Non-Motor Symptoms of Amyotrophic Lateral Sclerosis: A Multi-Faceted Disorder

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor pathways. A growing body of evidence from recent years suggests that ALS results in a wide range of non-motor symptoms as well, which can have a significant impact on patients’ quality of life. These symptoms could also, in turn, provide useful information as biomarkers for disease progression, and can shed insight on ALS mechanisms. Here we aim to review a wide range of non-motor symptoms of ALS, with emphasis on their importance to research and clinical treatment of patients.

Keywords

ALS symptoms biomarkers prognosis

GENERAL BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, at the motor cortex, corticospinal tract, brainstem, and spinal cord [1, 2]. The most prominent symptom accompanying neurodegeneration is muscle wasting and paralysis, eventually resulting in death from respiratory failure [1, 2], and the most widely used tool to measure and monitor disease progression is the Revised ALS Functional Rating Scale (ALSFRS-R) [2]. Patients are usually classified by the site of onset of neurological symptoms, with about 65% of patients showing limb (spinal) onset of symptoms, about 30% exhibit bulbar onset of symptoms, and about 5% have respiratory onset disease [2]. A recent meta-analysis has confirmed this estimation, where bulbar-onset patients comprised 34.5% of ALS patients, but the proportion varied between 22– 62%, depending on the study and the population [3].

Most ALS cases are sporadic (sALS), and about 5– 10% of cases are familial (fALS) with a Mendelian inheritance pattern, and more than 20 genes have been linked to ALS pathogenesis [4, 5]. The most common genetic mutations associated with fALS are in the Superoxide dismutase 1 (SOD1) gene, Chromosome 9 open reading frame 72 (C9ORF72), Trans-activation response (TAR) DNA-binding protein 43 (TARDBP) coding for the TDP-43 protein, and Fused in sarcoma (FUS) genes [5], causing to over 47% of fALS cases [4]. The frequencies of each mutated gene vary between different populations, as C9ORF72 and SOD1 are most frequent among European populations, whereas in Asian populations SOD1 mutations are most common among fALS patients [4]. This review focuses mainly on sALS patients, unless otherwise specified.

Estimates of the global ALS incidence rates range between 0.5– 3.6 / 100,000 person-years (median between 2.39– 2.68 / 100,000 person-years), and the prevalence is estimated between 1– 11.3 / 100,000 individuals (median between 4.04– 7.89 / 100,000 individuals), depending on the country and various populations [6].

While ALS is traditionally referred to as a motor neuron disease, a growing body of evidence suggests that many other systems are affected by this disease. In this review, we aim to shed light on non-motor symptoms of ALS, their prevalence, and clinical significance.

NEUROLOGICAL IMPAIRMENTS

Cognitive impairments

One of the most researched domains in non-motor impairments among ALS patients is the cognitive and behavioral domain, where ALS is regarded to be on a continuous spectrum with frontotemporal dementia (FTD) [7]. In fact, it is now recommended that diagnosis of ALS will be accompanied by cognitive and behavioral tests for memory and learning, attention and concentration, and executive functions such as planning and initiating plans, in order to diagnose ALS-FTD patients [8, 9]. Several studies have found that the prevalence of various cognitive impairments among ALS patients ranges between 34– 51% [10 –16], and the prevalence of patients meeting the criteria for FTD ranges between 11– 25% [10– 13 , 15], depending on the cohort and diagnosis methods. Importantly, ALS patients with cognitive or behavioral impairments have a worse prognosis compared to cognitively and behaviorally normal patients [16, 17], and patients with FTD have a shorter survival time compared to ALS patients with normal cognition [12], suggesting that cognitive assessment can serve as a prognostic tool in ALS patients. Finally, genetic factors appear to play a role in the risk for developing FTD, as cognitive deficits and FTD are less frequent among SOD1 fALS patients [18], and are more common among C9ORF72 fALS patients [9, 19]. A possible mechanism for mutated C9ORF72-mediated FTD is the accumulation of toxic proteins with dipeptide repeats (DPRs) [20], which can be detected in the frontal cortex and hippocampus regions of subjects with a mutation in C9ORF72 and with FTD, even in the absence of motor symptoms associated with ALS [21, 22].

