Cognitive and Affective Symptoms of Amyotrophic Lateral Sclerosis: Clinical and Prognostic Aspects

Abstract

Amyotrophic Lateral Sclerosis is a neurodegenerative disease characterized by progressive muscular impairment resulting in death, mainly from respiratory failure. Interest has recently grown around the clinical and prognostic aspects of cognitive and psychiatric dysfunctions in Amyotrophic Lateral Sclerosis. In fact, about 50% of Amyotrophic Lateral Sclerosis individuals have cognitive impairment, which may affect ALS patients’ quality of life. In this review, we carried out a literature search focusing on neuropsychiatric symptoms of Amyotrophic Lateral Sclerosis and on their relationship with the prognostic aspects of the disease. We pointed out that cognitive impairment in Amyotrophic Lateral Sclerosis as well as psychiatric symptomatology could have a significant effect on disease global outcome, also impacting motor impairment progression. Further studies are needed to shed new light on the biological and neurophysiological basis of cognitive functions and psychological problems in Amyotrophic Lateral Sclerosis and on their impact on disease prognosis.

1. Introduction

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease hitting motor neurons and leading to the progressive weakness of voluntary muscles that causes death in a median time of 3 years. About two-thirds of sALS cases have spinal onset of the disease, where patients develop a focal muscle weakness starting from upper or lower limbs. In the remaining one-third, people show a bulbar disease onset mainly consisting of dysarthria or dysphagia [1]. The most frequent cause of death is from respiratory failure. Accordingly, it seems that the earlier respiratory regions are involved, the worse the general prognosis is. Other causes of death include infections, such as bronchopneumonia, acute renal failure, and heart failure, which are typical of the bulbar onset forms, while pulmonary embolism seems to be more frequent in spinal onset ALS [2]. Paulukonis et al. [3] included ALS as an immediate cause of death after the occurrence of organ failure consistent with ALS. The other organ failures, including pneumonia, respiratory failure, cardiac arrest, or acute renal failure, were related to the ALS state.

The most common form of disease presentation is the sporadic one (90% of cases) (sALS), while the remaining 10% of ALS cases are familial (fALS) [4,5]. From an epidemiological point of view, a review by Wolfson et al. [6] reported that, even though most of the studies were carried out in Europe and North America, there was a significant variation in prevalence and incidence of ALS across the world. Some genes, such as SOD1, FUS/TLS, TARDBP, SEXT, c9orf72, and TDP-43, have been implicated in the etiopathogenesis of the disease [7].

Renewed interest has recently grown around cognitive impairment in ALS as well as the reciprocal relationship between cognitive decline and motor symptoms of the disease [8,9]. In fact, the impairment of cognitive ability may even influence health choices, thus leading to questions about the validity of consent or dissension of ALS individuals in later stages of the disease [10]. Meanwhile, it has been reported that psychological problems in ALS individuals without dementia are highly heterogeneous and that thinning of the right cingulate and frontotemporal cortex are useful markers for neuropsychiatric alterations in ALS [11].

It is known that another neurodegenerative disease, frontotemporal dementia (FTD), shares genetic and pathological features with ALS. In this framework, it was pointed out that about 10–15% of ALS subjects meet the criteria for FTD diagnosis, too [12]. Accordingly, FTD is often characterized by progressive cognitive and behavioral impairment, a low disease insight, and physical deterioration [13]. What is more, TDP-43 and FUS inclusions have been found to be common genetic markers for both ALS and FTD [14,15]. Among proteins, hyperphosphorylated tau depositions in the astrocytes of the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala, and basal ganglia seem to play a significant role in cognitive impairment in ALS [16].

Another neurodegenerative disease, part of the motor neuron diseases, Multiple System Atrophy, shares motor and cognitive deterioration with ALS, while psychiatric symptoms are generally not subject to significant worsening [17]. A study comparing neuropsychiatric burden across neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, Cerebrovascular Disease, ALS, and FTD highlighted a greater severity of neuropsychiatric symptoms among FTD patients compared to the others [18].

According to Strong et al. [19], ALS with cognitive impairment is diagnosed by the presence of both executive impairment, defined as impaired verbal fluency, and two non-overlapping measures, including social cognition and language impairment, which could include alterations in pragmatic functions. In addition, ALS with frontotemporal dementia (ALS-FTD) is diagnosed by the progressive deterioration of behavior and cognition, the presence of behavioral/cognitive symptoms also with the loss of insight or psychotic symptoms, and language impairment meeting criteria for semantic dementia. In terms of prevalence, Liscic and colleagues [20] performed an accurate analysis of genetic overlaps between ALS and FTD (Figure 1), pointing out at least 11 genes shared across the two disorders. Meanwhile, Devenney et al. [21] gave some insights into the prevalence of cognitive and behavioral alterations among ALS individuals, including mood, sleep quality, eating habits, and abnormal and repetitive behaviors (Figure 2).

Globally, ALS could be considered a multisystemic disease, where motor impairment overlaps with executive dysfunctions, impairments in verbal fluency, behavior, pragmatics, social cognition [22], altered responsiveness to emotional stimuli, emotional memory, and alexithymia [23]. In this framework, new biofluid biomarkers have been improving diagnostic accuracy and the identification of patients with faster progression rates of the disease [24].

The aim of this study is to review the existing literature on the neuropsychiatric aspects of ALS and to evaluate the possible link between these features and the clinical outcomes and prognosis of the disease. The cognitive and psychological aspects were investigated from the genetic, biological, and physiologic perspectives.

2. Materials and Methods

2.1. Inclusion and Exclusion Criteria

We focused on studies dealing with the neurobiological, genetic, physiological, clinical, and prognostic basis of cognitive and affective symptoms of ALS. We included the following: (1) based on the type of article, original research and reviews; (2) works written in English; and (3) studies dealing about neuropsychiatric aspects of ALS. We excluded works carried out on animal models.

2.2. Information Source and Search Strategy

To find the literature about cognitive and affective symptoms of ALS, a literature search was carried out mainly using the “PubMed” database from January to May 2025.

The search was performed using the following keyword terms: (1) ALS, (2) cognitive symptoms, (3) cognitive alterations, (4) depression, (5) anxiety, (6) affective symptoms, and (7) neuropsychiatric symptoms. The Boolean operators “AND” and “OR” were used to combine the key terms.

2.3. Study Selection and Quality Assessment

During the screening, the author assigned “yes” to studies fulfilling the above-mentioned criteria and “no” to those not fulfilling these criteria. “Not reported” was specified for studies reporting insufficient information for judgment. Moreover, randomized controlled trials were evaluated by means of the risk-of-bias criteria. Specifically, to prevent cultural bias, we avoided results generalization, while to prevent data bias, apart from employing reliable sources, we verified data quality and accuracy. Finally, by using the “Discrimination-Free Algorithm” model, which can generate an algorithm free of discrimination, we avoided algorithmic bias.

2.4. Data Collection Process and Data Items

The author assessed each paper for language suitability and subject matter relevance. Studies were also assessed for their appropriateness for inclusion and quality of methods.

3. Results

After an initial search, a total of 260 studies were identified. Articles not matching the above-mentioned characteristics were removed (n = 160), and the remaining 100 were considered for inclusion. Among them, 88 were assessed as eligible for inclusion, and 57 [15,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80] of them were finally included in the “Section 3” of the manuscript (Figure 3).

Results exposure is divided into three main sections. The first one reports the genetic, biological, and physiological aspects of cognitive and affective alterations in ALS, the second one points out the clinical implications, while the last part paves the way for prognostic implications.

3.1. Genetic Aspects

In this section, we analyzed five studies [15,25,26,27,28], three of which are better described [26,27,28] in

Table 1. Genetic, biological, and neurophysiological aspects of ALS in relation to neuropsychiatric symptoms.

