Cognitive and behavioral involvement in ALS has been known for more than a century

In spite of the seminal description of amyotrophic lateral sclerosis (ALS) delivered in 1869 by Jean-Martin Charcot and Alix Joffroy, who introduced the notion of “the mind [being] unaffected in ALS” [119], it took no longer than 23 years for Pierre Marie, one of the most distinguished protégés of Charcot himself, to firmly reply “yes” to his own question whether “mental functions are altered over the course of [ALS]” (p. 470) [65].

It is thereupon surprising that, among clinicians and researchers, the pathophysiological, genetic, and phenotypic link between frontotemporal degeneration (FTD) and ALS (i.e., the ALS-FTD spectrum) [18, 124] begun to be regarded as a fact only between the late 1990s and early 2000s of the twenty-first century.

Indeed, the scientific and clinical community has been provided with a nosographic system for FTD-spectrum disorders in these patients not earlier than 2009 [99, 100]. El Escorial diagnostic criteria, in fact, still under-addressed cognitive and behavioral features in ALS [16].

By contrast, within the present historical review, it is demonstrated that the recognition of extra-motor, FTD-spectrum disorders in ALS dates back at least 130 years. Herewith, European, American, and Asian reports starting from 1882 and suggestive of cognitive/behavioral changes in 174 ALS patients are presented. Such records were retrieved thanks to Biblioteca di Area Medica “Adolfo Ferrate,” Sistema Bibliotecario di Ateneo, University of Pavia, Pavia, Italy, and qualitatively synthetized. Records herewith described have been searched for up to 1981, as this being the date of publication of the first, pioneering review by Hudson [54] that actually acknowledged the association between ALS and cognitive/behavioral changes. However, Hudson’s [54] review was not exhaustive of all the records preceding 1981—which are, indeed, by far less known by the modern scientific community, and were thus intended to be brought to the light within this work.

Within the 10 years following the 1892 acknowledgment by Marie of “[mental] disturbances [being] not only highly frequent in [ALS] but also typical [of it]” (p. 470) [65], several authors worldwide begun reporting emotional lability, gelastic/dacrystic episodes, anosognosia as well as disinhibited and psychotic traits in ALS patients [80, 95, 115]. Notably, Marie [65] himself had already listed such alterations among the most characteristic features of their neuropsychological profile—in striking overlap with the current knowledge on dysexecutive behavioral phenotypes within the ALS-FTD spectrum [83].

As to cognition, early semeiotic reports described, besides a non-specific decrease in global efficiency [80, 39, 49, 95], memory deficits [105], as well as oral and written language disturbances [115, 56]—which are cognitive features currently acknowledged as typical of the ALS-FTD spectrum [83].

A turning point for the full recognition of neuropsychological involvement in ALS occurred after 1905, with Cullerre, in 1906, being the first to explicitly address it by entitling his report “Trouble mentales dans le sclerose laterale amyotrophique”—i.e., “Mental disturbances in [ALS]” [29]. Notably, the modern parallel of such a title dates back not earlier than 2003, with Lomen-Hoerth et al. [63] posing the question “Are amyotrophic lateral sclerosis patients cognitively normal?.” One year after Cullerre’s [29] report, Fragnito [37] forwarded the pioneeristic notion of motor and cognitive/behavioral features in ALS not being unrelated, but rather yielding from the same underlying pathology spreading to extra-motor, frontotemporal cortices. Notably, such a hypothesis subsequently gained greater support over the second-to-sixth decades of the twentieth century: for instance, Bartoloni and D’Angelo [9] delivered, exactly 40 years after Fragnito [37], strikingly clear post-mortem evidence of frontotemporal cortex involvement in ALS (Fig. 1).

As to ante litteram stances, Fragnito [37] and Gentile [42] also noticed that neuropsychological disorders in ALS are heterogeneous in severity, somehow anticipating the current notion of a continuum of these features, ranging from sub-clinical/mild deficits (i.e., the current nosological entities of ALS-cognitive/-behavioral/-cognitive and behavioral impairment, ALSci/bi/cbi) [99] to a full-blown dementing state.

Interestingly, Cullerre [29] further described sitophobia (i.e., aversive behaviors towards food) and anosognosia in ALS patients—both features being consistent with the current knowledge of FTD-spectrum dysfunction in ALS [83].

In respect to illness awareness, it is of note that several authors reported mild-to-absent [91], moderate [92], or severe [39] loss of insight into either motor disabilities or neuropsychological changes—this being consistent with the now recognized continuum of severity of anosognosic features in ALS [83]. Relevantly, Resegotti [92] also underlined the detrimental impact of anosognosic features on adherence to and compliance with treatments—which is a renowned issue in the clinical management of ALS patients [55].

Possibly due to the progressive acknowledgment of the aforementioned notions, starting from 1907, worldwide reports of neuropsychological impairment in ALS patients both increased in frequency and improved as to semeiotic accuracy (Table 1).