Several imaging studies were conducted to assess differences in brain pathology between ALS and ALS-FTD patients, in order to shed light on the neurodegenerative processes underlying cognitive impairments in patients. Compared to control subjects, ALS patients exhibit cortical thinning of the bilateral precentral gyri, the right precuneus, and the right frontal and temporal lobes [23]. Comparing ALS with ALS-FTD patients, ALS patients with FTD also showed greater gray matter atrophy in the motor cortex, anterior cingulate area, and anterior temporal lobe, compared to non-demented patients [24], as well as cortical thinning in the frontal and temporal gyri and the posterior cingulate cortex [23]. ALS patients with impaired cognition showed a similar pattern of cortical thinning to that observed in ALS-FTD patients, but the cortical thinning was less pronounced [23].

Likewise, investigation of white matter degeneration in the brain has shown that among ALS patients, impaired performance in tasks involving executive functions and attention was correlated with the extent of degeneration observed in white matter tracts such as the corpus callosum, corticospinal tract, long association tracts including the cingulum, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculus [25]. Lastly, Investigation of cerebellar atrophy has found that compared to controls, ALS patients show gray matter atrophy mainly in the inferior lobules and in the vermis of the cerebellum. ALS-FTD patients, on the other hand, showed atrophy in the superior lobules, crus, and vermis, compared to control subjects; whereas the bilateral superior lobules and crus show significantly more atrophy compared to cognitively normal ALS patients [26]. These findings suggest that the cognitive impairment continuum in ALS is associated with degeneration of disparate areas in the central nervous system.

Language abnormalities

A specific cognitive domain that received a lot of interest is language impairments. Indeed, many studies have found language impairments in ALS patients in multiple lingual domains such as syntax, pragmatics, grammar, semantic processing, word retrieval, verbal fluency, and naming and understanding action verbs [27 –37]. While not always reported, the prevalence of certain lingual deficiencies among patients ranges between 43– 72% in some cohorts [27 , 33], but in all cases did not correlate with ALSFRS-R scores [27, 28].

Several imaging studies were conducted in order to find brain abnormalities relating to lingual impairments among ALS patients: gray matter atrophy was observed in the inferior frontal lobe, anterior temporal lobe, and striatal regions of the left hemisphere, as well as white matter abnormalities in the corpus callosum, superior longitudinal fasciculus, and inferior frontal-occipital fasciculus [31]. Functional MRI (fMRI) analysis of patients during lingual tasks revealed reduced activation of the middle and inferior frontal gyrus and the anterior cingulate gyrus [29]. Lastly, TDP-43 accumulation was observed in patients’ brains in Brodmann areas 20 (inferior temporal gyri), 39 (angular gyrus), 41 (transverse temporal area, Heschl’s gyri), and 44 (inferior frontal gyrus, Broca’s area), which are all associated with various language functions [33].

An intriguing theory about lingual deficiencies in ALS patients focuses on impairments involving action verbs [35 –37]. It was suggested that neural degeneration spreads along with functional networks, and degeneration of the motor cortex affects the activation of lingual networks involving body actions, under the umbrella term ‘embodied cognition’ or ‘grounded cognition’ [38]. Indeed, lingual performance regarding body-related verbs is more impaired in ALS patients with greater disease severity [37]. It is important to mention that others have found no impairments in semantic memory for objects and actions in patients, arguing against this claim [30]. In our view, the differences in findings may be related to different languages spoken by the patients and the role of verbs in those languages. This interesting hypothesis merits further investigation in different populations and languages.

Mood disorders

Depression was reported and assessed in ALS patients using various measures of diagnosis, however studies based on DSM-IV criteria (Diagnostic and Statistical Manual of Mental Disorders) estimate depression prevalence at 9– 11% among ALS patients, which is higher than the general population [39]. This can be explained as a natural outcome of the diagnosis with a debilitating and fatal disease, and indeed depression is not correlated with disease progression or disease duration [40, 41], arguing against neurodegenerative processes underlying depression in ALS patients.