Reference	Participants	Materials and Methods	Main Findings
Wicks et al. [26]	41 sALS individuals (M = 26, F = 15), 17 fALS subjects, and 35 controls (M = 22, F = 13, mean age = 51.86 ± 10.5 years). The fALS group was divided based on the presence (n = 7, M = 3, F = 4, mean age = 48.57 ± 9.7 years) or absence of the SOD1 mutation (n = 10, M = 5, F = 5, mean age = 54.30 ± 10.7 years)	ALS-FRSR was used to assess functional aspects of the disease (mean range = 38.34 ± 4.1–35.71 ± 4.5), while HADS was used for psychological evaluation. Neuropsychological assessment was made by the NART, RSPM, WCST, WVFT, KOLT, RMT, TROG, JLO, and VOSP, behavioral change by the FRSBE, and emotional change by the ELQ.	SOD1- fALS patients were significantly more impaired in executive functions than other ALS patients (p < 0.05). For expressive language, sALS and SOD1- fALS patients performed significantly worse than controls (p < 0.05). In terms of apathy, SOD1- and SOD+ fALS patients had higher scores on the measures of apathy and executive dysfunction than sALS, who, in turn, performed worse than controls (p < 0.05). SOD1+ fALS and sALS patients had higher levels of lability, as assessed by the ELQ (p < 0.01).
Dalla Bella et al. [27]	14 SOD1+ individuals (M = 7, F = 7, mean age = 54.78 ± 6.2 years) and 274 SOD1- patients (M = 142, F = 132, mean age = 61.21 ± 11.5 years)	Cognitive assessment was performed by the FBI and the ECB-ALS screen; all participants underwent genetic analysis of the main genes implicated in ALS.	SOD1+ patients had more affective symptoms than SOD1-. SOD+ had higher level of mental rigidity than SOD- ones.
Geronimo et al. [28]	25 ALS individuals (M = 17, F = 7, mean age = 58 years) and 15 HCs (M = 8, F = 6, mean age = 55.3 years)	All patients were analyzed for c9orf72 allele variants and underwent P300 BCI training procedure. For neuropsychological assessment, the ALS-CBS and ALSFRS-R (range: 0–45) were employed.	4 ALS patients had a variant of the gene linked to lower performance on the P300 BCI test.
Dimond et al. [29]	18 ALS patients (M = 11, F = 7, mean age = 57.3 ± 11.1 years) and 22 HCs (M = 10, F = 12, mean age = 55.0 ± 8.7 years)	Participants underwent neuropsychological and biological assessment, respectively, by the VFF, DSF, DSB, and DOM. For general functioning, they were assessed by the ALS-FRS-R (mean range = 38.0 ± 8.6–44.0 ± 2.7). Finally, for a neurobiological assessment, participants underwent MRI.	ALSci patients showed reduced ALS-FRS-R, VFF, and DOM if compared to ALSci and ALScc groups. Executive dysfunction correlated with both frontal and global network dysconnectivity together with diminished white matter integrity.
Kasper et al. [30]	72 ALS individuals (ALSci and ALScc) (M = 46, F = 26, mean age = 59.3 ± 9.93 years) and 65 HCs (M = 38, F = 27, mean age = 60.1 ± 10.44 years)	MoCA and FRSBE, respectively, assessed cognitive and behavioral alterations. ALS-FRS (range: 14–46) was employed to assess general functioning. DTI assessed microstructural white matter changes.	ALSci had WMC both in motor and extra-motor regions such as in the frontal lobe, while ALScc showed WMC predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. A positive correlation was found between executive functions, memory and behavioral performances, and fiber tract integrity in large association tracts (p < 0.05).
Ahmed et al. [31]	209 participants, 58 with bvFTD (M = 38, F = 20, mean age = 61.74 ± 8.32 years), 41 with ALS-FTD (M = 31, F = 10, mean age = 64.46 ± 8.25 years), 52 with ALS (M = 42, F = 10, mean age = 60.27 ± 10.73 years), and 58 HCs (M = 25, F = 33)	Imaging assessment was performed by MRI, neuropsychological assessment by the ACE-III, processing speed by the TMT-A, executive functions by the TMT B-A, and severity and nature of psychological symptoms by the CBI-R. Participants also underwent MRI evaluation. ALS severity was assessed by the ALS-FRS-R (range = 41–42).	Extensive atrophy in fronto-insular, cingulate, temporal, and motor cortices characterized both bvFTD and ALS–FTD patients, while pure-ALS patients showed frontoparietal atrophy, namely in the right insular and motor cortices, pons, and brainstem regions. In addition, ALS-FTD was associated with disproportionate temporal atrophy and widespread subcortical involvement. Both bvFTD and ALS–FTD were characterized by volume decrease in the frontal lobes. Bilateral motor cortex characterized ALS-FTD. bvFTD, ALS-FTD, and ALS-pure groups shared alterations in the anterior part of the amygdala. Volumetric reduction in the amygdala, striatum, and thalamus positively correlated with abnormal behavior, thus suggesting a distinct atrophy profile across the ALS–FTD spectrum.
Abrahams et al. [32]	11 ALSi individuals (M = 8, F = 3, mean age = 59.5 ± 11.5 years), 12 ALSu (M = 9, F = 3, mean age = 53.8 ± 10.3 years), and 12 HCs (M = 9, F = 3, mean age = 54.8 ± 12.9 years)	Intellectual abilities were assessed by the NART, executive functions by the WVFT, CFT, DFT, and WCST, memory by the PAL, RMT, and KOLT, and language functions by the CSCT, GNT, BLOT, VOSPB, and PDOD.	There is a correlation between extra-motor cerebral and cognitive changes in ALS. ALSi patients showed a reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibers, which correlated with executive and memory dysfunction. On the other hand, ALSu had less extensive white matter reductions.
Hinault et al. [33]	17 ALS individuals (M = 9, F = 8, mean age = 61.28 ± 9.57 years) and 30 HCs (M = 18, F = 12, mean age = 51.28 ± 21.73 years)	ToM was assessed by the ToM-15 task questionnaire, executive functions by the TMT, and gray matter volume by MRI. Functional assessment was made by mean of the ALS-FRS.	Cortical hypermetabolism in the right temporal gyrus and hypometabolism in the right angular gyrus and thalamus were associated with cognitive performance. In addition, gray volume reduction in inferior frontal gyrus correlated with cognitive alterations (p < 0.01).
Shen et al. [34]	4 groups were formed: ALScc (n = 27, M = 15, F = 12, mean age = 52.5 ± 10.8 years), ALSci (n = 17, M = 8, F = 9, mean age = 54.0 ± 8.3 years), ALS-FTD (n = 11, M = 8, F = 3, mean age = 60.0 ± 12.7 years), and HCs (n = 20, M = 7, F = 13, mean age = 55.3 ± 8.4 years)	Neuropsychological assessment was made by category and phonemic verbal fluency, Stroop color–word interference effect, Clock Drawing Test, paired associate word learning of the clinical memory test, episodic memory of the modified Wechsler memory scale, Symbol Digit Modalities Test, digit span of the Wechsler Adult Intelligence Scale, repetition, and copy subsets of the aphasia battery of Chinese and the frontal assessment battery. Depression and anxiety were assessed by the HDARS. ALS severity was assessed by the ALSFRS-R (range = 30–47). Patients were also administered an MRI.	ALS-FTD had more significant alterations in the left frontal and temporal lobe compared with the HCs, ALScc, and ALSci. In addition, for both GM and CBF abnormalities, a similar pattern emerged from comparisons of ALS-FTD vs. ALSci, ALS-FTD vs. ALScc, and particularly ALS-FTD vs. HCs (p < 0.05).
Consonni et al. [35]	27 ALScc (M = 11, F = 16, mean age = 58.3 ± 10.4 years), 21 ALSci (M = 10, F = 11, mean age = 58.8 ± 10.8 years), and 26 HCs (M = 10, F = 16, mean age = 56.8 ± 10.0 years)	Patients were administered neuropsychological tests consisting of the GDS, FBI, DEX, SET, RAVLT, digit span forward, digit span backward, Stroop test, object naming, auditory sentence comprehension, and position discrimination. Disability was assessed by means of the ALS-FRS (mean range = 38.6 ± 6.87–37.7 ± 5.68).	The main characteristics of cognitive and behavioral deficits are inferior frontal, temporal, cingular, and insular thinning. Language impairment is mainly correlated with left temporal pole and insular involvement (p < 0.05).
Goldstein et al. [36]	14 ALS individuals (M = 9, F = 5, mean age = 52.6 ± 11.6 years) and 8 HCs (M = 6, F = 2, mean age = 52.4 ± 7.2 years)	Cognitive functions were assessed by the Stroop and negative priming tasks; emotions were evaluated by the HADS; and MRIs assessed biological aspects of neuropsychiatric conditions.	ALS patients showed increased activation in the left middle temporal gyrus, left superior temporal gyrus, and left anterior cingulate gyrus and decreased activation in the left cingulate gyrus, left precentral gyrus, and left medial frontal gyrus. The same patients had impairments in inhibitory processes (p < 0.05).
Crespi et al. [37]	22 ALS individuals (M = 15, F = 7, mean age = 60.40 ± 10.08 years) and 55 HCs (M = 32, F = 23, mean age = 61.61 ± 7.46 years)	Functional impairment was assessed by the ALS-FRSR (mean value = 39.86 ± 9.01). Neuropsychological tests included the RAVLT; RCPM; digit span back ward, letter, and category fluency tests; CET; Stroop interference test; and WCST or WST, FBI, and NPI. Emotional assessment was made by the E-60-FT and biological aspects by MRI.	Positive correlation emerged between microstructural changes in occipital, temporo-limbic, and orbitofrontal regions in the right hemisphere on the one side and deficits in emotion recognition among sALS without dementia from the other. A significant decline of emotion recognition skills, namely in the identification of negative emotions, emerged in ALS patients compared to controls. This impairment seems to correlate with the alteration of WM integrity along the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus (p < 0.05).
Benbrika et al. [38]	28 ALS individuals (M = 15, F = 13, mean age = 61.28 ± 11.17 years) and 30 HCs (M = 16, F = 14, mean age = 57.30 ± 9.72 years)	Alexithymia was measured by means of the TAS-20. Neuropsychological assessment was made by the MDRS, HSCT, TMT, VF, and the NPI-Q. Participants also underwent MRI. Disease severity was assessed by the ALS-FRS-R (range = 27–48).	ALS individuals had more emotional processing impairment, especially difficulties in identifying emotions, than controls. A significant and negative correlation was found between emotional processing impairment and gray matter volume of the prefrontal cortex, right superior temporal pole, and parahippocampal gyri in ALS subjects (p = 0.005).
Pinkhardt et al. [39]	22 ALS individuals (M = 19, F = 3, mean age = 58 ± 9 years) and 22 HCs (M = 17, F = 5, mean age = 59 ± 11 years)	Amygdala volume was measured by MRI; neuropsychological assessment was performed by the RFT, the 5-PFT, SDMT, WCST (PC version), and Doors Test; and depressive symptoms by the BDI. ALS severity was assessed by the ALS-FRS (mean range 20–40).	Alterations in amygdala volume correlated with affective symptoms in ALS. The total amygdala volumes, both as the absolute value and corrected for brain size, were lower in the ALS patients (p = 0.08).
Ratti et al. [40]	12 ALS individuals (M = 7, F = 5, mean age = 57.1 ± 10.7 years), 10 ALS-FTD subjects (M = 4, F = 6, mean age = 61.3 ± 8.8 years), and 115 HCs (M = 36, F = 79, mean age = 69.5 ± 7.4 years)	Cognitive and behavioral assessment was made by means of the MMSE and NPI-Q. ALS severity was assessed by the ALS-FRS (mean range = 37.6 ± 3.9–35.6 ± 4.7). Participants were also assessed by MRI.	ALS-FTD showed more precentral gyrus, prefrontal, and temporal regions atrophy than ALS ones, with severity of cognitive–behavioral symptoms in ALS-FTD correlating with regional prefrontal atrophy. In ALS-FTD, executive dysfunction, apathy, and disinhibition, respectively, correlated with dlPFC, ACC, dmPFC, and OFC atrophy (p < 0.10).
Hu et al. [42]	21 ALSci (M = 11, F = 10, mean age = 46.72 ± 5.42 years), 21 ALScc (M = 13, F = 8, mean age = 50.28 ± 9.04 years), and 21 HCs (M = 14, F = 7, mean age = 50.14 ± 8.77 years)	ALS severity was evaluated by the ALS-FRS-R (mean range = 41.86 ± 4.39–41.81 ± 4.17). Neuropsychological assessment was made by the ACE-R. Neurophysiological evaluation was made by MRI, which assessed the amplitude of regional homogeneity (ReHo).	ALSci had increased ReHo in the bilateral IPLs, precuneus, and inferior cerebellar areas, while the ALScc in the left IPL and left inferior cerebellar area. Both ALScc and ALSci had decreased ReHo in bilateral sensorimotor cortices. There was a negative correlation between the ReHo values in the right cerebellar area and the ACE-R total scores in all ALS patients. Functional coherence alterations in the right inferior cerebellar areas could correlate with ALS cognitive impairment (p < 0.05).
Santhosh et al. [44]	12 ALS patients (M = 9, F = 3, mean age = 46.75 years) divided into clear and unclear speech and 12 HCs (M = 10; F = 2)	EEG was used to assess planning capacity.	Individuals with unclear speech showed more reduction in planning a movement task than others with clear speech. Reduction in planning was related to hypofunction of prefrontal cortex. In addition, a relationship between speech impairment and cognitive deficits in patients with ALS was pointed out (p < 0.0001).
Volpato et al. [46]	15 ALS patients (M = 10, F = 5, mean age = 64.94 ± 14.33 years) and 15 HCs (M = 6, F = 9, mean age = 57.35 ± 8.60 years)	Functional assessment was made with the mean of the ALS-FRS (mean value = 28.66 ± 9.29). Neuropsychological assessment was made by the MoCA, RCPM, Aachener Aphasie Test, Rivermead Behavioral Memory Test, and WCST-M. Selective attention was analyzed by the ERPs paradigm. EEG signals were performed for all patients.	Compared to controls, ALS patients showed reduced amplitudes and delayed latencies. ALS subjects showed reduced neural processing efficiency which, in turn, led to defects in attentive functions (p < 0.05).
Kobeleva et al. [47]	22 ALS (M = 12, F = 10, mean age = 62.64 ± 9.06) subjects and 21 HCs (M = 11, F = 10, mean age = 63.45 ± 8.15 years)	Functional evaluation was made with the mean of the ALSFRS-R (mean value = 37.60 ± 4.97). Neuropsychological assessment was made by the ECAS. MRI was used for functional imaging.	Working memory performances were associated with more brain activity in frontotemporal and parietal regions among ALS individuals than in controls (p < 0.05).
Palmieri et al. [48]	24 (M = 14, F = 10, mean age = 61.6 ± 9.5 years) ALS individuals without dementia and 27 healthy controls (M = 13, F = 14, mean age = 61.0 ± 9.6 years)	Neuropsychological assessment was made by means of the PVFT, SVFT, TMT A/B, PMT, DSFB, BNT, MMSE, RCPM, and NPCB. Numerical abilities were assessed in terms of number comprehension (including tasks of Parity Judgments, Number Comparison, Judgment on Analog Number Scale, and transcoding from Arabic Numerals to Tokens), numerical transcoding (including tasks of transcoding between Written Number Words and Arabic Numerals), and calculation skills and arithmetic principles (including Arithmetic Facts, Arithmetic Rules, Multiplication Multiple Choice, Mental Calculation, and Approximation and Arithmetic Principles). Disease severity was assessed by the ALSFRS-R (mean value = 40.4 ± 5.1).	ALS patients had specific, previously unreported arithmetical deficits that could justify the damage to the cortico-subcortical circuits involved in some specific aspects of ALS (p < 0.05).
Fomina et al. [49]	10 ALS individuals (mean age 51.5 ± 11.7 years) and 10 HCs (mean age 61.4 ± 6.4 years)	Participants were assessed for EEG correlates of self-referential thinking.	ALS individuals had significantly altered bandpower in the medial prefrontal cortex when compared to HCs (p < 0.05).
Aho-Özhan et al. [50]	30 ALS individuals (M = 14, F = 16, mean age = 60 ± 10 years) and 29 HCs (M = 21, F = 8, mean age = 61 ± 8 years)	Functional assessment was made by the ALS-FRS (range = 0–48) while participants underwent fRMI study. Neuropsychological assessment was made by the MMSE, BDI, MWT-B, RFT, 5-PFT, and SDMT.	ALS individuals showed positive emotions and social interactions to compensate for the negative effects of the disease. In addition, they recognized disgust and fear less accurately than HCs, and, at fMRI, had reduced brain activity in areas involved in processing of negative emotions. Again, for sad stimuli, increased brain activity was seen in areas associated with social emotions in right inferior frontal gyrus and reduced activity in hippocampus bilaterally. Intriguingly, a positive correlation was found between inferior frontal gyrus activity for sad faces and number of social contacts of ALS patients (p < 0.05).

