Abstract Deficits in memory are seen as a canonical sign of aging and a prodrome to dementia in older adults. However, our understanding of age-related cognition and brain morphology occurring throughout a broader spectrum of adulthood remains limited. We quantified the relationship between cognitive function and brain morphology (sulcal width, SW) using three cross-sectional observational datasets (PISA, AIBL, ADNI) from mid-life to older adulthood, assessing the influence of age, sex, amyloid (Aβ) and genetic risk for dementia. The data comprised cognitive, genetic and neuroimaging measures of a total of 1570 non-clinical mid-life and older adults (mean age 72, range 49–90 years, 1330 males) and 1365 age- and sex-matched adults with mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Among non-clinical adults, we found robust modes of co-variation between regional SW and multidomain cognitive function that differed between the mid-life and older age range. These cortical and cognitive profiles derived from healthy cohorts predicted out-of-sample AD and MCI. Furthermore, Aβ-deposition and educational attainment levels were associated with cognition but not SW. These findings underscoring the complex interplay between factors influencing cognition and brain structure from mid-life onwards, providing valuable insights for future research into neurodegeneration and the development of future screening algorithms.

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.

Creativity refers to the ability to produce ideas or actions that are novel and useful, incorporating convergent and divergent thinking. Currently, limited attention has been paid to changes in creativity with disease progression (e.g. mild cognitive impairment and Alzheimer's disease). Therefore, this study examined the patterns of creativity between healthy controls (n = 36), adults with mild cognitive impairment (MCI; n = 23), and adults with Alzheimer's disease (AD; n = 21). The study explored whether performance on creativity tasks can predict clinical group and contributing cognitive processes. Various cognitive tests were administered to participants, including measures of creativity. Our findings suggested that creative thought is reduced in individuals with MCI and AD, such that the AD group generated the lowest number of correct responses and made the most errors on all creativity tasks, indicating that creative ability decreases as dementia progresses. Performance on creativity tasks could also predict clinical group (depending on the task, ranging from 49% to 82% of those having MCI), indicating sensitivity to novel idea generation, which has been linked to frontal lobe impairment. Our findings suggested that core cognitive processes underlying creativity, including semantic knowledge and executive functions, are critical for producing new creative thoughts.

Objective: Motor neurone disease [MND] encompasses broad cognitive impairments, which are not fully captured by most screening tools. This study evaluated the specificity and sensitivity of the Edinburgh Cognitive and Behavioral ALS Screen [ECAS] in detecting impairments in executive function and social cognition. Methods: Participants (MND = 64; Healthy Controls = 45) completed the ECAS and standard neuropsychology tests of executive function and social cognition. Sensitivity and specificity of the ECAS were assessed at three levels (ALS-Specific score, executive function domain score, individual subtests: social cognition, inhibition, working memory, alternation). Results: MND patients were impaired on standard social cognition, initiation, visuomotor alternation, and verbal learning tests but not on inhibition or working memory tests, relative to controls. ECAS results revealed that the ALS-Specific score was high in specificity but low-to-moderately sensitive in identifying social cognition, inhibition, and working memory deficits, and that both sensitivity and specificity were high for identifying alternation deficits. The ECAS executive function domain score was high in specificity but poor in sensitivity for all four executive function domain subtests. The individual ECAS subtests were highly specific with good sensitivity, but the social cognition subtest lacked sensitivity. Conclusions: Impairments in social cognition may go undetected when using the ECAS as a screening tool. Thus, social cognition may need to be considered as a standalone component, distinct from the other executive functions. In addition, the test itself may need to be adjusted to encompass other aspects of social cognition that are affected in MND.Key messagesCognitive screening tools are key to detect cognitive changes in MND, with the domains most affected being executive functions, language, and social cognition.The ECAS measure, developed for MND, has good specificity but lacks sensitivity to impairments in social cognition.Clinical implications are that cognitive impairments in social cognition may not be identified in MND patients by the ECAS.Adjustment to the ECAS cognitive screening tool widely-used in MND is suggested.

