Primary Lateral Sclerosis is an upper motor neuron disorder that typically presents with insidious spino-bulbar spasticity in adulthood (27, 90). It is often associated with pseudobulbar affect that may trigger self-imposed social isolation. Extra-motor manifestations are increasingly recognized in PLS (83, 91), occurring in a similar behavioral and cognitive profile to ALS (83), and rarely fulfilling the diagnostic criteria for FTD (83, 91). Such deficits include impaired social cognition, executive function, verbal fluency, language, or apathy (29, 82, 83, 91). The reported cases of frank FTD evolved several years after the insidious onset of UMN signs and were associated with progressive radiological frontotemporal atrophy (91). This is in line with the mounting body of neuroimaging evidence that supports widespread frontotemporal involvement in PLS (22, 29, 33).

The radiological profile of PLS varies from limited extra-motor involvement to widespread pathology (27). Structural and diffusion data revealed degenerative changes in the fornix, body of the corpus callosum, anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal, and temporal regions (22, 27, 29, 33, 37, 42). Some studies have explored associations with underlying structural abnormalities focusing on apathy, impaired executive function, language, and verbal fluency deficits (29, 33, 92). Longitudinal studies have yielded inconsistent findings with regards to progressive pathology (25, 26, 30–32, 35). A case report described progressive cortical atrophy over an 8.5-year timeframe (93). These observations would suggest that contrary to ALS, longer follow-up intervals may be required in PLS to characterize radiological trajectories. Extra-motor findings in PLS are also supported by metabolic and functional imaging studies. PET imaging studies have detected prefrontal and premotor areas of hypometabolism in PLS that are almost indistinguishable from the patterns seen in ALS (39, 43, 94). Whilst primarily used in a research setting, novel PET radioligand binding studies have also demonstrated alterations beyond the motor system, in the bilateral anterior cingulate gyri, and in left superior temporal lobe (2, 36, 39, 90, 95). MR Spectroscopy in PLS has mostly focused on the evaluation of the motor rather than extra-motor regions (24, 35). Similar to ALS, it shows reduced N-acetyl aspartate/creatinine ratios (23, 24, 35, 41, 44) and increased myo-inositol/creatinine ratios (41) in the motor cortex suggestive of neuronal dysfunction and gliosis, respectively. Resting-state fMRI studies report increased functional connectivity in frontotemporal networks (34, 92) which has been associated with executive dysfunction (4, 92). Similar to ALS, increased functional connectivity is typically considered a “compensatory response” to structural degeneration (92).

The few post-mortem studies are concordant with the extra-motor radiological profile of PLS (96–103). Frontotemporal lobar degeneration has been detected with some cases revealing ubiquitin- and TDP-43-immunoreactive neuronal cytoplasmic inclusion bodies in frontotemporal and hippocampal areas. Post-mortem studies seldom have accompanying comprehensive clinical information, but when available, features of nfvPPA or bvFTD have been described (96, 102).

Progressive Muscular Atrophy is a clinical diagnosis that is defined by a gradually progressive isolated lower motor neuron disorder, evolving over many years (104). Reports of extra-motor involvement are inconsistent which is further complicated by the debate on whether PMA is a distinct entity or embedded within the spectrum of ALS (105–108). There are undeniably shared clinical, radiological, and pathological features, albeit less severe compared to ALS. While the initial exclusive LMN clinical presentation distinguishes PMA from ALS, patients with PMA often later develop UMN signs (107). The cognitive profile is also strikingly similar to ALS, with varying levels of executive function, language, fluency, and memory affected (83, 109). In contrast, minimal behavioral impairment is observed, and very few patients with PMA fulfill the diagnostic criteria for FTD (83, 109).