Abbreviations: 5-PFT: 5-Point Fluency Test; ACC: anterior cingulate cortex; ACE-III: Addenbrooke’s Cognitive Examination, III Edition; ACE-R: Addenbrooke’s Cognitive Examination Revised; ALS-CBS: ALS-Cognitive–Behavioral Screen; ALScc: ALS cognitive competent; ALSci: ALS cognitive impaired; ALS-FRS-R: ALS Functional Rating Scale Revised; ALSFRS-R: ALS Functional Rating Scale–Revised; ALS-FTD: ALS and frontotemporal dementia; ALSi: ALS patients with cognitive impairment; ALSu: ALS patients without cognitive impairment; BCI: brain–computer interface; BDI: Beck Depression Inventory; BLOT: Benton Line Orientation Test; BNT: Boston Naming Test; ì; CBF: cerebral blood flow; CBI-R: revised Cambridge Behavioral Inventory; CET: Cognitive Estimation Task; CFT: category fluency test; CSCT: Computerized Sentence Completion Test; DEX: Dysexecutive Questionnaire; DFT: Design Fluency Test; dlPFC: dorsolateral prefrontal cortex; dmPFC: dorsomedial prefrontal cortex; DOM: digit ordering maximal span; DSB: digit span backward; DSF: digit span forward; DTI: Diffusion Tensor Imaging; E-60-FT: Ekman 60 Facets Test; ECAS: Edinburgh Behavioral and Cognitive ALS Screen; ECB-ALS: Edinburgh Cognitive and Behavior ALS screen; EEG: Electroencephalogram; ELQ: Emotional Lability Questionnaire; ERPs: event-related potentials; fALS: familiar ALS; FBI: Frontal Behavior Inventory; FRSBE: Frontal Systems Behavior Scale; GDS: Geriatric Depression Scale; GM: gray matter; GNT: Graded Naming Test; HADS: Hamilton Anxiety and Depression Scale; HCs: healthy controls; HDARS: Hamilton Depression and Anxiety Rating Scale; HSCT: Hayling Sentence Completion Test; IPLs: inferior parietal lobules; JLO: Judgment of Line Orientation; KOLT: Kendrick Object Learning Test; MDRS: Mattis dementia rating scale; MMSE: Mini Mental State Examination; MoCA: Montreal Cognitive Assessment; MRI: magnetic resonance imaging; MWT-B: Mehrfachwahl-Wortschatz-Intelligenz test; NART: National Adult Reading Test; NPCB: Number Processing and Calculation Battery; NPI: neuropsychiatric inventory; NPI-Q: Neuropsychiatric inventory—questionnaire; OFC: orbitofrontal cortex; PAL: Paired Associate Learning; PDOD: Position Discrimination and Object Decision; PMT: Prose Memory Test; PVFT: phonemic verbal fluency test; RAVLT: verbal immediate and delayed memory; RCPM: Raven’s colored progressive matrices; ReHo: regional homogeneity; RFT: Regensburg Fluency Test; RMT: Recognition Memory Test; RSPM: Raven’s Standard Progressive Matrices; sALS: sporadic ALS; SDMT: Symbol Digit Modalities Test; SET: Story-based Empathy Task; SOD1-: individuals without superoxide dismutase 1 variant; SOD1+: individuals with superoxide dismutase 1 variant; SVFT: Semantic Verbal Fluency Test; TAS-20: 20-items Toronto Alexithymia Scale; TMT B-A: trial making test time difference; TMT-A: trial making test—part A; ToM: theory of mind; TROG: Test for the Reception of Grammar; VF: verbal fluency; VOSP: Visual Object and Space Perception Battery; VOSPB: Visual Object and Space Perception Battery; WCST: Wisconsin Card Sorting Test; WMC: white matter changes; WST: Weigl’s Sorting Test; and WVFT: Written Verbal Fluency Test.

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3.1.1. Cognitive Impairment

When investigating a possible common genetic basis for ALS and other neurodegenerative diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Lewy Body Disease (LBD), two loci, TMEM175 and HLA, seem to be shared across these diseases [25]. In this framework, Wick et al. [26] pointed out that cognitive dysfunctions in ALS may have a genetic basis. For SOD1, it was reported that non-SOD1 fALS patients (SOD1-) present a loss in written verbal fluency and higher levels of executive problems when compared to the controls and those with an SOD1 mutation (SOD1+). Moreover, it seems that sALS and SOD- fALS patients had worse expressive language abilities than the controls. In addition, SOD+ fALS individuals generally have higher levels of mental rigidity than SOD- subjects [27]. Other genes implicated in executive dysfunction in ALS are TDP-43, whose accumulations are supposed to contribute to motor and cognitive impairment in ALS, and c9orf72, linked with frontotemporal dementia (FTD) [15,28].