Self-administered online cognitive testing offers a cost-effective and flexible alternative to in-person neuropsychological assessments. We used the Creyos platform (previously named Cambridge Brain Sciences) to assess cognitive function in a large sample (N = 1673) of middle aged and older adults participating in the PISA (Prospective Imaging Study of Aging) study. PISA aims to characterise the early symptoms and progression of Alzheimer’s disease at its prodromal phase. We have utilised our Australia-wide population based sample recruitment pool of research participants with genome wide genotyping. Participants completed a comprehensive online survey and online cognitive assessments, including Creyos, consisting of 12 self-administered tasks covering memory, executive function, language, and visuo-spatial domains. Using genetic profile scores in a sample size of 1,673 (70% female, aged 42-75 years, mean 60.8). We tested the association between cognitive test results and genetic risk for Alzheimer’s disease and related phenotypes including structural neuroimaging measures. Our findings indicate a significant association of Alzheimer’s polygenic risk scores (PRS) with cognitive test results in healthy individuals within memory and executive function domains. The results of analyses with additional genetic profile scores including psychiatric traits and structural neuroimaging measures will also be presented. Those who are at high genetic risk for Alzheimer’s disease have reduced cognitive function prior to dementia diagnosis from middle age. Our results highlight the utility of online cognitive testing as a cost-effective alternative to in person testing for large scale studies and the potential for it’s used as a pre-screening approach to identify those at high risk of Alzheimer’s disease.

Understanding how cognition and brain structure change across the lifespan is crucial for gaining insight into the healthy ageing process, as well as identifying early signs of neurodegenerative changes. In our recent prospective study of healthy ageing in midlife and older adults[1][1], we compared the association of two cognitive batteries with age-related variability in brain morphology. Our findings revealed that online cognitive testing, which is more cost-effective, demonstrated comparable association to sulcal width as comprehensive in person assessment. Both cognitive assays show similarly strong correlations with sulcal width. In addition, it was found that both cognitive assessment assays showed a more pronounced age-related decline in individuals with Aβ burden. These findings suggest that online assessment is able to detect accelerated cognitive ageing comparably to the in-person assay in our preclinical sample, even in the early stages of Aβ accumulation before significant structural brain changes occur. Taken together with their greater cost effectiveness, online cognitive testing could lead to more equitable early detection and intervention for neurodegenerative diseases.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study was funded by the National Health and Medical Research Council, Australia.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Data collection and analysis followed approval from the Human Research Ethics committees of QIMR Berghofer (P2193 and P2210), the University of Queensland (2016/HE001261), The University of Newcastle (H-2020-0439) and the National Statement on Ethical Conduct in Human Research. Written informed consent was obtained from all participants following local institutional ethics approval.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors [1]: #ref-1

Background: Apathy, characterized by a quantifiable reduction in motivation or goal-directed behavior, is a multidimensional syndrome that has been observed across many neurodegenerative diseases. Objective: To develop a novel task measuring spontaneous action initiation (ie, a nonverbal equivalent to spontaneous speech tasks) and to investigate the association between apathy and executive functions such as the voluntary initiation of speech and actions and energization (ie, ability to initiate and sustain a response). Method: We compared the energization and executive functioning performance of 10 individuals with neurodegenerative disease and clinically significant apathy with that of age-matched healthy controls (HC). We also investigated the association between self-reported scores on the Apathy Evaluation Scale (AES) and performance on energization tasks. Results: The individuals with apathy made significantly fewer task-related actions than the HC on the novel spontaneous action task, and their scores on the AES were negatively correlated with spontaneous task-related actions, providing preliminary evidence for the task’s construct validity. In addition, the individuals with apathy performed more poorly than the HC on all of the energization tasks, regardless of task type or stimulus modality, suggesting difficulty in sustaining voluntary responding over time. Most of the tasks also correlated negatively with the AES score. However, the individuals with apathy also performed more poorly on some of the executive function tasks, particularly those involving self-monitoring. Conclusion: Our work presents a novel experimental task for measuring spontaneous action initiation—a key symptom of apathy—and suggests a possible contribution of apathy to neuropsychological deficits such as poor energization.

Deficits in memory are seen as a canonical sign of ageing and a prodrome to dementia in older adults. However, the nature of cognitive and brain changes across a wider aperture of adulthood is not well known. We quantify the relationship between cognitive function and brain morphology from mid-life to older adulthood, and the influence of age, sex, amyloid and genetic risk for dementia. We analyzed three observational cohorts (PISA, AIBL, ADNI) with cognitive, genetic and neuroimaging measures comprising a total of 1570 healthy mid-life and older adults (mean age 72, range 49-90 years, 1330 males) and 1365 age- and sex-matched adults with mild cognitive impairment or Alzheimer’s disease. Among healthy adults, we find robust modes of co-variation between regional sulcal width and multidomain cognitive function that change from mid-life to the older age range. The most prominent cortical changes in mid-life are predominantly associated with changes in executive functions, whereas they are most strongly associated with poorer memory function in older age. These cognitive changes are accompanied by an age-dependent pattern of sulcal widening. Amyloid exerts a weak, but significant, influence on cognition, but not on sulcal width. The APOE ɛ4 allele also exerts a weak influence on cognition, but only significantly in the (larger and older) AIBL cohort. These findings provide new insights into brain and cognition in mid-life and older adults, suggesting that cognitive screening in mid-life cohorts should encompass executive functions as well as memory.