A contributing factor to depression among ALS patients may be pain. While classically not considered to be part of the disease, up to 55– 70% of patients report various degrees of pain, depending on the cohort and experimental design [40 , 43]. Similarly to disability levels, pain is correlated with patients suffering and reduced quality of life [43, 44], and, importantly, pain is more prevalent among ALS patients with depression, compared to non-depressed patients [40], suggesting pain as an important effector on mood disorders among ALS patients [45].

Similarly, anxiety was reported in ALS patients with prevalence ranging between 0– 30%, depending on diagnosis criteria, and tends to increase as patients are closer to death [39]. While anxiety can be seen as a natural and understandable symptom toward death, it is possible that neural mechanisms are involved, especially in the amygdala. ALS patients exhibit increased mean diffusivity (MD) in the amygdale [46], and a trend towards reduced amygdala volume [47], compared to control subjects. While the literature regarding the relationship between amygdala size and anxiety symptoms is inconsistent [48], the scarcity of anxiety studies in ALS patients warrants further research regarding the prevalence and pathophysiology of anxiety in ALS.

Lastly, a prominent symptom observed in ALS patients is the pseudo-bulbar affect (PBA), a condition characterized by the disparity between patients’ emotional state and emotional expressions. Such emotional expressions can be exaggerated or discordant with the patient’s emotional state and can result in embarrassment and social isolation, increasing disease burden [49]. While estimation on PBA prevalence varies depending on diagnosis methodology(49), PBA was found among 32– 36% of ALS patients in different cohorts [50, 51]. Importantly, a recent study showed that the occurrence of PBA at the early stages of ALS can serve as an indicator for a shorter survival time, suggesting PBA as a prognostic factor in patients(50).

PBA is attributed to disinhibition resulting from increased glutamate signaling and reduced serotonin signaling in the brain [49, 52]. Several serotonin agonists such as selective serotonin reuptake inhibitors (SSRIs) or glutamate antagonists were tested with beneficial results on PBA, and indeed the only currently FDA-approved treatment is based on dextromethorphan, a glutamate antagonist [49, 52].

Data from other neurological conditions such as multiple sclerosis and stroke suggested that several brain regions are involved in PBA pathology, including the basilar pontine nucleus, dorsal globus pallidus, left and right medial inferior frontal lobes, and the left inferior parietal lobe [52, 53]. In ALS patients, an imaging study that compared patients with and without PBA revealed that PBA is associated with a reduction in fractional anisotropy (FA) in a small region underlying the left motor cortex, and increased white matter mean diffusivity (MD) in the right middle cerebellar peduncle and in transverse pontine fibers, suggesting degeneration in these areas is linked to PBA in ALS patients [51].

Sleep disturbances

Several studies have found sleep disturbances in ALS patients, compared to control subjects. These include a higher frequency of awakening events after sleep onset; shorter and more fragmented rapid eye movement (REM) sleep periods; and an increase in breathing disturbances, namely apnea/hypopnea, especially during REM sleep [54 –59]. Several studies have found that the prevalence of patients complaining about sleep quality and present sleep abnormalities ranges between 59– 95% [57 –59].

Several causes can lead to poor sleep quality in ALS patients, including immobilization, depression, and anxiety [60]. It was also suggested that sleep disturbances are due to respiratory problems among these patients, as sleep disturbances are mainly prevalent in patients with diaphragmatic dysfunction, compared to patients with normal diaphragmatic functions [54]. Indeed, patients using non-invasive ventilation such as Bilevel Positive Airway Pressure (BiPAP) masks showed improved sleep quality including reduced awakening periods and increased REM time during sleep [58, 59]. Likewise, implantation of diaphragm pacers reduced the number of awakening events and reduced the number of apnea/hypopnea events during REM sleep [61].