3.1.2. Psychological Impairment

It is known that affective symptoms in ALS show significant variability, potentially related to genetic factors [26]. Della Bella et al. [27] suggested that SOD1+ ALS subjects often have more psychological problems than those without the variant. Accordingly, SOD+ fALS and sALS individuals reported significantly high levels of emotional lability [26]. Also, the presence of the APOE ε/2 allele was correlated with affective impairment in ALS [15].

3.2. Biological Aspects

In this section, we analyzed 12 studies [29,30,31,32,33,34,35,36,37,38,39,40], whose characteristics are summarized in Table 1.

3.2.1. Cognitive Impairment

From a biological point of view, executive dysfunction in ALS has been related to abnormal structural connectivity and white matter (WM) integrity, as shown by Dimond et al. [29] who reported a frontal and global network dysconnectivity together with diminished white matter integrity in ALS individuals with executive dysfunction.

In this framework, it has been reported that ALS individuals with executive dysfunctions and memory disorders have alterations of WM in both motor and extra-motor regions such as the frontal lobe, while ALS patients without these cognitive alterations mainly show impairment in motor regions, the corticospinal tract, and the body of corpus callosum [30]. Ahmed and colleagues highlighted that thalamic atrophy as well as the volume reduction in globus pallidus, caudate nucleus, putamen, and thalamus are associated with poorer executive functions in ALS [31].

Abnormalities in WM volume in frontotemporal associative fibers have been found in ALS individuals not only with executive dysfunctions but also memory, attention, language, visuospatial impairments, and psychological abnormalities [30,32]. Meanwhile, gray matter volume reduction in the inferior frontal gyrus as well as hypometabolism in this area have been related to theory of mind (TOM), including episodic memory, executive functions, and a verbal fluency task [33].

Similarly, Shen and colleagues showed that different levels of gray matter alterations in the left frontal and temporal lobes and the reduction in cerebral blood flow correlated with the cognitive status of ALS patients, including episodic memory and language abilities as well as psychological alterations [34].

Intriguingly, while frontoparietal involvement seems to indicate a disease-specific pattern of degeneration detectable in all ALS subjects, thinning of the inferior frontal, temporal, cingulate, and insular cortices has been associated with cognitive and psychological impairments in ALS. Specifically, the left temporal pole and insular involvement positively correlated with language impairment in ALS [35].

Impairment in attentional functions in ALS has been supposed to rely on altered patterns of cortical activation, as shown by Goldstein and colleagues, who pointed out some defects in inhibitory processes among ALS participants, a hyperactivation of the left middle and temporal gyrus, left superior temporal gyrus, and left anterior cingulate gyrus, and hypoactivation of the left cingulate gyrus, left precentral gyrus, and left medial frontal gyrus [36].

3.2.2. Psychological Impairment

WM alterations could be linked to emotional responses in ALS, as reported in a study analyzing motor regions, neuropsychological aspects, emotional recognition, and biological correlates in a group of ALS individuals and healthy controls. Specifically, it was highlighted that microstructural changes in occipital, temporo-limbic, and orbitofrontal regions in the right hemisphere positively correlated with defects in emotion recognition among sporadic ALS individuals without dementia. Moreover, alterations in WM integrity in the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus have been related to negative emotions in ALS, such as fear, disgust, anger, and sadness [37]. Consistent with these findings, Benbrika et al. [38] showed that the lower the gray matter volume of the prefrontal cortex, right superior temporal pole, and parahippocampal gyri in ALS subjects was, the greater the emotional processing impairment was. Interestingly, amygdala size, and specifically its volume reduction, has been correlated with the psychopathological impact and affective symptoms of the disease, especially in later stages [39]. In support of this evidence, Ratti and colleagues pointed out that ALS individuals with FTD had diffuse atrophy involving the precentral gyrus and prefrontal and temporal regions when compared with others without FTD. Particularly, executive dysfunction and psychiatric symptoms, including apathy and disinhibition, respectively, correlated with dorsolateral prefrontal cortex, dorsomedial prefrontal, anterior cingulate cortical, and orbitofrontal cortex atrophy [40]. In addition, when ALS is associated with frontotemporal dementia and accompanied by behavioral problems, extensive atrophy in fronto-insular, cingulate, temporal, and motor cortices has been implicated [31].

3.3. Neurophysiological Aspects

In this section, we analyzed 10 studies [41,42,43,44,45,46,47,48,49,50], 8 of which are given in better detail [41,42,44,46,47,48,49,50] in Table 1.

3.3.1. Cognitive Impairment

It has been shown that ALS individuals with executive dysfunctions have less activation in frontal brain areas as well as less neuronal activity than those without this cognitive impairment. Moreover, hypoactivation in the left inferior frontal gyrus was noted in low-cognitive-performing ALS subjects when compared to the controls [41]. A study provided evidence for MRI alterations in terms of brain functional coherence in ALS by finding that functional coherence alterations in the right inferior cerebellar areas could correlate with ALS cognitive impairment. Particularly, ALS patients with cognitive impairment presented increased brain activity in the inferior parietal locus (IPL), precuneus, and inferior cerebellar areas, while those without cognitive problems showed so in the left IPL and left inferior cerebellar area. Meanwhile, bilateral sensorimotor cortices were hypoactive in both groups [42]. When investigating the functional correlates of altered decision-making in ALS, in terms of neural hub networks, medial prefrontal areas were found to present lower hub function in ALS individuals compared to healthy controls [43].

From an electrophysiological point of view, when studied for the ability to plan a movement task and assessed by electroencephalogram (EEG) monitoring, ALS patients with unclear speech present a significant reduction in planning movement tasks, which are related to the hypofunction of the prefrontal cortex areas; these difficulties are not registered in patients with clear speech [44]. In addition, alterations in verbal fluency are associated with hypometabolism in the right inferior frontal gyrus, superior temporal gyrus, and anterior insula, while impairment in confrontation naming is positively correlated with hypometabolism in the left middle frontal gyrus and left cuneus [45].

When analyzing attentional and memory defects, and based on auditory event-related potential (ERP) revelations, ALS subjects have shown defects in attentive functions due to a reduced neural processing efficiency when compared to healthy controls [46], while Kobeleva et al. [47] pointed out more brain activity in frontotemporal and parietal regions among ALS individuals than in the controls during working memory performances.

Regarding difficulties in numerical capacity in ALS, it has also been suggested that arithmetical deficits could be justified by the damage to the cortico-subcortical circuits [48].

3.3.2. Psychological Impairment

In addition, ALS patients, when compared to healthy controls, have shown some impairments in self-referential thinking. Reason seems to rely on the serotonergic system and default mode network (DMN) abnormalities, as reported by Fomina and colleagues, who examined ALS patients for electroencephalography (EEG) correlates of self-referential thinking and found that, in these subjects, self-referential thinking was significantly altered in terms of bandpower in the medial prefrontal cortex compared to healthy subjects [49]. Increased brain activity, detected in areas associated with social emotions in the right inferior frontal gyrus and reduced activity in the hippocampus bilaterally, were detected for sad stimuli in ALS. Curiously, a positive correlation was found between inferior frontal gyrus activity for sad faces and the number of social contacts of ALS patients [50]. ALS patients with psychological impairments showed less brain activity in the right superior orbital gyrus than those without these problems [41].

Globally, brain network analyses revealed that the fronto-striatal, frontotemporal, and frontoparietal systems, Papez circuit, and the fronto-temporo-parieto-cerebellar circuit may play an important role for psychological disorders in ALS [15] (Table 1).

3.4. Clinical Implications

In this section, we analyzed 15 studies [51,52,53,54,55,56,57,58,59,60,61,62,63,64], 12 of which described better [53,54,55,56,57,58,59,60,61,62,63,64] in

Table 2. Clinical implications of neuropsychiatric symptoms in ALS.