OBJECTIVE:Hybrid teleneuropsychology has emerged as a useful assessment method to manage physical distancing requirements during the COVID-19 pandemic. We describe the development of a hybrid teleneuropsychology clinic and compare results of six neuropsychological tasks across testing modalities, as well as a participant experience survey. METHOD:Healthy middle-aged and older adults completed a face-to-face assessment two years previously. Participants either completed reassessment face-to-face or via the hybrid setup. Results were compared across time points and delivery modality. RESULTS:There were no significant differences in scores at reassessment between face-to-face and a hybrid setup on nonverbal fluid intelligence, verbal memory, visual memory, language, working memory or verbal initiation. Retest reliability was moderate to excellent for verbal and visual memory, attention and naming. Results of an anonymous survey indicated that participants felt comfortable and established good rapport with the examiner. CONCLUSIONS:This hybrid method of teleneuropsychology can be used to obtain high quality and reliable results including on tasks yet to be evaluated for teleneuropsychology, including the Graded Naming Test and the Topographical Recognition Memory Test.

Background: Parkinson's disease [PD] is associated with reduced motor and cognitive initiation, and decreased goal-directed behavior including language generation. The current study investigated a novel goal intervention for language generation impairments in PD patients. Methods: Twenty-one PD patients and 22 healthy controls, matched for gender, age, and education, completed a cognitive baseline and language generation tasks (complex scene descriptions and phonemic/semantic word fluency) with standard and adapted instructions, which implements a target 'goal'. In addition, participants completed self-report questionnaires for apathy and mood. Results: PD patients performed more poorly on two of three language generation tasks. The goal intervention was effective in increasing both the PD patient and healthy control groups' language generation. However, there was no differential benefit of increased goal specificity and difficulty for PD patients. As a group, PD patients reported higher levels of apathy and depression than healthy controls. Specifically, PD patients with executive apathy were more likely to have language generation impairments than PD patients without executive apathy and controls. Apathy subscales and goal benefit were unrelated. Conclusions: The goal intervention was effective for PD patients and older adults, suggesting that enhanced goal specificity and difficulty may benefit individuals with PD or those aging naturally.

The PISA study aims to characterise the natural history and symptom progression of Alzheimer’s disease (AD) at its prodromal phase. Utilising genetic risk prediction we have identified middle-aged and older Australians at high risk of dementia. In addition to onsite phenotyping, online surveys and cognitive testing have been used to economically collect information from an Australia-wide sample. We have utilised our population based sample recruitment pool (N=15,351) of previous research participants who have been genome wide genotyped. Participants are invited to complete a comprehensive online survey, then complete online cognitive assessments, including Cambridge Brain Sciences (CBS), Cogstate, and an emotion recognition task. Thus far nearly 4,000 participants have taken part in our online survey, and of these 2055 participants have completed the CBS assessment consisting of twelve subtests assessing memory, reasoning, attention, and planning. Recruitment for CBS and the other platforms is ongoing and participants are being invited to complete follow-up assessments after two years. At baseline we find significant association of both APOE genotype and polygenetic risk scores (PRS) for AD (omitting the APOE region) in healthy middle aged and elderly individuals with cognitive domains tested using the CBS platform. The utility of online cognitive testing for large scale testing in cohort and epidemiological studies will be discussed. The identification of cognitive changes associated with AD risk and prodromal disease gives important insights into mechanisms of AD development throughout the life span and is an opportunity to investigate prodromal markers to allow selection of individuals for early treatment strategies.