Some imaging studies have identified radiological abnormalities in a distribution that may explain these cognitive deficits (1, 109). Structural analyses have reported loss of white matter integrity in inferior frontal, dorsolateral pre-frontal, and hippocampal regions (42). A task-based fMRI study utilizing a letter fluency task as a test of executive function showed impaired letter fluency and abnormal pre-frontal activation (47). As a counter-argument, a recent study in PMA reported preserved structural integrity with no functional connectivity alterations (4). Neither MRI spectroscopy nor PET imaging studies have identified radiological abnormalities in extra-motor regions (45, 46). It is noteworthy that a dedicated neuropsychological study failed to find a difference between patients with PMA compared to controls (110). Potential shortcomings of the study designs must be considered, including small numbers of patients and the lack of sensitivity of either the chosen task or the imaging modality (46).

The shared neuropathological hallmarks also lend support to the opinion that PMA is part of the ALS clinicopathological continuum (105–107). The pathological substrates of TDP-43 positive inclusions and occasional fused-in-sarcoma (FUS)-positive basophilic inclusions are observed in both conditions, but at a lesser burden and more limited distribution in PMA (108, 111). Post-mortem studies in PMA typically describe LMN degeneration, occasional pyramidal tract degeneration, and additional TDP-43 positive inclusions in the primary motor cortex and hippocampus even in the absence of UMN degeneration (108, 111). These findings raise the question, if in fact the results of PMA studies should be streamlined, interpreted, and analyzed under the umbrella of ALS.

Spinal Muscular Atrophy is an autosomal recessive disorder that is caused by either homozygous deletions or loss of function mutations in the survival motor neuron 1 (SMN1) gene resulting in a deficiency of survival motor neuron (SMN) protein (112). It typically manifests as a proximal, predominantly symmetrical motor weakness. The phenotype is stratified in levels of decreasing severity from type 0 to type IV, depending on age of symptom onset and achievement of developmental milestones (112). There are preliminary signals of cerebral involvement in the more severe phenotypes, but it is not yet clear if there is preferential involvement of frontotemporal regions.

The only two cross-sectional quantitative multimodal MRI brain studies evaluated the same 25 treatment naïve adults with type III or type IV SMA initially focusing on the cerebrum and then the cerebellum (48, 50). No supratentorial cortical atrophy was detected (50), but focal cerebellar changes were noted. In the more severe clinical phenotypes, qualitative MRI brain scans have captured more dramatic findings (49, 113–115). In type 0 SMA, widespread supratentorial, and sometimes infratentorial, brain atrophy has been reported. A longitudinal case series of patients with type 0 SMA showed interval radiological abnormalities involving the thalamus and basal ganglia (49, 114). Similar radiological findings have been described in type I SMA (115). For the most part, neuropsychological studies demonstrate preserved cognition (116–119). This is with the caveat that these studies are mostly limited to children and omit the more severe clinical phenotypes (120). Some aspects of childhood development are even deemed superior compared to healthy controls (121–125). The only neuropsychological study of adults with type II or type III SMA described normal rather than superior cognitive abilities. This study reported a possible adaptive mechanism of an inverse correlation between executive function and physical ability, but the level of executive function did not exceed healthy controls (116). In contrast, there are indications of attention and executive function deficits in children with type I SMA (120, 126).

The post mortem examination of the brain is often confounded by coexistent anoxic changes (127, 128). The more severe clinical phenotypes display more widespread features of degeneration involving the cerebral cortex, thalamus, brainstem, and some cranial nerve nuclei that are congruent with ante mortem radiological abnormalities (49, 129). Most of these regions seem spared in the milder phenotypes (127, 128, 130). This has been interpreted as selective neuronal network degeneration occurring below a threshold of SMN protein, although the true clinical significance of this is unknown (129). Overall, the radiological characterization of the more severe clinical phenotypes has proven challenging because of the rarity of the condition, significant disability, and limited life expectancy. In the advent of gene therapy, there may be opportunities for future research in this cohort.

Spinal and Bulbar Muscular Atrophy, also known as Kennedy's disease, is an X-linked trinucleotide repeat disorder due to expansion of cytosine-adenine-guanine (CAG) repeat in the androgen receptor gene (131). It is a multisystem disorder that typically presents in men in their fourth decade of life with slowly progressive weakness, bulbar involvement, and muscle atrophy due to insidious lower motor neuron degeneration (132, 133). Relatively mild cognitive deficits have been consistently described (134–136). While it is a multi-system disorder, the involvement of the central nervous system has been relatively under-evaluated from a radiological viewpoint (131).