Reference	Participants	Materials and Methods	Main Findings
Pérez et al. [53]	42 ALS individuals (M = 27, F = 15, mean age = 61.5 ± 11.8 years) and 42 HCs (mean age = 61.5 ± 11.8 years).	BFRT and the Spanish Version of NART were used for immediate and delayed recognition, specific problems in facial recognition, and premorbid intelligence, while the ALS-FRS (mean value = 35.98 ± 8.38) was employed for ALS symptoms severity.	ALS subjects had lower scores in immediate and delayed discriminability. Motor problems and behavior alterations were, respectively, associated with delayed recognition and delayed discriminability (p < 0.05).
Strong et al. [54]	13 ALS individuals (M = 11, F = 2, age range = 39.9–74.0 years, mean age = 54.2 ± 9.6 years) were examined at baseline and after 6 months follow-up.	Neuropsychological functions were assessed by the WCST, ConTrig, RAVLT, RMT, and MFVPT, while depression was assessed by the GDS. Language was assessed based on the standardized protocol from BDAE. Speech was evaluated in terms of respiratory laryngeal, resonatory, and oral articulatory. Participants also underwent MR 1H spectroscopy.	ALS patients showed mild impairment in word generation, anomia on a confrontation naming test, recognition memory (faces), and motor-free visual perception, while bulbar-onset individuals in working memory, problem-solving/cognitive flexibility, visual perception, and recognition memory for words and faces (p < 0.001).
Schreiber et al. [55]	52 ALS individuals, 37 with spinal onset (M = 28, F = 9, mean age = 56.72 ± 11.43 years) of the disease and 15 with bulbar onset (M = 9, F = 6, mean age = 60.80 ± 11.56 years).	ALS progression was evaluated by the Norris scale and vital capacity measurement. Neuropsychological testing was performed for executive functions by the CWIT, COWAT, and 5-PFT WCST, memory by the DS of the WAIS, RFT, AVLT, and attentional control by the alertness and reaction time.	ALS patients showed executive dysfunctions, particularly in non-verbal and verbal fluency, concept formation, phasic and tonic alertness, and divided attention. Intriguingly, cognitive deficits appeared earlier and did not decline with time. Bulbar-onset ALS patients had poorer performances in verbal, non-verbal fluency, and interference tests than spinal onset ones. It was concluded that there is a relationship between morphological deficits outside the primary motor system and cognitive dysfunctions, specifically for the nature and evolution of the disease (p < 0.01).
Manera et al. [56]	609 ALS individuals (M = 346; F = 263, mean age at onset = 69 years; age range at onset = 60–74 years), with bulbar and Sbil and lateralized onset of the disease, namely Sri and Sle.	Neuropsychological assessment consisted of the MMSE, FAB, TMT A/B, digit span forward and backward (digit span FW/digit span BW), FAS, CAT, RAVLT, BSRT, ROCFT, WCST, and CPM47. Based on cognitive status, patients were divided into ALS-FTD, ALSbi, ALSci, ALScbi, and ALS-CN.	Patients with bulbar and bilateral spinal onset of the disease reported lower neuropsychological performances than those with lateralized onset. Bulbar and Sbil patients were characterized by poorer cognitive performances in neuropsychological tests when compared to Sri and Sle. ROCFT scores were higher in Sri patients when compared to bulbar/Sbil patients, while RAVLT and BRST were significantly higher in Sle (p < 0.05).
Stukovnik et al. [57]	22 ALS individuals (10 with bulbar onset and 12 with spinal onset, M = 14, F = 8, age range = 51.7–64.0 years) were compared to 21 HCs (M = 10, F = 11, age range = 49.5–63.0 years).	Disease progression was assessed by the ALS-FRS (range = 26–33.7). Neuropsychological assessment was based on the VF, HDI, SCWIT, TOL, CTMT, and MST.	ALS patients presented significant patterns of cognitive dysfunctions, with MST being an accurate indicator of cognitive impairments (p < 0.05).
Schrempf et al. [58]	214 ALS individuals (M = 130, F = 84, mean age = 60.1 ± 12.5 years) with and without behavioral problems.	Cognitive assessment was made with the German version of the ECAS. Quality of life was evaluated by the SEIQoL-DW and ACSA. Depressive symptoms were evaluated by the ADI-12. ALS severity was assessed by the ALS-FRS-R (mean range = 37 ± 11.0–41.0 ± 9.0).	ALS subjects with behavioral impairment had poorer psychological well-being than patients without behavioral alterations (p = 0.05). Cognitive aspects, if compared to behavioral manifestations of ALS, have a limited impact on everyday functioning of ALS individuals.
Wicks and Frost. [59]	247 ALS individuals (M = 139, F = 108, mean age = 53.0 ± 10.2 years) and 87 caregivers.	Participants underwent a two-part online survey; physical and psychological aspects of ALS were assessed with an ALS quiz.	ALS patients usually receive more information from clinicians about their physical symptoms than psychological and cognitive ones, even if they desire to be informed about cognitive symptoms (p < 0.01).
Flaherty-Craig et al. [60]	25 ALS individuals (M = 15, F = 10, mean age = 62.56 ± 11.72 years) with brief examination impairment and 13 HCs (M = 8, F = 5, mean age = 62.00 ± 10.44 years).	Neuropsychological assessment was made with Guilford’s Structure of Intellect model, WAIS-R3, and facial recognition tasks. Mood was evaluated by the POMS. Brief examination was made by the PSFTS. Finally, cognitive anosognosia ratios were calculated to examine the degree of “unawareness of cognitive deficit”. ALS-FRS-R (mean range = 34.48 ± 8.42–32.00 ± 6.94) assessed ALS severity.	Cognitively impaired ALS patients presented lower levels of insight of cognitive abilities than HCs (p < 0.05).
Zimmerman et al. [61]	13 ALS patients (M = 5, F = 8) and 12 HCs.	Affective and cognitive symptoms were, respectively, assessed by the GDS and the MMSE. Participants also underwent emotional recognition tasks.	ALS individuals, especially those with bulbar onset, had more defects in emotional recognition than HCs. These defects could be present with or independent from depressive and dementia symptoms (p < 0.05).
Moretta et al. [62]	55 ALS patients (M = 36, F = 19, mean age = 60.3 ± 12.5 years) and 41 caregivers (M = 17, F = 24, mean age = 56.5  ±  10.7 years).	Cognitive assessment was made by the MMSE, ECAS, WCST, Stroop test, phonemic and semantic fluency tests, DSFT, RAVLT, ROCFTDR, RCPM, and CDT. From a cognitive point of view, patients were classified into ALS-CN, ALSbi, ALSci, and ALScbi. Depression and anxiety were assessed by the HDS and BAI. HRV was measured by the ECG. Interoception was assessed by the SAQ, MAIA, alexithymia by the TAS-20, and apathy by the AES. ALSFRS-R was employed for ALS severity (mean range = 34.5 ± 6.8).	ALS patients had difficulties in interoceptive sensitivity, describing feelings and in localizing pain (p < 0.05).
Lulé et al. [63]	12 ALS individuals with spinal onset of disease (M = 10, F = 2, mean age = 59 years) and 18 HCs (M = 11, F = 9, mean age = 54 years).	Psychological assessment consisted of the BDI, MMSE, a German version of the WMS, RFT, 5-PFT, WCST, SDMT, and Doors Test. Physiological assessment included heart rate, startle response, galvanic skin response, and eye movements.	When compared to healthy controls, ALS individuals had lower physiological responses to extreme emotional stimuli and more positive emotional judgments than HCs, independent from depression or frontal lobe dysfunction (p < 0.05).
Semler et al. [64]	12 patients with bvFTD (M = 6, F = 6, age range = 50–81 years), 22 ALS individuals (M = 13, F = 9, age range = 42–75 years), and 19 neurological HCs (M = 10, F = 9, age range = 46–80 years).	Functional assessment was made by means of the ALS-FRS (mean range = 18–46). Anxiety and depression were assessed with the HADS and GDS, while behavioral assessment was made with the ECAS. Morality and religiosity were evaluated by the MCT, EPQ, and IIR, while cognition was assessed with the CERAD-plus.	bvFTD and ALS patients shared a moral position with the HCs but showed a lower judgment consistency in the MCT. MCT performance was independent from general cognitive functioning, moral orientation, and religiosity.

Abbreviations: 5-PFT: 5 point Fluency Test; AES: Apathy Evaluation Scale; ALSbi: ALS patients with behavioral impairment; ALScbi: ALS patients with cognitive and behavioral impairment; ALSci: ALS patient with cognitive impairment; ALS-CN: cognitively normal ALS patients; ALS-FRS: ALS- Functional Rating Scale; ALS-FTD: ALS patients with frontotemporal dementia; AVLT: auditory verbal learning test; BAI: Beck anxiety inventory; BDAE: Boston Diagnostic Aphasia Examination; BDI: Beck Depression Inventory; BFRT: Benton’s face recognition test; BSRT: Babcock Story Recall Test; bvFTD: behavioral frontotemporal dementia; CAT: category fluency test; CDT: Clock Drawing Test; CERAD-plus: Consortium to Establish a Registry for Alzheimer’s Disease; ConTrig: Consonant Trigrams Test; COWAT: Controlled Word Association Test; CPM47: Raven’s colored progressive matrices; CTMT: Comprehensive Trail Making Test; CWIT: Color Word Interference Test; DS: digit span; DSFT: digit span forward test; ECAS: Edinburgh Behavioral and Cognitive ALS Screen; ECG: electrocardiogram; EPQ: Ethics Position Questionnaire; FAB: frontal assessment battery; FAS: letter fluency test; GDS: Geriatric Depression Scale; HADS: Hamilton Anxiety and Depression Scale; HCs: healthy controls; HDI: Hamilton Depression Inventory; HDS: Hamilton Depressive Scale; HRV: heart rate variability; IIR: Idler Index of Religiosity; MAIA: Multidimensional Assessment of Interoceptive Awareness; MCT: Moral Competence Test; MFVPT: Motor-Free Visual Perception Test; MMSE: Mini Mental State Examination; MR 1HH: magnetic resonance; MST: Medication Scheduling Task; NART: National Adult Reading Test; POMS: Profile of Mood States; PSFTS: Penn State Brief Exam of Frontal and Temporal Dysfunction Syndromes; RAVLT: Rey Auditory Verbal Learning Test; RCPM: Raven’s colored progressive matrices; RFT: Recurring Figure Test; RMT: Recognition Memory Test; ROCFT: Rey–Osterrieth complex figure test; ROCFTDR: Rey–Osterrieth complex figure test different recall; SAQ: Self-Awareness Questionnaire; S_bil: bilateral spinal onset; SCWIT: Stroop Color Word Interference Test; SDMT: Symbol Digit Modalities Test; S_le: left onset; S_ri: right onset; TAS-20: 20-items Toronto; TMT A/B: trial making test A/B; TOL: Tower of London; VF: verbal fluency; WAIS: Wechsler Adult Intelligence Scale; WAIS-R3: Wechsler Adult Intelligence Scale–Revised 3; WCST: Wisconsin Card Sorting Test; and WMS: Wechsler memory scale.

.

3.4.1. Cognitive Impairment

In terms of prevalence, a study by Chowdhury et al. [51]) reported a prevalence of 24% of ALS individuals with executive dysfunction and about 10% of them with mild cognitive impairment. Among neuropsychological tests, to evaluate cognitive impairment in ALS, the frontal assessment battery, as well as the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and the ALS Cognitive–Behavioral Screen (ALS-CBS) are the most useful tools to detect cognitive functions and behavior in ALS [52].

Beeldmann and colleagues delineated a peculiar neuropsychological profile of ALS subjects by reporting social cognition, verbal memory, verbal fluency, and executive functions as the main altered cognitive domains among ALS individuals with psychological disorders [52].

In keeping with these findings, a study examining ALS individuals and healthy controls for neuropsychological functions, such as visuospatial abilities, immediate and delayed recognition, specific problems in facial recognition, and premorbid intelligence, reported that ALS individuals had lower scores in immediate and delayed discrimination [53].

