Dysfunctional sodium channel kinetics as a novel epilepsy mechanism in chromosome 15q11-q13 duplication syndrome.

OBJECTIVE: Duplication of the maternal chromosome 15q11.2-q13.1 region causes Dup15q syndrome, a highly penetrant neurodevelopmental disorder characterized by severe autism and refractory seizures. Although UBE3A, the gene encoding the ubiquitin ligase E3A, is thought to be the main driver of disease phenotypes, the cellular and molecular mechanisms that contribute to the development of the syndrome are yet to be determined. We previously established the necessity of UBE3A overexpression for the development of cellular phenotypes in human Dup15q neurons, including increased action potential firing and increased inward current density, which prompted us to further investigate sodium channel kinetics. METHODS: We used a Dup15q patient-derived induced pluripotent stem cell line that was CRISPR-edited to remove the supernumerary chromosome and create an isogenic control line. We performed whole cell patch clamp electrophysiology on Dup15q and corrected control neurons at two time points of in vitro development. RESULTS: Compared to corrected neurons, Dup15q neurons showed increased sodium current density and a depolarizing shift in steady-state inactivation. Moreover, onset of slow inactivation was delayed, and a faster recovery from both fast and slow inactivation processes was observed in Dup15q neurons. A fraction of sodium current in Dup15q neurons (~15%) appeared to be resistant to slow inactivation. Not unexpectedly, a higher fraction of persistent sodium current was also observed in Dup15q neurons. These phenotypes were modulated by the anticonvulsant drug rufinamide. SIGNIFICANCE: Sodium channels play a crucial role in the generation of action potentials, and sodium channelopathies have been uncovered in multiple forms of epilepsy. For the first time, our work identifies in Dup15q neurons dysfunctional inactivation kinetics, which have been previously linked to multiple forms of epilepsy. Our work can also guide therapeutic approaches to epileptic seizures in Dup15q patients and emphasize the role of drugs that modulate inactivation kinetics, such as rufinamide.

The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.

Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is the only imprinted gene expressed solely from the maternal allele. Nevertheless, the exact role of UBE3A has not been determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, we generated an isogenic control line for a Dup15q patient-derived induced pluripotent stem cell line. Dup15q neurons exhibited hyperexcitability compared with control neurons, and this phenotype was generally prevented by normalizing UBE3A levels using antisense oligonucleotides. Overexpression of UBE3A resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes but also suggest a role for other genes in the duplicated region.

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort. METHODS: Longitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out. RESULTS: CR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out. CONCLUSIONS: These findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.

A unifying mechanism of ketogenic diet action: The multiple roles of nicotinamide adenine dinucleotide.

The ability of a ketogenic diet to treat seizures and render a neuronal network more resistant to strong electrical activity has been observed for a century in clinics and for decades in research laboratories. Alongside ongoing efforts to understand how this therapy works to stop seizures, metabolic health is increasingly appreciated as critical buffer to resisting and recovering from acute and chronic disease. Accordingly, links between metabolism and health, and the broader emerging impact of the ketogenic diet in improving diverse metabolic, immunological and neurological conditions, have served to intensify the search for its key and/or common mechanisms. Here we review diverse evidence for increased levels of NAD+, and thus an altered ratio of NAD+/NADH, during metabolic therapy with a ketogenic diet. We propose this as a potential unifying mechanism, and highlight some of the evidence linking altered NAD+/NADH with reduced seizures and with a range of short and long-term changes associated with the beneficial effects of a ketogenic diet. An increase in NAD+/NADH is consistent with multiple lines of evidence and hypotheses, and therefore we suggest that increased NAD+ may be a common mechanism underlying beneficial effects of ketogenic diet therapy.

Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus.

The ketogenic diet's (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 (PARP-1). As a result, activation of NAD+-dependent enzymes' downstream pathways could be the origin of KD's broad beneficial effects. Here rats were fed ad libitum regular chow or KD for 2 days or 3 weeks and the levels of hippocampal sirtuins, PARP-1, and the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine were quantified. We found a significant immediate and persistent increase in the collective activity of nuclear sirtuin enzymes, and a significant augmentation of Sirt1 mRNA at 2 days. Levels of PARP-1 and 8-hydroxy-2'-deoxyguanosine decreased after 2 days of treatment and further declined at 3 weeks. Our data show that a KD can rapidly modulate energy metabolism by acting on NAD+-dependent enzymes and their downstream pathways. Thus, therapy with a KD can potentially enhance brain health and increase overall healthspan via NAD+-related mechanisms that render cells more resilient against DNA damage and a host of metabolic, epileptic, neurodegenerative, or neurodevelopmental insults.

Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?