The few brain imaging studies indicate various degree of frontotemporal involvement (53, 54, 56). Quantitative MRI analyses demonstrate a spectrum of frontal gray and white matter abnormalities ranging from entirely unaffected to subtle gray matter atrophy and extensive white matter degeneration (53, 56). Widespread loss of white matter integrity has been reported in the brainstem, corticospinal tracts, and limbic system (40, 51, 56). A single PET imaging study showed hypometabolism in frontal areas (54). The results of conflicting MR spectroscopy studies highlight that subclinical neuronal dysfunction may not be detected by certain imaging protocols (52, 55). A long echo-time MR spectroscopy study demonstrated altered metabolite ratios in the brainstem and motor regions (52); however, a short echo-time MR spectroscopy study failed to reproduce these findings (55). The discrepancy in these results may be explained by the potential pitfall of artificial metabolite elevation because of either metabolite signal overlap or incorrect baseline determination in short echo-time MR spectroscopy (137). These radiological findings are complemented by consistent reports of neuropsychological dysfunction in this cohort albeit mostly at a subclinical level (134–136). Deficits may be so subtle that performance on standard tests of executive function can be normal (134, 135). Mild deficits in social cognition have also been recorded (135). In contrast, single cases of more severe frontal dysfunction have been repeatedly described (138, 139).

Most post-mortem studies in SBMA focus on cardinal spinal cord, peripheral nerve, and proximal muscle changes (133, 139, 140). The pathological examination of cerebral hemispheres is seldom reported. A post-mortem report of an SBMA patient with significant cognitive impairment demonstrated marked diffuse subcortical gliosis in the pre-frontal region, hippocampus, and the degeneration of fronto-bulbar fibers in the midbrain without accompanying cortical pathology (139). Immunohistochemical studies have shown that the pathogenic nuclear mutant AR protein is present in abundance in the central nervous system; supporting the rationale to systematically evaluate cerebral changes in future SBMA studies (141).

Post-polio syndrome is characterized by progressive muscular weakness with or without pain, fatigue, and muscle atrophy in patients who have recovered from a distant polio infection (61). Patients often report diverse cognitive symptoms, mostly deficits in attention or memory; however objective evidence is strongly confounded by comorbid factors such as fatigue (57, 142–144). The reportedly high prevalence of extra-motor symptoms is contrasted by the relative lack of cerebral radiological abnormalities in post-polio syndrome (59).

A quantitative MRI study detected minimal cortical and subcortical atrophy, involving the cingulate gyrus, temporal pole, and left nucleus accumbens (59). These subtle changes were not appreciated in other studies (60, 61). Qualitative MRI studies either identified no abnormalities or discrete subcortical hyperintensities that were hypothesized to contribute to the disabling comorbid fatigue (57, 58, 145). Patients with post-polio syndrome frequently exhibit high levels of self-reported fatigue, apathy, and verbal fluency deficits. In the absence of widespread frontotemporal imaging abnormalities, these extra-motor symptoms are postulated to be multifactorial in origin with factors such as low mood, poor sleep, and polypharmacy all playing an additive role (59).

These observations are corroborated by historical pathological studies that demonstrate preferential involvement of the brainstem rather than the cerebrum (57, 146, 147). This is further complicated by reports of patients with a history of polio, who later develop sporadic ALS and demonstrate mixed neuropathological features including the hallmarks of both diseases (148, 149).

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogenous group of neurodegenerative disorders that present as progressive limb weakness and spasticity. They were traditionally divided into “pure” or “complicated” phenotypes based on the absence or presence of extra-motor involvement, respectively (63). In recent times, there has been a shift to stratify these cohorts in accordance with their genetic diagnoses (150). Interestingly, there are radiological indicators of frontotemporal dysfunction irrespective of the subgroup.