Regarding language abilities, it has been reported that, when compared with healthy controls, ALS individuals have more mild impairments in word generation, such as anomia on a confrontation naming test, recognition memory (faces), and motor-free visual perception. In addition, those with a bulbar onset of the disease presented worse performances in working memory, problem-solving/cognitive flexibility, visual perception, and recognition memory for words and faces, together with a more progressive cognitive impairment, even though language and speech abilities did not change significantly over time [54]. Similarly, Schreiber and colleagues pointed out more dysfunctions in the non-verbal and verbal fluency of ALS subjects with bulbar onset than those with a spinal onset [55].

When dealing with the correlation between motor and cognitive symptoms of ALS, it was found that motor problems were associated with delayed recognition abilities [53].

In this framework, Manera and colleagues deepened the relationship between motor and cognitive dysfunction in ALS, namely, executive function, memory, visuospatial function, and language, and highlighted that patients with bulbar and bilateral spinal onset of the disease had lower neuropsychological performances than those with lateralized onset, such as right-side or left-side spinal onset [56]. In keeping with this evidence, Schreiber et al. [55] investigated the relationship between cognitive functions, including executive functions, memory, and attentional control, in ALS and the presence of motor symptoms, finding that morphological deficits outside the primary motor system positively correlated with cognitive dysfunctions; in addition, these alterations seem to be specific to the nature and evolution of the disease. Intriguingly, cognitive deficits do not seem to progress in synchrony with motor decline but are distinctly slower. What is more, executive dysfunction symptoms seem to persist even when accounting for motor disabilities. In fact, when also considering motor impairment, ALS individuals present significant differences in cognitive dysfunctions [57].

3.4.2. Psychological Impairment

ALS is often associated with psychiatric symptoms such as depression, suicidal ideation, and daytime sleepiness [51]. In addition, Schrempf and colleagues suggested that poor psychological well-being, notably associated with ALS, may limit patients’ everyday functioning more than cognitive impairment [58].

Arguably, it seems that ALS patients usually receive more information from clinicians about their physical symptoms than psychological and cognitive ones, even though they would like to know about the risk of cognitive change or the psychological aspects of the disease, such as emotional lability [59]. Meanwhile, it has been reported that they have little insight into their compromised cognitive abilities. In fact, when examined for neuropsychological functions as well as for judgment and problem-solving, cognitively impaired ALS patients often present lower levels of insight into cognitive abilities than healthy controls [60].

In this framework, many studies reported difficulties in emotion recognition, also known as alexithymia, among ALS individuals. Zimmerman et al. [61] pointed out that ALS subjects, especially those with bulbar disease onset, showed more defects in emotional recognition than healthy controls regardless of depression or dementia symptoms. Additionally, Moretta et al. [62] reported that ALS individuals have difficulties in interoceptive sensitivity as well as in describing feelings and in localizing pain.

Contrasting evidence came from Lulè and colleagues, who suggested that ALS patients had lower responses to extreme emotional stimuli and showed more positive emotional judgments than controls [63]. Intriguingly, when examining morality and religiosity, ALS individuals as well as FTD subjects had similar positions towards morality, even though the latter showed a lower judgment consistency [64] (Table 2).

3.5. Prognostic Aspects

In this section, we reported 17 studies [12,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80], 14 of which are detailed better [65,66,67,68,69,70,71,74,75,76,77,78,79,80] in

Table 3. ALS neuropsychiatric alterations and prognostic implications.

Reference	Participants	Materials and Methods	Main Findings
Burke et al. [65]	317 ALS individuals (M = 162, F = 155, mean age = 63.00 ± 11.13 years) and 66 HCs (M = 30, F = 36, mean age = 61.39 ± 13.67 years).	Behavioral symptoms were assessed with the BBI, while neuropsychological assessment was made with the SCWT, BSAT, BDS, CF, PVF, LM, VPA, CVLT, ROCFT, and BNT. Participants were also evaluated for c9orf72 mutations. Disease severity was assessed by the ALSFRS-R (mean range = 35.17 ± 7.88).	In ALS subjects, c9orf72 mutation was associated with more aggressive and bizarre behaviors and less awareness of mistakes. The most frequently altered behaviors among ALS individuals were reduced concern for hygiene, irritability, new unusual habits, and increased apathy. Social cognitive performance was considered predictive of behavior change (p < 0.05).
Chiò et al. [66]	797 ALS individuals (M = 435, F = 362, mean age at onset = 65.5 ± 10.5 years) with different levels of cognitive and behavioral impairment (ALS-FTD, ALSci, ALSbi, ALScbi).	Neurobehavioral assessment was made by the MMSE, FSBS, WCST, TMT A/B, DSFB, LCFT, BNT, RAVLT, BSRT, ROCFT, RCPM, FAB, and ECAS. Cognitive status and motor severity impairment were, respectively, evaluated with the revised ALS–FTD Consensus Criteria, the King System, and the MiToS. ALS severity was assessed by the ALSFRS-R (mean range = 41.3 ± 5.7–39.0 ± 7.4).	According to King staging, ALS-FTD frequency progressively increased from stage 1 to 4; conversely, the frequency of ALSci, ALSbi, and ALScbi increased from stage 1 to 3. ALS-FTD was generally associated with bulbar involvement, while c9orf72 expansion correlated with more severe cognitive impairment. Bulbar involvement was associated with worse cognitive performance.
Wiesenfarth et al. [67]	51 ALS patients with C9orf72 mutation (M = 28, F = 23, mean age = 61.1 ± 9.1 years), 51 ALS individuals without C9orf72 mutation (M = 33, F = 18, mean age = 64.1 ± 10.7 years), and 51 HCs (M = 23, F = 28, mean age = 61.4 ± 7.4 years).	Participants underwent genetic tests for C9orf72 mutation. Cognitive testing was performed with the ECAS. Functional assessment was made by means of the ALS-FRS (range = 35–45). Neuroimaging assessment was performed by MRI.	ALS subjects had alterations in axonal structures of the white matter, especially in the corticospinal tracts and in fibers projecting to the frontal lobes. Compared with ALS individuals without C9orf72 mutation, those with C9orf72 mutation had lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus. A significant correlation was found between cognitive performances in ECAS and frontal association fibers, while a negative correlation was found between age of onset and gray matter volume (p < 0.05). Globally, white matter alterations and volume reductions in gray matter in ALS subjects with C9orf72 mutation were associated with more aggressive cognitive phenotypes.
Stojkovic et al. [68]	48 ALS individuals without dementia (M = 19, F = 29, mean age = 54.90 ± 12.40 years) and 37 HCs (M = 15, F = 22, mean age = 53.89 ± 11.56 years).	Psychological assessment was performed by the RPM, HDRS, AS, while cognitive evaluation by the MMSE, LFT, CFT, CANTAB, SSP, SWM, and SOC. ALS severity was assessed at baseline by the ALSFRS-R (mean value = 35.72 ± 6.91).	Executive dysfunctions, namely in verbal fluency, working memory and planning, and problem-solving performances predicted a worse outcome in terms of survival in ALS, increasing risk of death by three times (p < 0.01).
Bock et al. [69]	49 ALS individuals (M = 28, F = 21, mean age = 64.8 ± 11.1 years).	Participants were assessed for cognitive and affective symptoms, respectively, by the ALS-CBS, CNSLS, GDS, and MQOL-SIS. Disease severity was established by the ALSFRS-R (31.2 ± 11.9–35.7 ± 8.5).	Patients’ executive functions did not significantly change over the period of observation, while caregivers reported increased behavioral symptoms in that time of observation. Behavioral problems of patients, initially classified as normal, increased over time and were correlated with decline in forced vital capacity and ALS-FRS. Even though ALS cognitive symptoms generally remain stable for over 7 months, patients may develop caregiver behavioral symptoms over the same time (p < 0.05).
Castelnovo et al. [70]	29 ALS individuals (M = 19, F = 6, mean age = 61.56 ± 10.9 years) and 39 HCs (M = 20, F = 19, mean age = 64.17 ± 7.44 years).	Cognitive and behavioral assessment was performed by the MMSE, RAVLT, digit span forward, digit span backward, CET, WST, WCST, CPM, phonemic and semantic fluency tests, Italian battery for the assessment of aphasic disorders, BDI, ALS-FTD-Q (administered to patients’ caregivers), and TAP. In addition, patients were administered an MRI. Disease severity was assessed at baseline by the ALSFRS-R (mean value = 42.36 ± 4.02).	ALS patients had fronto-striatal and frontoparietal network impairments, as well as defects in frontal-executive functions. These network impairments progressed together with resting state functional connectivity changes in ALS patients. Specifically, middle frontal gyrus impairment seems to be related with frontotemporal lobar degeneration (p < 0.05).
Consonni et al. [71]	101 ALS patients (M = 48, F = 53, mean age = 61.30 ± 11.3 years).	Clinical staging was estimated by the KCSS and the MiToS. Neuropsychological status was assessed with the Italian version of the ECAS. Behavioral features were assessed by the FBI. CR was measured based on years of education, occupational attainment, amount of leisure activities, and bilingualism. ALS severity was assessed by the ALSFRS-R (mean range = 41.3 ± 4.5–39.5 ± 5.2).	CR could protect from cognitive and motor impairment in ALS. Specifically, CR was positively associated with executive functions, verbal fluency, and memory domains. A negative association was made between motor impairment and educational level and occupational attainment (p < 0.05).
De Marchi et al. [74]	318 ALS individuals, some of them with cognitive impairment (n = 112, M = 57, F = 55, mean age = 64.22 ± 9.93 years) and others without dementia (n = 206, M = 121, F = 85, mean age = 55.94 ± 11.56 years). Patients were also divided in ALS-FTD, ALSbi, ALSci, ALScbi, and ALS-CN.	Neuropsychological assessment was made by the FAB, MMSE, RCPM, CET, CDT, DST, SST, TMT A/B, AM, and NPI. ALS severity was assessed by the ALSFRS-R (mean range = 39.45 ± 5.79–38.42 ± 7.07).	Depression and cognitive impairment are frequent among ALS patients and are associated with lower survival (p < 0.06).
Rabkin et al. [75]	72 ALS individuals: 58 dying without LTMV (M = 31, F = 27, mean age = 65.3 ± 13.0) and 14 opting for LTMV (M = 7, F = 7, mean age = 51.4 ± 12.3 years).	Neuropsychological assessment was made by the PHQ, BDI, BHS, HSBI, SAHD, QOL, MPPSS, and VAS. ALS severity was assessed by the ALSFRS (mean range = 24.0 ± 8.0).	Results showed that patients did not opt for LTMV about desperation ignorance or inability to have clear ideas, but their choice underlined the desire to live in any way possible, at least for some time and within certain boundaries (p < 0.05).
Benbrika et al. [76]	43 ALS patients (M = 25, F = 18, mean age = 61 ± 11 years) and 28 HCs (M = 17, F = 11, mean age = 57.8 ± 8.9 years).	Affective symptoms were assessed by the BDI, STAI-Y, and MDRS. Cognitive functions were evaluated by theHSCT, LN sequencing, TMT, and a letter and categorical verbal fluency task, FET. ALS severity was assessed by the ALSFRS (mean range = 24.0 ± 8.0).	ALS individuals with cortical thinning showed impaired mental flexibility and significant depressive symptoms. At baseline, ALS individuals showed poor executive function and recognition of complex emotions from the eyes, as well as more anxious and depressive symptoms than HCs. In addition, ALS subjects had bilateral and precentral cortical region thinning. At follow-up, inhibition abilities had worsened, together with an involvement of motor and extra-motor areas. Finally, a correlation between executive functions and the thinning in the middle, inferior frontal gyrus, and orbitofrontal cortex was detected (p = 0.05).
Lillo et al. [77]	61 deceased patients with FTD, 43 with bvFTD, and 18 with ALS-FTD.	Psychiatric symptoms were assessed by the DSM-IV, while behavioral and cognitive symptoms in ALS were assessed by the EL Ecsorial Criteria. ALS severity was assessed by the ALSFRS (mean range = 24.0 ± 8.0).	Individuals with FTD often have delusions, which should induce the suspicion of ALS. There was a positive correlation between the presence of delusions and FTD/ALS. The interval between the onset of behavioral changes and diagnosis of ALS was less than 2 years among FTD/ALS patients. FTD/ALS patients had shorter survival than the bvFTD group (p < 0.05).
Ye et al. [78]	42 pure-ALS individuals (M = 31, F = 12, mean age = 52.90 ± 11.16 years), 41 ALS patients with cognitive and behavior alterations (M = 27, F = 14, mean age = 56.98 ± 9.95 years), and 4 ALS-bvFTD (M = 4, F = 0, mean age = 63.50 ± 10.34 years).	Cognition was assessed by the ECAS. Functional assessment was made by means of the ALS-FRS (mean range = 40.25 ± 4.42–41.55 ± 5.49).	ALS-bvFTD participants had shorter survival times than those of other groups. ALS-bvFTD patients had lower survival rates than the other two groups. ALS-FRS progression was faster in the ALS-bvFTD group than in the pure-ALS group. ECAS score was positively correlated with survival time (p < 0.01).
Wei et al. [79]	1013 Chinese ALS individuals, 720 without apathy (M = 450, F = 270, mean age = 54.5 ± 12.0 years), and 293 with apathy (M = 180, F = 113, mean age = 54.2 ± 11.7 years).	Apathy was assessed by the FBI, while depression, anxiety, and cognitive functions by the HDRS, HARS, and Chinese version of ACE-R. Executive functions were assessed by the FAB. Quality of life was assessed by the EQ-5D-5L, BADL, and IADL. Caregivers’ depressive symptoms were assessed by depressive symptoms and burden were investigated by the BDI and ZBI. ALS severity was assessed by the ALSFRS-R (mean range = 40.3 ± 5.2–38.8 ± 5.7).	It was found that apathy is quite common among Chinese patients with ALS and is associated with the severity of the disease and the presentation of non-motor symptoms in ALS, including depression and anxiety disorders. Finally, it is considered a significant prognostic factor in terms of survival (p < 0.05).
Kasper et al. [80]	98 ALS individuals (M = 65, F = 33, mean age = 60.0 ± 11.2 years) and 70 HCs (M = 41, F = 29, mean age = 59.9 ± 10.5 years).	Functional assessment was made by means of the ALS-FRS (range = 14–46). Neuropsychological assessment consisted of the WST, MoCA, CVLT-K, and VLMT. Behavioral alterations were evaluated by means of the FrSBe; depressive symptoms were assessed by the BDI, ADI.	Most cognitively impaired ALS patients without FTD had executive impairment in initiation and shifting domains. Apathy was the most frequent behavioral symptom. ALS individuals with FTD showed significant impairment in problem-solving skills with no behavioral defects.

