, odor discrimination, and odor identification. ALS patients were mildly but significantly impaired in TDI score, the composite of the three subtests (ALS 27.7 ± 7.9, Controls 32.3 ± 5.8). In contrast to Parkinson's disease, ALS patients did not show impaired performance in the suprathreshold tests identification and discrimination. However, the odor threshold was markedly decreased (ALS 6.0 ± 3.4, Controls 8.77 ± 3.6). This pattern of olfactory loss resembles sinonasal diseases, where olfactory dysfunction results from impeded odorant transmission to the olfactory cleft. The evaluation of medical history and clinical data of ALS patients showed that patients with perception of dyspnea (TDI 25.7 ± 8.0) performed significantly worse in olfactory testing compared to those who did not (TDI 30.0 ± 7.4). In line with that, we found that in patients with preserved respiratory function (vital capacity >70% of index value), olfactory performance did not differ from healthy controls. These findings suggest that the mild impairment of olfaction in patients suffering from ALS should at least partly be considered as a consequence of impaired respiratory function, and odor threshold might be a marker of respiratory dysfunction in ALS.

Swallowing impairments in Amyotrophic Lateral Sclerosis and Myotonic Dystrophy type 1: Looking for the portrait of dysphagic patient in neuromuscular diseases.

Dysphagia is a critical symptom of Neuromuscular Diseases and is often associated with considerable morbidity and mortality. This study is designed to investigate the prevalence of dysphagia and to identify different clinical profiles of swallowing disorders in Myotonic Dystrophy type 1 (DM1) and Amyotrophic Lateral Sclerosis (ALS), the most common Neuromuscular Diseases in the adult age. Consecutive DM1 and ALS patients from 2013 to 2015 referred to a Centre for Neuromuscular Disease were enrolled. A comprehensive assessment of swallowing function with a Clinical Swallowing Examination and Fluid and Food Trials was performed. 157 patients were included: 86 ALS, 71 DM1. The dysphagic patients affected by ALS and DM1 (79% and 86% of the respective samples) showed two different profiles. ALS patients with dysphagia were older and underweight. They experienced a global dysfunction of the oral and pharyngeal phases with more difficulty in swallowing thin liquids. Conversely, DM1 patients with dysphagia were younger and tended to obesity. Most of them showed impairment of oral phase and had more frequently difficulty in swallowing solid bolus. The recognition of specific clinical profiles supports and guides the detection of swallowing disorders in patients with neuromuscular diseases.

Structural and functional papez circuit integrity in amyotrophic lateral sclerosis.

Cognitive impairment in amyotrophic lateral sclerosis (ALS) is heterogeneous but now recognized as a feature in non-demented patients and no longer exclusively attributed to executive dysfunction. However, despite common reports of temporal lobe changes and memory deficits in ALS, episodic memory has been less explored. In the current study, we examined how the Papez circuit-a circuit known to participate in memory processes-is structurally and functionally affected in ALS patients (n = 20) compared with healthy controls (n = 15), and whether these changes correlated with a commonly used clinical measure of episodic memory. Our multimodal MRI approach (cortical volume, voxel-based morphometry, diffusion tensor imaging and resting state functional magnetic resonance) showed reduced gray matter in left hippocampus, left entorhinal cortex and right posterior cingulate as well as increased white matter fractional anisotropy and decreased mean diffusivity in the left cingulum bundle (hippocampal part) of ALS patients compared with controls. Interestingly, thalamus, mammillary bodies and fornix were preserved. Finally, we report a decreased functional connectivity in ALS patients in bilateral hippocampus, bilateral anterior and posterior parahippocampal gyrus and posterior cingulate. The results revealed that ALS patients showed statistically significant structural changes, but more important, widespread prominent functional connectivity abnormalities across the regions comprising the Papez circuit. The decreased functional connectivity found in the Papez network may suggest these changes could be used to assess risk or assist early detection or development of memory symptoms in ALS patients even before structural changes are established.

Trajectories of impairment in amyotrophic lateral sclerosis: Insights from the Pooled Resource Open-Access ALS Clinical Trials cohort.

Rate of decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score is a common outcome measure and a powerful predictor of mortality in ALS. Observed rate of decline (postslope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (preslope) were examined in the Pooled Resource Open-Access ALS Clinical Trials cohort by using longitudinal mixed effects models. Mean ALSFRS-R postslope in 3,367 patients was -0.99 points/month. Preslope and postslope were correlated and had powerful effects on survival. ALSFRS-R trajectories were slightly accelerated overall, but slope and direction/degree of curvature varied. Subscore decline was sequential by site of onset. Respiratory subscore decline was the least steep. Variable curvilinearity of ALSFRS-R trajectories confounds interpretation in clinical studies that assume linear decline. Subscore trajectories recapitulate phenotypic diversity and topographical progression of ALS. ALSFRS-R is better used as a multidimensional measure. Muscle Nerve 57: 937-945, 2018.