Brain imaging studies have shown a reduction in whole brain volume in both clinical phenotypes (68). In pure HSP the volume of gray matter volume is thought to be mostly preserved, whereas in complicated HSP the volume of cortical and deep gray matter may be reduced. The only longitudinal study detected no change in cerebral volume over a 2-year follow-up period (72). This is with the caveat that longer time intervals may be required to detect a significant change. Loss of white matter integrity has been identified in the corpus callosum, in the frontotemporal and parietal regions in both groups (40, 62–64, 72, 73). The severity of these findings correlate with the degree of cognitive impairment (63). Given the relative cortical sparing, cognitive deficits in these cohorts were postulated to be primarily subcortical in origin (64, 66, 67). This was supported by MR spectroscopy reports of abnormal metabolic ratios in the subcortical white matter (65, 72, 77, 151–155). PET imaging studies detected cortical hypometabolism, sometimes implicating the frontotemporal regions (76, 156–161). This was accompanied by clinical measures of frontal dysfunction (76, 161). Resting-state fMRI studies have shown altered functional connectivity involving the primary motor cortex, insula, and superior frontal gyrus (70). Task-based fMRI studies typically report abnormal activation patterns in sensorimotor areas whilst performing motor tasks (69, 78).

In the advent of genotyping, there has been a focused effort to define the radiological signatures of specific genotypes. Spastic paraplegia 4 (SPG 4) is the most common autosomal dominant HSP subtype that is characterized by widespread white matter degeneration with relatively preserved gray matter (64, 71, 75). Subclinical cognitive deficits have been described that later follow a more rapid trajectory of decline escalating in the eights decade of life (162–165). Spastic paraplegia 11 (SPG11) and spastic paraplegia 7 (SPG7) are rare autosomal recessive HSP subtypes that reveal white matter degeneration involving the frontotemporal regions amongst other features (67, 74, 79, 150, 152, 166–168). Varying degrees of cognitive deficits including attention, memory, and executive dysfunction have been described in these genotypes and others (66, 79, 169).

The few post-mortem studies corroborate the radiological descriptions of frontotemporal pathology. Autopsy reports of those with a clinical rather than genetic diagnosis must be interpreted with caution. In clinically defined cases, marked cerebral atrophy and severe gliosis of the cerebral white matter has been described sometimes preferentially involving prefrontal and frontal areas (170–172). In SPG11, widespread frontotemporal cortical degeneration has been described (85). Similar pathological observations have been reported in SPG4, in addition to widespread ubiquitin positivity (164).

Amyotrophic lateral sclerosis is the most common form of MND that is characterized by progressive upper and lower motor neuron degeneration in the motor cortex, brainstem nuclei, and anterior horn of the spinal cord. It begins with progressive limb-onset or bulbar-onset muscle weakness that clinically manifests as cramps, fasciculations, muscle wasting, difficulty swallowing, or speaking before ultimately advancing to respiratory failure (173). Additional cognitive and/or behavioral impairment is universally recognized and a minority of patients with ALS also fulfill the diagnostic criteria for FTD (174).