In contrast to the aforementioned studies, REM sleep disturbances were also observed in a cohort of patients with normal respiratory functions, suggesting that REM impairment is not solely dependent on respiratory problems [56]. A possible neural mechanism underlying these impairments can be attributed to the brainstem areas involved in REM initiation, and especially in the ventral oral pontine reticular nucleus (vRPO) [62] and the mesopontine tegmentum [62, 63]. Indeed, recent findings have shown that ALS patients exhibit brainstem atrophy compared to controls, including a reduction in the volume of the pons [64], accompanied by increased glucose metabolism [65] and marked microglial activation in the pons [66]. These findings suggest the possibility that atrophy of REM-related neural circuits is an underlying cause for sleep disturbances in a subset of ALS patients, but a further examination of specific REM-related pontine structures in patients is required in order to establish this hypothesis.

Olfactory disturbances

Olfactory disturbances were observed in ALS patients in several studies [67 –71]. Division of these olfactory impairments into subgroups of patients have yielded mixed findings: while some studies found these impairments to be more prominent in bulbar-onset patients [68], others have found only a minor tendency for worse olfactory performances in bulbar-onset patients [70] or no difference in olfactory dysfunction between bulbar and non-bulbar patients [69]. Another association of olfactory impairments is with cognitive decline in patients: impaired olfactory performance is correlated with lower Mini-mental state examination (MMSE) scores and was mainly observed in patients with mild cognitive impairment or FTD, suggesting olfactory testing as a tool to distinguish between ALS patients with normal cognition and patients with cognitive impairments [71, 72].

A mechanistic explanation for olfactory impairments in ALS patients be in part due to respiratory problems among these patients, as patients complaining about shortness of breath (dyspnea) have significantly lower scores for olfactory performance compared to other patients, and the decline of respiratory functions was correlated with a decrease in olfactory performances [70]. On the other hand, histological analyses of olfactory pathways in ALS patients have yielded mixed findings. While post-mortem histological analysis of olfactory-related pathways in the brains of totally locked-in patients did not find significant abnormalities in these pathways [73], others have reported an increase in lipofuscin-positive neurons in the olfactory bulb, similar to those observed in the anterior horn of the spinal cord, suggesting neuronal damage in the olfactory bulb [68]. Finally, post-mortem histopathological analysis of TDP-43 pathology found a marked accumulation of TDP-43 inclusions in the piriform cortex and dentate gyrus (which represent primary and secondary olfactory centers, respectively), and to a lesser extent in the olfactory bulb; suggesting that TDP-43 pathology in this pathway arises from hippocampal regions and eventually spreads to the olfactory bulb as a later event [71].

Abnormalities in the sensory nervous system

Unlike the motor symptoms that characterize ALS, there are generally no marked sensory deficits among patients compared to control subjects [74 –76]. However, at later stages of the disease, subclinical neural deficits in sensory fibers are recorded in ALS patients, such as axonal loss in peripheral sensory nerves [77] and abnormalities in the conduction or amplitudes of neuronal signals in the sensory system, in up to 22% of patients [74]. Interestingly, while some have not found a difference in sensory system abnormalities in ALS patients with different disease sites of onset [74], a recent study has found that sensory nerve fibers neuropathy is common in spinal-onset ALS patients, but not in bulbar-onset patients [78].

Neuronal recordings of patients also showed impaired functioning of sensory fibers: About 1.5 years after onset of the disease, ALS patients have a higher peak-to-trough amplitude in a component of somatosensory evoked potentials (N20-P25) in the median nerve compared to control subjects, suggesting hyperexcitability in the sensory cortex [79]. The same group also recently reported a case study of a patient with progressive deterioration of excitability of the sensory cortex and a progressive reduction of the N20-P25 peak-to-trough amplitude in an evoked potential, accompanied by cortical and brainstem atrophy(80). Such findings suggest a deterioration of the somatosensory cortex with ALS progression along with disease progression [80, 81]. Likewise, in patients with disease duration exceeding 2 years, a reduction in neural bursts thought to represent GABAergic inhibitory neurons was observed in the brain, thus suggesting sensory disinhibition as a feature of late stages of ALS [76]. A similar finding was reported by another group, which found that patients exhibit disinhibition in the somatosensory cortex compared to controls, as measured by a paired-stimulation inhibition paradigm [82].

