Gloria M. Grace

Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a multisystem disorder which includes both clinical and neuropathological features of a frontotemporal lobar degeneration (FTLD). In order to provide a common framework within which to discuss the characteristics of the cognitive and behavioural syndromes of ALS, and with which to conduct clinical and neuropathological research, an international research workshop on frontotemporal dementia (FTD) and ALS was held in London, Canada in June 2007. The recommendations arising from this research workshop address the requirement for a concise clinical diagnosis of the underlying motor neuron disease (Axis I), defining the cognitive and behavioural dysfunction (Axis II), describing additional non-motor manifestations (Axis III) and identifying the presence of disease modifiers (Axis IV).

A prospective study of cognitive impairment in ALS.

Objective: To characterize prospectively the cognitive profile in ALS. Methods: Clinically definite ALS patients (11 men, 2 women), age 39.9 to 74.0 years (mean age, 54.2 ± 9.6 years; mean disease duration, 21.1 ± 10.5 months) underwent neuropsychologic, language, and speech testing followed by MR 1H spectroscopy (4 T). Five spousal control subjects completed an identical protocol. Eight ALS patients participated in follow-up studies at a 6-month interval. Results: Relative to control subjects, ALS patients showed mild impairment in word generation, recognition memory (faces), and motor-free visual perception. Bulbar-onset patients showed greater impairment in a number of measures (working memory, problem solving/cognitive flexibility, visual perception, and recognition memory for words and faces), and cognitive impairment appeared more progressive over time. ALS patients demonstrated anomia on a confrontation naming test, with no significant problems following commands or repeating. Speech motor performance scores and intelligibility scores were not significantly different. No significant declines in forced vital capacity, forced expiratory volume, or peak expiratory flow rates were observed. Although normal at initial testing (T1), MR 1H spectroscopy demonstrated a reduction of the N-acetylaspartate/creatine (NAA/Cr) ratio in the nondominant precentral motor strip across the two testing intervals. In contrast, the NAA/Cr ratio obtained from the anterior cingulate gyrus at T1 was already reduced in bulbar-onset patients (p < 0.001), whereas no deficits were observed in limb-onset individuals in the same region. Conclusions: Bulbar-onset ALS patients with cognitive impairments and neuronal loss in the anterior cingulate gyrus subsequently developed more profound neuropsychological dysfunction whereas both language and speech capabilities remained relatively preserved. Of note, the absence of bulbar signs did not predict an absence of cognitive decline.

Cognitive impairment in sporadic ALS A pathologic continuum underlying a multisystem disorder

Background: Traditionally considered a motor neuron–selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. Methods: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. Results: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. Conclusions: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia.

Cognition, Language, and Speech in Amyotrophic Lateral Sclerosis: A Review

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder manifesting as a relentless loss of motor capabilities and, ultimately, death. Traditionally thought to affect solely the lower motor neurons and corticospinal tracts, recent studies suggest that the pathogenic process of ALS is more extensive, involving dysfunction of cortical grey and white matter with clinical correlates of impairment in cognition and language. The impact of speech and motor deficits are discussed in relation to the issues of assessment of cognition and language. Three case studies are presented for illustrative purposes. Finally, direction for future research to investigate cognitive dysfunction in ALS are presented.

Cerebral haemodynamic changes accompanying cognitive impairment in primary lateral sclerosis

Our objective was to elucidate the relationship between cognitive decline and cerebral haemodynamics in patients with PLS. We examined 18 patients with PLS and contrasted both neuropsychological and cerebral perfusion findings with seven age- and education-matched non-PLS controls. PLS patients were stratified into two groups based on the number of abnormal neuropsychological test scores: 1) cognitively intact PLS patients (PLS; those having zero or one abnormal scores (n =14)), and 2) cognitively-impaired PLS patients (PLSci; those having two or more abnormal test scores (n =4)). There was considerable heterogeneity in level of cognitive functioning with four patients meeting the criteria for cognitive impairment. The findings were highly consistent with a frontotemporal lobar dysfunction. Using CT perfusion to assess cerebral haemodynamics, the PLSci group had increased cerebral blood volume (CBV) and mean transit time (MTT) with reduced cerebral blood flow (CBF). More specifically, MTT was significantly increased (p<0.05) in the PLSci group compared with controls in all regions and affected both grey and white matter, with the exception of the temporal lobe and subcortical parietal white matter. These observations suggest that a subset of PLS patients is subject to cognitive decline and that this process is associated with changes in cerebral haemodynamics.

Widespread cerebral haemodynamics disturbances occur early in amyotrophic lateral sclerosis

Abstract We wished to longitudinally assess early changes in cerebral perfusion (CP) and its relationship to cognitive impairment (CI) in ALS. Fourteen ALS patients at time of diagnosis and 11 spousal controls, both without CI, were longitudinally assessed to determine a relationship between CP and incidence of CI in early stage disease. Neuropsychological testing and CP measurements were performed in both ALS and control groups at the initial assessment (T0) and two time-periods post initial assessment, T1 and T2, taken on average 6.1 and 17.0 months after initial assessment (T0), respectively. CT perfusion was used to measure cerebral blood flow, blood volume, and mean transit time (MTT) for all cortical lobes, and subcortical grey and white matter. Two of 14 ALS patients progressed to CI. No differences in CP measurements existed at T0 or T1 between the ALS and control groups. At T2, widespread cortical differences in MTT were present between the two groups. The ALS group had significantly increased MTT in all cortical regions, as well as the thalamus, compared with the control group. Our findings suggest early widespread changes in CP occur outside the motor area in the absence of CI in ALS.