Abbreviations: ACE-R: Addenbrooke’s Cognitive Examination—Revised; ADI: ALS Depression Inventory; ALSbi: ALS patients with behavioral impairment; ALS-bvFTD: ALS people with behavioral variant of frontotemporal dementia; ALScbi: ALS patients with cognitive and behavioral impairment; ALS-CBS: Amyotrophic Lateral Sclerosis Cognitive–Behavioral Screen; ALSci: ALS patients with cognitive impairment; ALS-CN: ALS cognitive normal ALS-FRS: ALS Functional Rating Scale; ALSFRS-R: ALS Functional Rating Scale–Revised; ALS-FTD: Amyotrophic Lateral Sclerosis Frontotemporal Dementia; ALS-FTD-Q: Amyotrophic Lateral Sclerosis Frontotemporal Dementia—Questionnaire; AM: Attentive Matrices; AS: Apathy Scale; BADL: basic activities of daily life; BBI: Beaumont Behavioral Inventory; BDI: Beck Depression Inventory; BDS: backward digit span; BHS: Beck Hopelessness Scale; BNT: Boston Naming Test; BSAT: Brixton spatial anticipation test; BSRT: Babcock Story Recall Test; bvFTD: behavioral frontotemporal dementia; CANTAB: Cambridge Neuropsychological Test Automated Battery; CDT: Clock Drawing Test; CET: Cognitive Estimation Task; CF: category fluency; CFT: category fluency test; CNSLS: Center for Neurologic Study Lability Scale; CPM: Raven’s colored progressive matrices; CR: cognitive reserve; CVLT: California Verbal Learning Tests; CVLT-K: California Verbal Learning Test—Short Form; DSFB: digit span forward and backward; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition; DST: digit span test; ECAS: Edinburgh Cognitive and Behavioral ALS Screen; EQ-5D-5L: five-level EuroQol five-dimension; FAB: frontal battery assessment; FBI: frontal battery inventory; FET: Face Eyes Test; FrSBe: Frontal System Behavior Scale; FSBS: Frontal Systems Behavior Scale; FTD: frontotemporal dementia; GDS: Geriatric Depression Scale; HARS: Hamilton Anxiety Rating Scale; Hcs: healthy controls; HDRS: Hamilton Depressive Rating Scale; HSBI: Holland Systems of Beliefs Inventory; HSCT: Hayling Sentence Completion Test; IADL: instrumental activities of daily life; KCSS: King’s Clinical Staging Criteria System; LCFT: letter and category fluency test; LFT: letter fluency test; LM: logical memory; LN sequencing: Letter–Number Sequencing task; LTMV: long-term mechanical ventilation; MDRS: Montgomery–Asberg Depression Rating Scale; MiToS: Milano Torino Staging System; MMSE: Mini Mental State Examination; MoCA: Montreal Cognitive Assessment; MPPSS: Manne Perceived Partner Support Scale; MQOL-SIS: McGill Quality of Life Single-Item Scale; MRI: magnetic resonance imaging; NPI: neuropsychiatric inventory; PHQ: Patient Health Questionnaire; PVF: phonemic verbal fluency; QOL: Quality of Life Enjoyment and Satisfaction Questionnaire; RAVLT: Rey Auditory Verbal Learning Test; RCPM: Raven’s colored progressive matrices; ROCFT: Rey–Osterrieth complex figure test; RPM: Raven’s Progressive Matrices; SAHD: Schedule of Attitudes Toward Hastened Death; SCWT: Stroop Color Word Test; SOC: Stockings of Cambridge; SSP: Spatial Span; SST: Short Story Test; STAI-Y: Spielberger State-Trait Anxiety Inventory; SWM: Spatial Working Memory; TMT A/B: Trail Making Test A/B; VAS: Visual Analog Scales;; VPA: verbal paired associate; WCST: Wisconsin Card Sorting Test; WST: Weigl’s Sorting Test; ZBI: Zarit Burden Interview.

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3.5.1. Cognitive Impairment

For the genetic influence on ALS cognitive impairment progression, C9orf72 mutations have been related to cognitive impairment in ALS and seem to give interesting insight into survival predictions, as shown by Burke and colleagues. In fact, c9orf72 mutations have been associated with early disease onset, more aggressive progression, and cortical atrophy. In addition, it is quite uncommon in Japan, while a higher prevalence is reported in the USA and Europe, also for FUS and SOD1 mutations [15,65].

Starting from these premises, it was pointed out that WM alterations and volume reductions in gray matter found in ALS subjects with the C9orf72 mutation predicted more aggressive cognitive phenotypes [15,66,67].

Bock and colleagues examined whether the progression of cognitive and behavioral function impairment could affect the general clinical outcome of ALS, concluding that changes in cognition and behavior are highly heterogeneous in ALS subjects who do not significantly change their executive functions over 7 months. Partially in contrast with this evidence, Stojkovic and colleagues reported that executive dysfunction is supposed to be related to survival in ALS. Specifically, executive deficits in the form of verbal fluency, working memory and planning, and problem-solving performances are positively related to a worse outcome in terms of survival in ALS [68].