In addition to nerve recordings, Diffusion tensor imaging (DTI) of the dorsal column of the spinal cord at the neck region (C5-T1 vertebrae) showed increased mean diffusivity (MD) in patients compared to control subjects, suggesting neural damage to this tract [81]. Similar findings were observed by another group that imaged the dorsal column of the spinal cord and found that ALS patients exhibit decreased fractional anisotropy (FA) and increased radial diffusivity (RD) of water molecules in white matter fibers, compared to control subjects, indicative of sensory pathways atrophy [83]. Lastly, biopsies of ankle nerve fibers of patients showed axon swelling and were negative to growth-associated protein 43 (GAP-43) staining, suggesting subclinical degenerative processes in peripheral sensory nerves [75].

Importantly, abnormalities in sensory nerves can serve as a prognostic marker: among ALS patients, subjects with higher excitability as measured by the N20-P25 ratio had shorter survival, compared to patients with lower excitability values [79], and experiments in paired-stimulation of sensory neurons showed that higher paired-stimulation ratios in patients were negatively correlated with arm muscle strength and with ALSFRS-R scores in general [82]. These findings suggest that abnormalities in the sensory system could serve as an auxiliary marker for disease progression and severity in ALS.

INFLAMMATORY SYMPTOMS AND BIOMARKERS

Neuroinflammation in the central nervous system is a known hallmark of ALS, similar to that observed in other neurodegenerative diseases [84]. In addition, several lines of evidence indicate a peripheral immune activation in ALS and a possible association with disease progression.

Gene expression analysis of peripheral blood cells in ALS patients with a recent diagnosis showed dysregulation of several cytokines, and upregulation of factors involved in extracellular matrix remodeling and extravasation of leukocytes, suggesting that immune dysregulation is an early event in ALS pathology [85]. Similarly, A recent meta-analysis found that ALS patients have increased serum levels of several inflammatory cytokines [86]. Another study has found low-grade inflammation in ALS patients, manifested by increased serum levels of wide-range C-reactive protein (wrCRP), fibrinogen, neutrophil-to-lymphocyte ratio (NLR), and increased erythrocyte sedimentation rate (ESR) [87]. Likewise, ALS patients exhibit higher serum ferritin levels, compared to control subjects, which are correlated with a faster decline in ALSFRS-R scores among patients and shorter survival [88, 89]. Importantly, there was also a negative correlation between the levels of CRP, fibrinogen, and ESR with ALSFRS-R scores, suggesting a link between inflammatory markers and disease severity [87]. Lastly, a recent longitudinal study has found that along the disease course, ALS patients exhibit an increase in the mean count of total immune cells [90]. This study has also shown that an increase in neutrophil counts and conversely, a decrease in CD4⁺ T cell counts, were associated with a decline in ALSFRS-R scores [90].

Finally, a recent study found that, surprisingly, compared to control subjects, ALS patients have significantly lower rates of inflammation-related antecedent diseases, such as arthritis, liver diseases, chronic obstructive pulmonary disease (COPD), kidney disease, adult asthma, and diabetes [91]. Moreover, antecedent conditions such as hypertension, hyperlipidemia, arthritis, COPD, or thyroid disease, are associated with a later age of onset for ALS [92]. Interestingly, most of these antecedent diseases are also associated with shorter disease duration, raising the intriguing possibility that attrition of homeostatic mechanisms exacerbates ALS symptoms after disease onset [92].

RENAL TRACT DISTURBANCES

ALS patients exhibit dysfunction in the urinary system, reporting urinary incontinence and urgency [93 –95], but also urinary retention, as measured by increased post-void residual (PVR) [95]. Urinary symptoms are attributed to overactive detrusor and non-relaxing sphincter [94] and are reported at a prevalence ranging between 36– 43% in ALS patients, suggesting autonomic dysfunction [93 –95].

