Niall Pender

Cognitive impairment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. ALS is the most common neurodegenerative disorder of young and middle-aged adults, and few treatments are available. Although the degeneration predominantly affects the motor system, cognitive and behavioural symptoms have been described for over a century, and there is evidence that ALS and frontotemporal dementia overlap clinically, radiologically, pathologically, and genetically. Cognitive decline in ALS is characterised by personality change, irritability, obsessions, poor insight, and pervasive deficits in frontal executive tests. This presentation is consistent with the changes to character, social conduct, and executive function in frontotemporal dementia. We highlight genetic, imaging, and neuropathological evidence that non-motor systems are affected in ALS and explain the importance of recent discoveries. We review studies of cognitive impairment in ALS and common neuropsychological test results. We also provide advice about clinical assessment of frontotemporal dysfunction in patients with ALS, and suggest future research. Understanding of cognitive impairment in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration.

The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study

Background Despite considerable interest, the population-based frequency, clinical characteristics and natural history of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not known. Methodology The authors undertook a prospective population-based study of cognitive function in 160 incident Irish ALS patients and 110 matched controls. Home-based visits were conducted to collect demographic and neuropsychological data. Patients were classified using the recently published consensus criteria and by a domain-based classification of both executive and non-executive cognitive processes. Results 13.8% of patients fulfilled the Neary criteria for frontotemporal dementia. In addition, 34.1% of ALS patients without evidence of dementia fulfilled the recently published consensus criteria for cognitive impairment. Non-demented ALS patients had a significantly higher frequency of impairment in language and memory domains compared to healthy controls. These deficits occurred primarily in patients with executive dysfunction. 14% of ALS patients had evidence of cognitive impairment without executive dysfunction, and no cognitive abnormality was detected in almost half the cohort (46.9%). Conclusion Co-morbid dementia occurs in approximately 14% of patients with a new diagnosis of ALS. Cognitive impairment, predominantly but not exclusively in the form executive dysfunction, is present in more than 40% of ALS patients who have no evidence of dementia. Cognitive impairment in ALS is not a universal feature, and its manifestations may be more heterogeneous than previously recognised.

Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study

Summary Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion. Methods A population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS. Findings Samples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50% vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1–3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansion Interpretation Patients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members. Funding Health Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association.

Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia

Background: The prognostic implications of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not established. Objectives: To investigate the survival effect of the comorbid frontotemporal dementia (FTD) and to determine whether, in the absence of dementia, impairment in different cognitive domains affects outcome. Methods: A prospective population-based study of incident cases of ALS in the Republic of Ireland included home-based neuropsychological assessments using age-, sex-, and education-matched controls. Four cognitive domains were evaluated: executive function, memory, language, and visuospatial skills. Results: Mean age of the participants (n = 139) was 63.3 years; 61.2% were male and 35.3% had bulbar-onset ALS. Factors associated with shorter survival included age more than 60, severe disability at baseline, shorter delay to diagnosis, and early respiratory involvement. Comorbid FTD was associated with significantly shorter survival time (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.04–6.85, p = 0.041). In patients with ALS without dementia, the presence of executive dysfunction was significantly associated with shorter survival. This was confirmed in a multivariate model that included age, delay to diagnosis, disease severity at baseline, education, and respiratory status (HR 3.44, 95% CI 1.45–8.18, p = 0.005). In the absence of executive dysfunction, single or multi-domain impairment in other cognitive domains had no significant effect on survival. Conclusion: Comorbid frontotemporal dementia is a negative prognostic indicator. In patients with ALS without dementia, executive dysfunction, but not impairment in other cognitive domains, is an important negative prognostic indicator.

Cognitive changes predict functional decline in ALS A population-based longitudinal study

Objective: To determine whether cognitive status in patients with amyotrophic lateral sclerosis (ALS) is a useful predictor of attrition and motor and cognitive decline. Methods: Cognitive testing was undertaken in a large population-based cohort of incident ALS patients using a longitudinal, case-control study design. Normative data for neuropsychological tests were generated using age-, sex-, and education-matched healthy controls who also underwent repeated assessments. Data were analyzed to generate models for progression/spread. Results: One hundred eighty-six patients with ALS who had no evidence of C9orf72 hexanucleotide repeat expansion were enrolled. A second and third assessment were undertaken in 98 and 46 of the patients with ALS, respectively. Executive impairment at the initial visit was associated with significantly higher rates of attrition due to disability or death and faster rates of motor functional decline, particularly decline in bulbar function. Decline in cognitive function was faster in patients who were cognitively impaired at baseline. Normal cognition at baseline was associated with tendency to remain cognitively intact, and with slower motor and cognitive progression. Conclusions: Non-C9orf72–associated ALS is characterized by nonoverlapping cognitive subgroups with different disease trajectories. These findings have important implications for models of ALS pathogenesis, and for future clinical trial design.