Oppenheim and Siemerling [80] for the first time reported, in 1886, 5 patients with dementia and predominant-bulbar motor neuron signs whose autopsy revealed frontal and temporal atrophy. After a few years, also Sarbó [95] and Haenel [49] described relatively widespread, extra-motor cortical abnormalities in ALS patients showing dysexecutive, behavioral features.

However, neuropathological examinations of clinically diagnosed ALS patients showing cognitive/behavioral changes started to be more frequently reported and described with a higher degree of detail starting from the second decade of the twentieth century (Table 1). Such findings appear to be of even greater interest as often including, besides evidence on extra-motor involvement, histopathological verification of pyramidal system alterations (i.e., motor cortex and corticospinal tract) [72, 116, 61].

Pre-/orbital-/medial-frontal and temporal cortex involvement, at both macroscopic (atrophy) (Table 1) and microscopic levels (glial proliferation, astrocytosis, morphological neuronal alterations, and neuronal loss) [72, 116, 107, 110], were noted in a number of patients that nowadays would be likely to be classified as ALSci/bi/cbi, ALS-FTD, or FTD-MND, as well as fall under the relative spectrum of TDP-43 proteinopathies [18].

Moreover, sub-cortical white matter and diencephalic involvement (basal ganglia, thalamus, subthalamic nuclei) happened to be also reported (Table 1), consistently with the current notion of such structures possibly being affected by the spreading of both ALS and FTD pathology [18, 117]. Notably, Teichmann [103] and Kurachi et al. [59] also reported both macroscopic/microscopic cerebellar alterations within the post-mortem examination of ALS patients with neuropsychological involvement, this also being in line with the nowadays acknowledged possibility of the cerebellum being involved within the ALS-FTD spectrum [58].

Of interest, a number of reports allegedly succeeded in identifying the histological signature of Pick’s disease (Table 1), by also disentangling it from both Alzheimer’s disease (AD) [72, 94] pathology and senile-related physiological alterations or cerebrovascular lesions [31, 51]. By contrast, also the co-existence of Alzheimer’s and Pick’s disease pathology [87], as well as that of AD alone [125], happened to be reported—this being in line with the current knowledge of AD-like burden possibly being found at post-mortem examination of ALS cases presenting with neuropsychological changes [50].

Notes on lateralization and relative selectivity of damages can also be detected in a number of the aforementioned reports. For instance, Miskolczy and Csermely [76] envisaged a relevant anatomo-clinical correlation when describing an alleged FTD-MND patient with prominent language impairment whose post-mortem examination was suggestive of a left-greater-than-right frontotemporal cortex atrophy. Similarly, Kurachi et al. [59] described an ALS patient with prominent long-term memory impairment whose autopsy revealed a selective right-greater-than-left temporal pole atrophy—this possibly being the first description of ALS associated with the nowadays so-called right temporal variant FTD (rtvFTD) [27].

Overall, it is striking that, already in the first four decades of the twentieth century, the notion of a progressively spreading pathology beyond the motor cortex had been acknowledged as being the biological basis of neuropsychological changes in ALS [9, 48]—somehow anticipating current theories of sequential, corticofugal stages underlying both motor and cognitive/behavioral involvement within the ALS-FTD spectrum [93].

Starting from the fourth decade of the twentieth century, several authors also reported in vivo evidence of neuroanatomofunctional changes in ALS patients showing neuropsychological impairments, albeit rarely and limitedly to a restricted range of instrumental examinations (Table 1)—i.e., pneumoencephalography, EEG, CSF analysis, and, starting from 1969, CT scans [30, 34].

In this respect, the report by Miskolczy and Csermely [76] is of great relevance, as being the first to concurrently described consistent in vivo and post-mortem findings in a probable PPA case who later developed motor neuron signs—i.e., a neuropathologically confirmed Pick’s disease patient whose EEG had showed alterations within the frontal and temporal lobes.

As to the contribution of neuropsychology to the acknowledgment of the link between ALS and FTDs, the report by Lechélle et al. [61], Michaux et al. [73], Campanella and Bigi [21], and Boudouresques et al. [14] are of particular interest, as being the first to deliver psychometric evidence of cognitive dysfunctions—along with post-mortem and, at times, in vivo, neuroanatomofunctional correlations (Table 1).

Lechélle et al. [61] and Michaux et al. [73] described a series of ALS patient seemingly presenting with SD. A comprehensive battery of language tests indeed revealed a severe, progressive, and amodal impairment of the lexical-semantic component (with word frequency effects being also described), along with dyslexic (single-letter recognition deficits and predominantly phonological paralexias) and dysgraphic features (morpho-syntactic and phonological paragraphias). Notably, Michaux et al. [73] also described a preservation of object vs. action semantics—this possibly representing the first report of noun–verb dissociation within the ALS-FTD spectrum, a neurolinguistic phenomenon systematically documented within the last 30 years [85].