With regard to kidney function, the estimated glomerular filtration rate (eGFR) for creatinine was markedly higher in ALS patients compared to control subjects, and this can be explained by lower creatinine levels observed in patients’ blood [96]. This suggests that serum creatinine is not a reliable marker for renal function in ALS patients, unlike serum cystatin C levels which were not different between ALS patients and control subjects [96]. Of note, the expression of the metal-binding protein metallothionein is increased in the kidneys and liver of ALS patients [97, 98], and a similar increase in metallothionein expression is also observed in a mouse model of ALS during disease progression [99], suggesting metallothionein is a possible marker for deleterious processes during ALS progression.

Interestingly, several serum markers can also demonstrate kidney abnormalities in relation to disease course and severity. ALS patients exhibit a lower level of serum creatinine compared to control subjects, due to muscle atrophy [96], and lower levels of creatinine in patients are associated with lower ALSFRS-R scores, a faster decline in the physical condition, and shorter survival rates [88,100– 102 , 88,100– 102]. In contrast, bilirubin measurements in ALS patients show mixed results: while one study found an increase in serum bilirubin levels in patients combined with decreased bilirubin transport [103], another study did not found differences in bilirubin levels compared to control subjects, and found a decrease in bilirubin levels in patients with longer disease duration compared with patients with shorter disease duration [104]. Lastly, meta-analysis studies have shown ALS patients to have significantly lower levels of serum uric acid (UA) compared to control subjects, and lower UA levels are associated with higher mortality risk among patients [102 , 106].

METABOLIC ABNORMALITIES

General metabolic impairments

Several metabolic abnormalities were observed in ALS patients. These include high serum levels of triglycerides and lower levels of high-density lipoprotein HDL) [107], as well as increased levels of adiponectin and lower serum levels of Ghrelin, gastric inhibitory peptide (GIP), and pancreatic polypeptide (PP) [108]. Such metabolic parameters also serve as prognostic factors, as ALS patients with lower cholesterol levels have a significantly shorter survival [107], and patients with higher glucagon levels have lower ALSFRS-R scores [108]. Body-max index (BMI) is also a commonly used predictor for ALS patients’ survival: it was shown that lower BMI increases the risk of developing ALS, and overweight reduces the risk of developing ALS [109]. Moreover, it was shown that obese patients survive for longer periods of time [110] and that there is in fact a U-shaped relation between BMI and mortality, where the highest survival time was with patients with BMI values ranging between 30– 35 [102 , 112].

Another interesting finding among patients is hypermetabolism, or increased energy expenditure at rest, which was observed both in sporadic ALS (sALS) patients at a prevalence of 52– 62% [112, 113] as well as in familial ALS (fALS) patients [113]. Of note, the general hypermetabolism observed in patients may be beneficial, as resting energy expenditure was in a positive correlation with survival in patients [112]. Similar metabolic changes were observed in the brains of ALS patients, as patients showed increased metabolism in the amygdalae, midbrain, and pons, compared to controls subjects [65]. Hypermetabolism was also observed in the midbrain and the spinal cord, while hypometabolism in the frontal dorsolateral cortex, precentral, and temporal cortex [114].

Lastly, there appears to be an intriguing connection between ALS and type 2 diabetes (T2D). while diabetes is associated with many neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [115], its relation with ALS seems more complex: in Danish, Swedish and Italian cohorts, T2D was shown to be a protective factor against developing ALS [116 –118]. In contrast, large cohort studies in Taiwan found T2D to be a risk factor for developing ALS [119], especially for subjects with young-onset T2D combined with hyperlipidemia [120]. This discrepancy was confirmed in a recent genome-wide association study (GWAS) using single nucleotide polymorphisms (SNPs) of diabetes-related genes, which showed that T2D reduces the risk for ALS in European subjects, while slightly increasing the risk for ALS among east Asian subjects [121]. These findings suggest a complex interaction between metabolic and other genetic and environmental factors in the pathogenesis of ALS.