The number produced on fluency tasks is widely used to measure voluntary response generation. To further evaluate the relationship between generation, errors, and the area of anatomical damage we administered eight fluency tasks (word, design, gesture, ideational) to a large group of focal frontal (n = 69) and posterior (n = 43) patients and controls (n = 150). Lesions were analysed by a finer-grained frontal localisation method, and traditional subdivisions (anterior/posterior, left/right frontal). Thus, we compared patients with Lateral lesions to patients with Medial lesions. Our results show that all fluency tasks are sensitive to frontal lobe damage for the number of correct responses and, for the first time, we provide evidence that seven fluency tasks show frontal sensitivity in terms of errors (perseverations, rule-breaks). Lateral (not Medial) patients produced the highest error rates, indicative of task-setting or monitoring difficulties. There was a right frontal effect for perseverative errors when retrieving known or stored items and rule-break errors when creating novel responses. Left lateral effects were specific to phonemic word fluency rule-breaks and perseverations for meaningless gesture fluency. In addition, our generation output and error findings support a frontal role in novelty processes. Finally, we confirm our previous generation findings suggesting critical roles of the superior medial region in energization and the left inferior frontal region in selection (Robinson et al., 2012). Overall, these results support the notion that frontal functions comprise a set of highly specialised cognitive processes, supported by distinct frontal regions.

Aphasia assessment tools have primarily focused on classical aphasia type and severity, with minimal incorporation of recent findings that suggest a significant role of executive control operations in language generation. Assessment of the interface between language and executive functions is needed to improve detection of spontaneous speech difficulties. In this study we develop a new Brief Executive Language Screen (BELS), a brief tool specifically designed to assess core language and executive functions shown to be involved in spontaneous generation of language. Similar to other measures of aphasia, the BELS assesses articulation and core language skills (repetition, naming and comprehension). Unique additions to the BELS include assessments of spontaneous connected speech, word fluency (phonemic/semantic) and sentence completion (verbal initiation, inhibition and selection). One-hundred and eight healthy controls and 136 stroke patients were recruited. Confirmatory factor analysis was used to determine construct validity and logistic regression was used to evaluate the discriminative validity, informing the final version of the BELS. The results showed that the BELS is sensitive for articulation and nominal language deficits, and it measures executive aspects of spontaneous language generation, which is a hallmark of frontal dynamic aphasia. The results have encouraging theoretical and practical implications.

Language disorders are increasingly recognised in Amyotrophic lateral sclerosis (ALS), supporting the view of ALS as a multi-system disorder, impacting cognitive and motor function. However, the language impairments are heterogeneous and recent focus has been on determining the language profile across the ALS spectrum with little focus on spontaneous speech. The current study systematically investigated a wide range of language abilities in an unselected ALS sample (N = 22), including spontaneous speech. We analysed the ALS patients' performance as a group, compared to age-, education- and IQ-matched healthy controls (N = 21), and as a case series to identify dementia and specific language profiles. The ALS group was impaired on measures of spontaneous speech, word fluency and action naming. By contrast, object naming, semantic memory (object and actions), sentence comprehension and repetition (word and sentences) were comparable to healthy controls. In line with recent suggestions, our ALS patients’ action naming (but not action semantic) deficit does not support the notion that action processing may be selectively impaired in ALS. The case series demonstrated that 14% of patients had probable dementia, 31% showed significant cognitive and/or language impairment and 55% were unimpaired, consistent with the spectrum of cognitive and language impairments reported in the literature. In addition, 36% of ALS patients produced significantly fewer words per minute on a spontaneous speech task than the control group, with this difference remaining when the ALS patients with frontotemporal dementia were excluded from the analysis. This pattern was observed across the ALS spectrum and in both limb and bulbar onset patients. The pattern of performance observed in the present study suggests that spontaneous speech is reduced across the ALS spectrum even in those with intact core language abilities.

Internally generated responses are centrally affected in parkinsonian disorders. This study investigated the cognitive components crucial for response generation as reflected in performance on verbal and non-verbal fluency tasks, which require voluntary internal generation of multiple responses. Participants with parkinsonian disorders (N = 58: 29 Parkinson's disease [PD], 22 corticobasal syndrome [CBS], 8 progressive supranuclear palsy [PSP]) and 89 age-matched controls completed baseline cognitive assessments and eight fluency tasks of four types: word, design, gesture, and ideational. We analysed the total number of correct responses generated and error rates (including repetitions and rule breaks) for PD, CBS and Control groups. The small PSP patient group's performance is reported for comparative purposes only. CBS patients were significantly reduced in the number of correct responses generated across all fluency tasks, without incurring significant errors. The only exception was that CBS patients produced a significantly higher number of repetitions on one nonverbal task (design fluency). By contrast, PD patients' generation was reduced on only three fluency tasks (phonemic word, meaningless gesture, conventional idea). However, they also produced a high error rate on four fluency tasks (rule-break errors: phonemic/semantic word; repetitions: semantic word, meaningless gestures). Overall, the pattern of fluency task performance differs between patient groups. Specifically, the quantity of responses generated is differentially and primarily affected in CBS patients, whereas the quality of responses generated is primarily affected in PD patients. This suggests potentially different patterns of performance for parkinsonian disorders and has implications for the cognitive processes crucial for internally-guided response generation.