By contrast, Campanella and Bigi [21] and Boudouresques et al. [14] reported fine-grained semeiotic and psychometric descriptions of cognition and behavior in ALS patients with probable bvFTD—describing verbal inertia, apathy, anosodiaphoria, hypomanic features, and, at testing, predominant executive-attentive deficits, accompanied by possibly secondary dysfunctions of instrumental domains such as memory, praxis (including closing-in phenomena), visuo-spatial skills, and calculation.

Along with other reports alluding to psychometric testing in ALS patients [30], the abovementioned ones express an ante litteram need to objectively assess the cognitive/behavioral status of these patients. Notably, several ALS-specific psychometric screeners have been developed within the last decade, in order to provide cognitive/behavioral measures free from disease-related confounders (e.g., upper limb impairment during paper-and-pencil tasks or dysarthria within tasks requiring timed, verbal responses) [47].

Starting from the nineteenth century and more frequently in the twentieth century, a number of cases have been reported of familial and possibly genetic ALS patients presenting with cognitive/behavioral dysfunctions (Table 1), both across [123, 30] and within generations [21, 36].

A number of these reports specifically suggested an autosomal dominant transmission/a high genetic penetrance [30]. Relevantly, cognitive/behavioral phenotypes were often reported as similar within such familial/genetic cases—e.g., familial cases of progressive bulbar palsy with aphasic dementia [94], slowly progressing ALS with or without dementia [21], early-onset psychosis with dementia developing within the fifth/sixth age decades [123], or slowly progressive, juvenile-onset ALS with psychosis [77].

Of note, the report by [30], who described a series of familial, probable ALS-FTD patients within an Italian kindred was revisited and extended by Giannoccaro et al. [45], who followed a number of individuals belonging to the same family and performed genetic analyses in four of them, detecting mutations consistent with the current neurogenetics of ALS-FTD spectrum disorders, among which the C9orf72 expansion. Giannoccaro et al. [45] concluded that the family described by [30] carried the C9orf72 expansion.

Finally, it is noteworthy that, within twentieth-century case series of ALS with FTD-like involvement, a familiarity with other neuropsychiatric disorders (e.g., psychosis, mood disorders, and epilepsy) was noted (Table 1) this possibly representing an ante litteram recognition of the genetic association between the ALS-FTD spectrum and unrelated brain disorders, which is nowadays believed to be underpinned by the phenotypic heterogeneity yielded from C9orf72 mutations [25]. Such evidence appear to be even more consistent when referring to psychotic disorders (Table 1), as well as in line with the current knowledge on schizophrenia spectrum disorders frequently occurring within the genealogical tree of ALS and FTD patients, possible due to C9orf72-related genotypes [70].

As early as 1963 [4], also the nowadays certified occurrence of extra-pyramidal systems possibly being involved in ALS with FTD-spectrum disorders [88] had been reported in Europe. It is of note that such cases were addressed as resembling the ALS-parkinsonism-dementia complex (ALS-PDC), identified as endemic in Guam and in the Kii peninsula starting from the 1950s (Supplementary Material 1).

For instance, Boudouresques et al. [14], who reported a French ALS patients with co-morbid frontal-like dementia who also showed parkinsonisms within the early stages of the disease. Similarly, La Maida et al. [60] described a patient whose onset symptoms included both pyramidal and extra-pyramidal involvement, as well as depressive and apathetic features.

Within this historical review, strong evidence for the acknowledgment of extra-motor, frontotemporal-like cognitive/behavioral alterations in ALS dating back over 130 years ago is provided. Despite being flawed by the inherent lack of scientific progress nowadays achieved, these early reports outstandingly align with the current notion of ALS and FTDs being linked, not only at a phenotypic level but also from anatomofunctional, histopathological, and genetic points of view. It is indeed not incautious to state that several landmarks on the link between ALS and FTD had been reached way before the late 1990s of the twentieth century (Fig. 2). It has then to be noted that, between 1981 and the early 2000s, a number of reports can be traced that somehow paved the path to the full acknowledgment of the ALS-FTD spectrum occurred with the first, dedicated nosographic system by Strong et al. [100]—as indexed by a number reviews that elegantly summarized evidence at that time available, among the most remarkable being those by Strong et al. [101] and Neary et al. [79], with some other, relevant reports between 1981 and the early 2000s being also more recently brought to the light by Alberti et al. [2]. The present work also follows up to and completes the previous one by Bak and Hodges [7], who pioneeristically addressed certain of the historical records herewith described, and is complemented by an extremely recent, historical work by Carlos and Josephs [22] who focused on the centenary journey leading to the acknowledgment of the neuropathological basis of FTD-spectrum disorders.