Liver abnormalities

Several abnormalities in liver structure and function were observed in ALS patients. Tissue analysis of liver biopsies from patients revealed enlarged mitochondria with a high percentage of paracrystalline inclusions in the liver, accompanied by prominent perisinusoidal fibrosis, and mild liver fibrosis [103]. Likewise, hepatic steatosis was reported to be a frequent phenomenon among patients, with liver enzymes and lipid profiles resembling a cohort of patients with dyslipidemia [122]. The prevalence of these abnormalities ranged between 74– 76% of ALS patients [103, 122]. Supporting findings were obtained from a mouse model for ALS, in which the liver shows increased expression of inflammatory and oxidative stress markers during disease duration, and proteins related to liver fibrosis are also increased during disease progression [123].

Gastrointestinal impairments

Similarly, gastrointestinal abnormalities were reported among ALS patients, and the main symptom being constipation [93 , 124– 126]. Imaging studies have shown patients to have delayed gastric emptying compared to control subjects [125] and delayed colonic transit time especially in the right and left colon, but not in the rectosigmoid colon, suggesting a possible involvement of the autonomic nervous system [124, 127]. The prevalence of these symptoms has not been systematically investigated, however gastrointestinal abnormalities were reported in 16– 83% of ALS patients, depending on the symptom [93 , 125]. While immobilization in patients may have an effect on bowel movement, a sedentary lifestyle in itself cannot fully explain this phenomenon, suggesting a possible impairment in the enteric nervous system [124].

Microbiome abnormalities

Microbiome analyses have become more prevalent in recent years, and indeed such analyses revealed abnormalities in microbiota population in ALS patients [128]. Decreased bacterial and archaeal flora richness was observed in ALS patients compared to control subjects, including an imbalance in the flora of microorganisms as potentially harmful bacteria populations are increased and beneficial bacteria populations such as Bacteroides are reduced [129, 130]. Additional support to a possible causal role of the microbiome in ALS is derived from the mutated SOD1 mouse model, in which treatment of mice with butyrate restored microbial populations in the mice compared to WT mice, delayed weight loss, and increased life span of the model mice [131]. In addition, this treatment also reduced SOD1 aggregation in the colon of mutant SOD1 mice [131]. Likewise, Studies in mutant SOD1 mice show several microbial species which are correlated with disease progression: Akkermansia muciniphila has a beneficial effect on the disease course, as treating mice with these bacteria improves the motor function of the mice, and increases survival in the mice. Conversely, treating mice with Ruminococcus torques and Parabacteroides distasonis showed deleterious effects on mice phenotype and survival [132]. Importantly, A. muciniphila-released nicotinamide (NAM) was shown to mediate the beneficial effect in mice, and administration of NAM significantly improved motor function in mutant SOD1 mice. Lastly, NAM levels were found to be lower among ALS patients, both in the serum and in the CSF, compared to age-matched family members [132]. These findings certainly merit further investigation regarding the crosstalk between microbiota and disease onset and progression in ALS patients.

CARDIOVASCULAR ABNORMALITIES

A large body of evidence suggests that ALS patients have impairments in the ability to maintain normal blood pressure, through reduced baroreflex sensitivity [133 –136]. Patients may exhibit episodes of fluctuations in blood pressure which include attacks of blood pressure elevation followed by sudden drops in blood pressure, especially at end stages of the disease [137 –139]. Cardiovascular abnormalities can ultimately result in higher rates of leukoaraiosis (white matter abnormalities) in the brain, which was correlated with the duration of hypertension and increases the risk of death [140], and finally even circulatory collapse and sudden death [137, 139].

ALS patients also exhibit higher baseline blood pressure compared to control subjects [136, 141]. Interestingly, riluzole may also contribute to this phenomenon, as riluzole-treated patients had a higher systolic blood pressure compared to patients not treated with riluzole [141]. Finally, blood pressure has been recently suggested as a prognostic feature among ALS patients [102]. ALS Patients are also reported to have a higher resting heart rate, compared to control subjects [133 , 142], but this finding is not consistent and others have found no difference in heart rate between patients and control subjects [143]. While no systematic analysis of cardiovascular abnormalities was performed on large cohorts of ALS patients, studies have found the prevalence of these abnormalities to range between 35– 80% of patients [137 , 141]. Although blood pressure fluctuations are usually observed at end stages of the disease [137, 138], and thus are unlikely to facilitate with the prognosis of the disease, the fact that pulse rates were suggested as a prognostic feature in ALS patients [102] argues in favor of a further investigation of cardiovascular abnormalities in ALS patients.