AbstractBackgroundNeuropathology accumulates for decades prior to the onset of cognitive decline in Alzheimer’s disease (AD). Interventions to modify the course of the disease have the greatest potential to avert neuronal death and later disease burden if they are introduced during this crucial window. Our prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) aims to characterise the natural history of AD at its prodromal phase. Using genetic risk prediction we have identified middle‐aged and older Australians at high risk of dementia to enable the discovery of biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease conversion.MethodWe utilized APOE genotype and polygenic risk scores (PRS) to identify individuals at high and low risk of AD. We have leveraged our extensive in‐house cohorts, comprising ∼15,000 individuals aged 40‐70 years with available genome wide genotyping data to generate a genetically enriched cohort for investigating prodromal markers for AD. Online surveys and cognitive testing are used to collect information from a national sample currently totally nearly 3,000 participants. Subjects (N = 400) from a defined at‐risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment and/or early AD) have taken part in onsite visits for lifestyle monitoring, cognitive testing, blood sample donation, MRI and PET imaging.ResultA high prediction accuracy for AD with an AUC of 78.2% can be achieved by a prediction model including APOE genotype, and PRS (containing GWAS association SNPs with P value <0.5) with the PRS adding significant predictive value over APOE alone. The association of genetic factors with baseline imaging and neuropsychological phenotypes will be presented as well as multivariate analysis investigating the influence of genetic risk on inter‐individual phenotypic relationships.ConclusionThe PISA study is an at risk AD cohort enriched by genome‐wide risk prediction, aiming to validate early markers of prodromal Alzheimer’s disease that can be utilized in middle age. This study will help elucidate changes in early prodromal AD risk variants observed in middle age, and evaluate which measures show the earliest changes.

This prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer’s disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

The ability to select an idea from an array of competing options is critical for successful propositional language production, and deficient idea selection contributes to propositional language impairments in clinical populations. We investigate whether three clinical idea selection tasks are sensitive to selection demands in neurologically unimpaired adults, and whether performance relates to age. 154 neurologically normal adults aged 18-89 years completed a neuropsychological baseline and three idea selection tasks. Stimuli either activated a dominant response or multiple competing response options. All three idea selection tasks were sensitive to selection demands in terms of reaction times but not errors. Older age was associated with greater effects of selection demands on Sentence Completion task performance only. Exploratory analyses revealed a potential role of executive functioning. Overall, we demonstrate that clinical idea selection tasks are sensitive to idea selection demands in a non-clinical sample, and show some age-related differences in performance.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by the presence of upper and lower motor neuron dysfunction. Clinical presentation and disease progression are variable between patients with ALS, with psychosocial, neuropsychological, nutritional and genetic factors all related to ALS outcome. We present a detailed characterisation of a patient with familial ALS with a novel TBK1 mutation with coexistent brain atrophy, behavioural changes and metabolic dysfunction.This male patient was first seen at age 62 years with a 3-month history of gait unsteadiness, weakness of the right arm and emotional lability. There was a history of depression. His father had died of ALS at age 67 years. At first assessment, there was weakness of the right upper limb, ALS Functional Rating Scale-Revised (ALSFRS-R) was 39 and his weight was 72 kg. After 6 months, there was onset of dysphagia. He had tongue fasciculations, brisk jaw jerk, weakness, wasting, brisk reflexes and fasciculations of upper and lower limbs. The ALSFRS-R was 34 and weight had further declined to 65 kg. Three months later, he had deteriorated further with severe weakness, nausea, anorexia and depression. ALSFRS-R was 25 and weight was 54 kg. His respiratory function declined from FVC of 4.57 L to 1.05 L over 6 months. He died ~16 months after the onset of symptoms.The patient participated in a series of neuropsychological, imaging and metabolic studies of unselected consenting patients with ALS enrolled from our clinic.1 Neuropsychological assessment results for this patient are presented in online supplementary table 1. Comparison of his individual results with those of other patients with ALS is presented in online supplementary tables 2 to 4. Genetic assessment was done by massively parallel sequencing using a custom-designed neuromuscular gene capture panel that tests for 66 genes known to be associated …

ObjectiveTo determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival.MethodsFifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment.ResultsHypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (−0.68 points/month vs −0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03).Conclusions and relevanceHypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.