Clinical observations are widely supported by extra-motor neuroimaging findings. Structural imaging consistently reveals frontotemporal gray and white matter degeneration (14, 15, 18, 175–188). Gray matter atrophy has been described in the anterior cingulate, insula, operculum, inferior frontal gyrus, superior temporal gyrus, cerebellum, parietal, and occipital cortex (1, 6, 7, 14, 15, 20, 179, 185, 187–191). White matter degeneration has been detected in the body of the corpus callosum, inferior longitudinal fasciculus, uncinate fasciculus, cerebellum, inferior frontal, middle temporal, superior temporal, orbitofrontal, occipital, and parietal regions (1, 5–7, 11, 14, 15, 18, 20, 175–191). These anatomical findings are often linked to structure-specific behavioral or cognitive deficits (1, 3, 11, 13–15, 186–188, 192–195), but similar patterns have been described in the absence of overt cognitive impairment (1, 17, 189, 191, 196). Extra-motor changes were initially considered to be more prominent in those with C9orf72 genotype compared to those with sporadic ALS (187, 196), but widespread frontotemporal involvement is not unique to C9orf72 (197). Subcortical gray matter involvement can also be readily detected in the hippocampus, amygdala, thalamus, caudate nucleus, putamen, nucleus accumbens, and globus pallidus (6, 10, 11, 13, 16, 21, 185, 189, 196, 198, 199). Progressive brainstem pathology has also been reported preferentially involving the pons and the medulla oblongata (8, 9). Structural and diffusion studies are complemented by robust metabolic and functional imaging studies. PET imaging studies have shown frontotemporal hypometabolism involving the dorsolateral prefrontal, orbitofrontal, anterior frontal, and anterior temporal areas (94, 200–202) and regional hypometabolism has been linked to cognitive deficits in ALS (201, 203, 204). PET imaging abnormalities may precede the detection of cortical atrophy (205). While in their infancy, novel PET radioligand studies highlight microglial activation in frontotemporal regions, suggestive of localized inflammatory processes (2, 206–210). MR spectroscopy detects extra-motor abnormalities, potentially before the emergence of clinical symptoms (211). It shows reduced N-acetylaspartate indicative of neuronal dysfunction in the mid-cingulate gyrus (212), dorsolateral (46, 213), ventrolateral (214), and mesial prefrontal cortices (211, 215). Sometimes these frontal lobe abnormalities are subtle (19) and may be associated with measures of executive dysfunction (19, 46, 213). Resting-state fMRI studies captured both increased and decreased functional connectivity within networks that mediate specific behavioral and cognitive functions (216–222). Task-based fMRI studies have linked these abnormal activation patterns with different facets of cognition, specifically executive function (223–225), social cognition (224, 226–230), memory (227, 231, 232), and language (233). Executive dysfunction is associated with increased activation of the right superior and inferior frontal areas (224), left superior and mid temporal gyrus and left anterior cingulate gyrus (223) and decreased activation in the left precentral gyrus (223), and dorsolateral pre-frontal cortex (223, 225, 233); impaired social cognition is associated with increased activation in the prefrontal cortex (224, 226, 228, 229), right supramarginal area (230), right posterior temporal sulcus, and decreased activation in the bilateral hippocampus (229); memory deficits are associated with increased activation in the hippocampus (231) and superior frontal gyrus (232), and decreased activation in the right pre-frontal cortex (232); and finally impaired language is associated with decreased activation patterns in the pre-frontal cortex, right cingulate gyrus, and left temporal lobes (233). For the most part there are increased (224, 226, 228–231) or co-existing (223, 225, 227, 229, 230, 232) activation patterns which suggests either loss of inhibitory dysfunction or partial compensation to overcome early functional impairment (234–236). Overall there does not seem to be a consistent compensatory or inhibitory effect which suggests that these patients may have been captured at different stages of disease. Functional studies have also been widely utilized to evaluate extra-pyramidal dysfunction in ALS (237, 238). Emerging functional modalities, such as magnetoencephalography or spectral EEG have also confirmed widespread extra-motor dysfunction and as these technologies develop they are likely to contribute important additional insights (239–243). The majority of imaging studies in ALS explored the underpinnings of the most commonly affected neuropsychological domains (233, 244), such as the substrate of verbal fluency deficits, executive dysfunction, and behavioral impairment, but with the recognition of the relatively high prevalence of impairments in social cognition, memory deficits, and of apathy, the focus of imaging studies is likely to gradually shift (12, 245–249). Imaging changes in ALS are typically solely interpreted based on genetic and clinical profiles, and seldom correlated with other markers such biofluid markers (250–252). The radiological patterns identified by various imaging studies are largely congruent with the distribution of pathological TDP-43 (pTDP-43) aggregates in extra-motor brain regions (253–257). Patients with ALS-FTD are thought to carry increased extra-motor pTDP-43 burden compared to patients without cognitive impairment (256). A study of patients with cognitive impairment revealed correlations between regional pTDP-43 load and executive, language and fluency deficits (253).