Multiparametric MRI study of ALS stratified for the C9orf72 genotype

Objective: To describe the patterns of cortical and subcortical changes in amyotrophic lateral sclerosis (ALS) stratified for the C9orf72 genotype. Methods: A prospective, single-center, single-protocol, gray and white matter magnetic resonance case-control imaging study was undertaken with 30 C9orf72-negative patients with ALS, 9 patients with ALS carrying the C9orf72 hexanucleotide repeat expansion, and 44 healthy controls. Tract-based spatial statistics of multiple white matter diffusion parameters, cortical thickness measurements, and voxel-based morphometry analyses were carried out. All patients underwent comprehensive genetic and neuropsychological profiling. Results: A congruent pattern of cortical and subcortical involvement was identified in those with the C9orf72 genotype, affecting fusiform, thalamic, supramarginal, and orbitofrontal regions and the Broca area. White matter abnormalities in the C9orf72-negative group were relatively confined to corticospinal and cerebellar pathways with limited extramotor expansion. The body of the corpus callosum and superior motor tracts were affected in both ALS genotypes. Conclusions: Extensive cortical and subcortical frontotemporal involvement was identified in association with the C9orf72 genotype, compared to the relatively limited extramotor pathology in patients with C9orf72-negative ALS. The distinctive, genotype-specific pathoanatomical patterns are consistent with the neuropsychological profile of the 2 ALS cohorts. Our findings suggest that previously described extramotor changes in ALS could be largely driven by those with the C9orf72 genotype.

Basal ganglia involvement in amyotrophic lateral sclerosis

Objectives: To characterize the nature and extent of basal ganglia involvement in amyotrophic lateral sclerosis (ALS) genotypes in vivo. Methods: Forty-four healthy controls and 39 patients with ALS were included in the study. Thirty patients with ALS had a negative C9orf72 status and 9 patients with ALS carried the C9orf72 hexanucleotide repeat expansion. High-resolution T1-weighted MRI data were used for model-based subcortical registration and segmentation. Fifteen subcortical structures were studied with both volumetric and vertex-wise approaches. Changes in basal ganglia diffusivity parameters were also assessed. Results: Using age as a covariate, patients with ALS who were C9orf72 repeat negative showed significant volume reductions in the left caudate nucleus (p = 0.01), left hippocampus (p = 0.007), and right accumbens nucleus (p = 0.001) compared with healthy controls. Vertex-wise shape analyses revealed changes affecting the superior and inferior aspects of the bilateral thalami, the lateral and inferior portion of the left hippocampus, and the medial and superior aspect of the left caudate. Basal ganglia pathology was more extensive in patients with ALS carrying the C9orf72 hexanucleotide repeat expansion. Conclusions: ALS is associated with widespread basal ganglia involvement. Caudate nucleus, hippocampus, and nucleus accumbens atrophy are key features of ALS. Dysfunction of frontostriatal networks is likely to contribute to the unique neuropsychological profile of ALS, dominated by executive dysfunction, apathy, and deficits in social cognition. Our quantitative imaging findings are consistent with postmortem studies and indicate that subcortical gray matter structures should be included in future biomarker studies of ALS.

Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality

Background Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS). Objectives To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability. Methods We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability. Results Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions. Conclusions Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.

Social cognition in neurodegenerative disorders: a systematic review

Social cognitive neuroscience is the study of the neurobiological systems underlying effective social behaviour. The neural processes supporting effective social interactions in everyday life and the consequences of dysfunction in these processes have been the focus of intense research over the last two decades. It is becoming increasingly apparent that the identification of social cognitive deficits in neurodegenerative conditions and their neural basis may provide a better understanding of the behavioural changes observed in these disorders. In addition, accumulating data suggest that detection of early impairment in social cognitive skills may aid in the early diagnosis of cognitive or behavioural impairment in some of these disorders, and may even play a role in the investigation of new therapeutic options. In this review, we outline the basic components of social cognitive processing, provide a systematic review of the literature pertaining to common neurodegenerative conditions, discuss current controversies and make recommendations for future research.

The Irish epilepsy surgery experience: Long-term follow-up

AIM To assess the long-term seizure outcome of Irish patients who underwent resective surgery for refractory epilepsy since 1975. We also wished to determine the impact of pathology and surgical technique (with particular reference to neocorticectomy) on seizure outcome. METHODS A retrospective review of medical notes, radiological and histopathological records, was undertaken between 1975 and 2005. Missing data was supplemented by telephone calls to patients. One hundred and ninety-nine patients suited the criteria for inclusion and had at least 1-year follow-up (1-24 years, mean 7.0 years). Engels criteria were used to classify seizure outcome at 1, 2, 5, 10, 15 and >15 years follow-up. RESULTS The percentage of patients seizure free at 2, 5, 10, 15 and >15 years were, 56.6%, 41.4%, 44%, 25% and 31.3%, respectively. Of patients with a pathologically confirmed diagnosis of mesial temporal sclerosis, 55.6% were seizure free at 10 years. Equivalent figures for tumour were 62.5%, for cortical dysplasia, 34.8%, for those without any demonstrable pathologic abnormality, 50%, for dual pathology, 50% and for all others, 33.3%. Of those with 10 years or greater follow-up only 20% of neocorticectomy patients were in Engel class 1, compared with an average of 58.5% for the other surgical techniques. CONCLUSION Seizure freedom rates for Irish Patients were comparable to other large retrospective studies. Patients who underwent selective procedures tended to do better than those undergoing lobar resections, in keeping with international trends. The surgical technique unique to the Irish cohort, temporal necocorticectomy, had the worst long-term outcome.