In this framework, caregivers’ reports of patients’ symptoms play a decisive role in predicting future clinical decline, increased caregiver burden, and worsening patient quality of life (QOL) [69].

In addition, the progression of frontal cognitive alteration in ALS has been investigated from a neurophysiological point of view. ALS patients seem to present, in the long term, a fronto-striatal and frontoparietal network impairment, as well as an impairment in frontal-executive functions [70].

Intriguingly, cognitive reserve (CR) is known to exert a protective role from both cognitive and motor decline in ALS [71].

Finally, interesting findings also came from a study of non-invasive positive pressure ventilation (NIPPV) on the cognitive functions, such as attention, memory, and executive functions, of ALS individuals. The authors showed that, by mitigating nocturnal hypoventilation, NIPPV could partially improve cognitive dysfunctions in ALS, thus stressing the role of ventilation to ameliorate quality of life and prevent cognitive decline in ALS patients without dementia [72].

3.5.2. Psychological Impairment

In the framework of the relationship between neuropsychiatric symptoms and disease progression, Crockford et al. [73] reported that ALS-specific cognitive defects and behavioral impairment are associated with more severe stages of the disease. Arguably, the authors proposed cognitive and behavioral impairment to be included among ALS diagnostic criteria.

About psychiatric problems, it is known that depression may affect cognitive functions and, in turn, has also been associated with lower long-term survival in ALS [74].

An interesting study examined psychological factors influencing ALS patients’ decisions about the tracheostomy of long-term mechanical ventilation (LTMV). Despite the common idea that LTMV could be associated with unrealistic expectations, the authors reported that the patient’s choice was to live in any way possible, at least for some time and within certain boundaries, which is something clinicians should recognize and properly support [75].

Benbrika et al. [76] investigated disease symptoms at baseline and follow-up, finding that, while ALS individuals initially showed poor executive function and recognition of complex emotions from the eyes, as well as more anxious and depressive symptoms than healthy controls, at follow-up, inhibition abilities had worsened, together with the involvement of motor and extra-motor areas. It was also found that patients with cortical thinning had impaired mental flexibility. In addition, those with impaired theory of mind showed significant depressive symptoms.

A significant contribution to predicting progression from FTD to ALS with FTD seems to come from the presence of delusions. In fact, it has been reported that the interval between the onset of psychiatric symptoms and diagnosis of ALS is less than 2 years among FTD patients who develop ALS [77].

Overall, given the reciprocal relationship between cognitive and psychological alterations in ALS, it was pointed out that ALS-bvFTD participants had a worse prognosis in terms of survival than ALS subjects without psychological problems or FTD [78].

Also, apathy has been related to advanced phases of the disease. In fact, ALS patients in the late stage of the disease generally have more apathy than those in the early stage and, in turn, higher levels of anxiety, depression, and global clinical impairment. Consequently, apathy could be considered as an independent prognostic factor for survival requiring early diagnosis and treatment [79,80] (Table 3).

4. Discussion

In the first section, this work analyzes the genetic, biological, neurophysiological basis of cognitive and psychological impairment in ALS [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]. In the second part, clinical aspects of the disease are explained in terms of cognitive alterations and affective symptoms [51,52,53,54,55,56,57,58,59,60,61,62,63,64]. Finally, in the last part, the work discusses how ALS neuropsychiatric symptoms influence global disease prognosis [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]. Among genes, SOD1, TDP-43, c9orf72, and APOE ε/2 seem to be the most frequently implicated in worse cognitive performances and emotional lability of ALS individuals [15,26,27,28]. The main biological correlates of cognitive symptoms in ALS discussed in this review are alterations in the frontotemporal cortex, gray matter abnormalities, volume reduction in the globus pallidus, caudate nucleus, putamen, thalamus, inferior frontal gyrus, left temporal pole, amygdala, and insula, as well as tau deposition in the anterior cingulate gyrus, entorhinal cortex, amygdala, and basal ganglia [29,30,31,32,33,34,35,36]. Similarly, biological correlates of affective alterations in ALS are microstructural changes in occipital, temporo-limbic, and orbitofrontal regions, alterations in amygdala size, dorsolateral prefrontal cortex, dorsomedial prefrontal, anterior cingulate cortical, and orbitofrontal cortex atrophy. Again, white matter integrity alterations in the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus, gray matter volume reduction in the right superior temporal pole, and parahippocampal and precentral gyri seem to play a significant role in altered emotional recognition and processing in ALS [31,37,38,39,40,41,42].

Meanwhile, reduced neural processing efficiency, coherence alterations in the right inferior cerebellar areas, low activation in frontal and prefrontal brain areas, significant brain activity in frontotemporal and parietal regions during working memory performances, and alteration of bandpower in the medial prefrontal cortex are some of the main electrophysiological correlates of neuropsychiatric defects in ALS [42,44,46,49]. On the other side, hyperactivation of the IPL, precuneus, and inferior cerebellar areas has been associated with cognitive impairment in ALS [39]. Other correlates of attentional and cognitive performance impairment in ALS are the hyperactivation of the left middle and temporal gyrus, left superior temporal gyrus, and left anterior cingulate gyrus and hypoactivation of the left inferior frontal gyrus, left cingulate gyrus, left precentral gyrus, and left medial frontal gyrus [36,41]. Reduced hippocampal and right superior orbital gyrus activity, together with the increased function of the right inferior frontal gyrus, have been suggested to underlie sadness and depressive symptoms in ALS [41,49].

In keeping with these findings, Christidi and colleagues reported hippocampal metabolic alterations as an important anatomical correlate of ALS impairment in cognitive performances [81]. Intriguingly, Ghaderi and colleagues proposed MRI biomarkers to follow memory-related impairment in ALS [82].

From a clinical point of view, executive functions, social cognition, verbal memory, verbal fluency, working memory, problem-solving, cognitive flexibility, visuospatial abilities, immediate and delayed recognition, specific problems in facial recognition, attentional control, premorbid intelligence, and numerical capacity have been reported as the main cognitive problems among ALS individuals [52,53,54,55]. Furthermore, some studies focused on the reciprocal relationship between motor symptoms and cognitive and psychological decline in the disease [53,55,56,57].

Accordingly, Urso et al. [83] suggested a reciprocal relationship between motor and cognitive symptoms of the disease. Specifically, the authors highlighted the importance of an accurate assessment of psychiatric symptoms, such as depression, pain, and sleep, among ALS patients with different levels of motor impairment. Similarly, Beswick and colleagues, starting from the consideration that the available works on neuropsychiatric symptoms in ALS have not used proper instruments and impairment thresholds, stressed the need for further studies [84,85].

When investigating psychiatric symptoms most frequently found among ALS patients, depression, suicidal ideation, daytime sleepiness, apathy, anxiety, emotional recognition, interoceptive sensitivity, alexithymia, and disinhibition [51,61,62] could play an important role in the general clinical outcome. This argumentation is consistent with evidence reporting significant psychiatric implications of ALS [86].

From a prognostic point of view, among variables mostly involved in ALS aggressive progression and early disease onset, there seem to be executive dysfunction, such as verbal fluency, working memory and planning, and problem-solving [68] and psychological problems, including moral judgment alterations, apathy, and low mental flexibility [76,79,80] as well as c9orf72 mutations [15,65,67]. From a neurophysiological point of view, fronto-striatal and frontoparietal network impairments have been pointed out as significant predictors of frontal cognitive decline [70], while CR and NIPPV seem to have a protective role against cognitive decline in ALS [71,72]. In keeping with these findings, a recent study supports the role of CR as a modulator for both cognitive and psychological aspects of the disease [87]. Our study also suggested that there is a significant negative influence of psychiatric symptoms, including depression, apathy, anxiety, and delusions, on the cognitive and global outcome of the disease [73,74,76,77,78,79,80]. Consistent with these results, a study by Didcote et al. [88] pointed out that, even though both psychological and cognitive impairment may influence ALS informant distress, the former had more impact than the latter.

This work has some limitations. First, given the fact that ALS is a rare disease, lots of studies were conducted on a small sample size. Second, different groups were not homogeneous in terms of measure and questionnaires employed for cognitive and psychological assessment. Third, there is a disproportion in terms of psychiatric symptoms analyzed, with anxiety and depression being the main ones investigated, and less studies involving, for example, eating and post-traumatic stress disorders. Fourth, this is a literature review and not a systematic review. Fifth, not all the studies included in this review used the same neuropsychological tests or diagnostic criteria, thus potentially leading to differences in data interpretation and comparability across studies

However, there are also some strengths. First, for each section of the results—biological, neurophysiological, genetic, clinical, and prognostic implications—we stratified for different cognitive alterations on the one side and psychological aspects on the other. Second, various assessment scales are employed, as described accurately in tables, which report, for each study, detailed methods and results.

According to the author’s opinion, further research could be displayed on psychological and cognitive responses as well as on motor outcomes in ALS by employing homogeneous samples in terms of demographic, diagnostic, and clinical characteristics; increasing sample numbers; and focusing on other psychiatric comorbidities such as psychosis, stress disorders, obsessive compulsive disorders, and so on.

5. Conclusions

This work specifically reviews the reciprocal relationship between the biological, genetic, and neurophysiological basis of neuropsychiatric dysfunction and the clinical outcome and prognosis of ALS. We suggested that cognitive dysfunction and psychiatric aspects make important contributions to both patients’ quality of life and the disease course. In fact, we reported a positive correlation between cognitive impairment, including executive, memory, language, and ALS prognosis, as well as between psychiatric conditions, namely, apathy, depression, sadness, and ALS general outcome. In addition, it appears that the same cognitive and psychiatric disorders may sometimes influence motor impairment in ALS. Further studies are needed to better clarify reciprocal relationships between disease cognitive, psychological, and psychiatric alterations on the one side and biological and neurophysiological bases on the other, finally leading to prognostic implications.