Another method to examine cardiac sympathetic function is using cardiac [¹²³I] metaiodobenzylguanidine (MIBG) scintigraphy, by using a norepinephrine analogue that is a sensitive marker for sympathetic postganglionic innervations [142, 144]. One study did not find a difference in MIBG uptake shortly after administration between patients and control subjects, but rather increased washout of MIBG in patients, suggestive of increased cardiac sympathetic activity, which was correlated with a higher decline in ALSFRS-R scores and with significantly shorter survival [144]. Another study measured the MIBG signal after a longer period of time and found a lower signal of MIBG in the hearts of patients compared to controls, suggestive of sympathetic postganglionic dysfunction, and abnormal MIBG signal in those patients was correlated with higher disability scores [142].

A possible explanation for cardiovascular symptoms observed in ALS patients lies in parasympathetic dysfunction and sympathetic dominance [135, 142], as patients exhibit high levels of epinephrine and norepinephrine [137, 145]. These cardiovascular symptoms are a risk factor for a higher decline in ALSFRS-R scores and shorter survival time among patients [140, 144].

CONCLUSION

In this work, we reviewed a wide range of non-motor symptoms observed in ALS patients, which are summarized in Table 1 and Fig. 1. While motor degeneration and subsequent muscle atrophy are the main cause of disability and death in patients, the non-motor symptoms can have a significant effect on patients’ quality of life, and in some cases even contribute to deleterious processes observed in the disease. These symptoms do not affect all the patients, and we believe that systematic research on the prevalence and significance of such symptoms among ALS patients can promote better treatments for patients, and further our understanding regarding the mechanisms underlying the disease.

Table 1

Summation of non-motor symptoms, impairments and biomarkers observed in ALS patients

Domain	Symptom/feature	Prognostic potential	Therapeutic potential	Reference
Cognitive and behavioral	cognitive or behavioral impairments, including FTD	+		12, 16, 17
	Thinning of frontal and temporal cerebral cortex			23
	Degeneration of white matter tracts including the corpus callosum and long association tracts			25
	Language impairments			27– 37
	Gray matter atrophy in language-associated brain regions			29, 31, 33
	Pseudo-bulbar affect (PBA)	+		50
Sensory	Olfactory impairments	+		67– 72
	Hyperexcitability in sensory nerves	+		79, 82
Inflammatory	Increased serum levels of ferritin, CRP, fibrinogen, and increased erythrocyte sedimentation rate	+		87– 89
	An increase in neutrophil counts and a decrease in CD4⁺ T cell counts	+		90
Kidney and liver	Increased expression of the metal-binding protein metallothionein in the kidneys and liver	+		97– 99
	Low serum levels of creatinine	+		88, 100– 102
	Low serum levels of uric acid	+		102, 105, 106
	Paracrystalline inclusions in the liver, accompanied by prominent perisinusoidal fibrosis, and mild liver fibrosis	+		103, 122, 123
Metabolism	Lower cholesterol levels; increased glucagon levels	+		107– 108
	Body-mass index (BMI)	+		102, 109, 110– 112
	Hypermetabolism	+		112
	Occurrence of type II diabetes	+		116– 121
	Gastrointestinal impairments			124, 125, 127
	Altered microbiome composition	+	+	128– 132
Cardiovascular	Increased blood pressure	+		102
	parasympathetic dysfunction and sympathetic dominance	+		140, 142, 142

Fig. 1

Schematic representation of possible non-motor symptoms in ALS patients. Together with the classical motor symptoms, ALS patients may exhibit some non-motor symptoms, with varying prevalence and degrees of severity. This image has been designed using resources from Freepik.com.

CONFLICT OF INTEREST

The authors report no conflict of interest

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