The ketogenic diet's (KD) anticonvulsant effects have been well-documented for nearly a century, including in randomized controlled trials. Some patients become seizure-free and some remain so after diet cessation. Many recent studies have explored its expanded therapeutic potential in diverse neurological disorders, yet no mechanism(s) of action have been established. The diet's high fat, low carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose and improve mitochondrial function and biogenesis. Cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. Based on differential NAD+ utilization during glucose- vs. ketone body-based acetyl-CoA generation for entry into the tricarboxylic cycle, we propose that a KD will increase the NAD+/NADH ratio. When rats were fed ad libitum KD, significant increases in hippocampal NAD+/NADH ratio and blood ketone bodies were detected already at 2 days and remained elevated at 3 weeks, indicating an early and persistent metabolic shift. Based on diverse published literature and these initial data we suggest that increased NAD during ketolytic metabolism may be a primary mechanism behind the beneficial effects of this metabolic therapy in a variety of brain disorders and in promoting health and longevity.

Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of Patients With Amyotrophic Lateral Sclerosis.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior. Objective: To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS. Design, Setting, and Participants: In this population-based, case-control family aggregation study, all 202 patients included in the Irish ALS Register between January 1, 2012, and January 31, 2014, with definite, probable, or possible ALS as defined by El Escorial criteria were invited to participate. A total of 75 patients were unable or refused to participate and were excluded; the remaining 127 patients with incident ALS were genotyped for the C9orf72 repeat expansion and 132 age- and sex-matched controls were included in the study. Main Outcome and Measures: The prevalence of defined neuropsychiatric disease in first-degree and second-degree relatives of patients with ALS and matched controls was determined. Results: Mean (SD) age at diagnosis of the 127 patients in the study (58 women and 69 men) was 64.2 (10.7) years. Data from 2116 relatives of patients with ALS were reported, including 924 first-degree relatives, 1128 second-degree relatives, and 64 third-degree relatives. Data from controls were reported from 829 first-degree and 1310 second-degree relatives. A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95% CI, 1.08-2.17; P = .02). Cluster analysis suggested the following 2 subgroups based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (≥3). Within the high subgroup, ALS kindreds presented a significantly higher rate of psychiatric illness than did controls (28 of 39 [71.8%]; mean [SD] number of siblings, 4.29 [1.41]; P = .001). A strong family history of schizophrenia (RR, 3.40; 95% CI, 1.27-9.30; P = .02), suicide (RR, 3.30; 95% CI, 1.07-10.05; P = .04), autism (RR, 10.10; 95% CI, 1.30-78.80; P = .03), and alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P = .045) was reported in ALS kindreds. A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (≥3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion. Conclusions and Relevance: Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls. The presence of the C9orf72 repeat expansion does not fully account for this finding, suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population.

Assessing behavioural changes in ALS: cross-validation of ALS-specific measures.

The Beaumont Behavioural Inventory (BBI) is a behavioural proxy report for the assessment of behavioural changes in ALS. This tool has been validated against the FrSBe, a non-ALS-specific behavioural assessment, and further comparison of the BBI against a disease-specific tool was considered. This study cross-validates the BBI against the ALS-FTD-Q. Sixty ALS patients, 8% also meeting criteria for FTD, were recruited. All patients were evaluated using the BBI and the ALS-FTD-Q, completed by a carer. Correlational analysis was performed to assess construct validity. Precision, sensitivity, specificity, and overall accuracy of the BBI when compared to the ALS-FTD-Q, were obtained. The mean score of the whole sample on the BBI was 11.45 ± 13.06. ALS-FTD patients scored significantly higher than non-demented ALS patients (31.6 ± 14.64, 9.62 ± 11.38; p < 0.0001). A significant large positive correlation between the BBI and the ALS-FTD-Q was observed (r = 0.807, p < 0.0001), and no significant correlations between the BBI and other clinical/demographic characteristics indicate good convergent and discriminant validity, respectively. 72% of overall concordance was observed. Precision, sensitivity, and specificity for the classification of severely impaired patients were adequate. However, lower concordance in the classification of mild behavioural changes was observed, with higher sensitivity using the BBI, most likely secondary to BBI items which endorsed behavioural aspects not measured by the ALS-FTD-Q. Good construct validity has been further confirmed when the BBI is compared to an ALS-specific tool. Furthermore, the BBI is a more comprehensive behavioural assessment for ALS, as it measures the whole behavioural spectrum in this condition.

Semi-quantitative analysis of cerebral FDG-PET reveals striatal hypermetabolism and normal cortical metabolism in a case of VGKCC limbic encephalitis.

In the context of delayed autoimmune encephalitis antibody results, functional imaging can support the diagnosis of limbic encephalitis associated with anti-voltage-gated potassium channel complex (VGKCC) antibodies. Here we present a typical case of VGKCC encephalitis in a 69-year-old woman whose symptoms responded to plasmapheresis. A cerebral 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan performed prior to commencing treatment revealed striatal hypermetabolism assessed qualitatively and semi-quantitatively, with normal uptake in the cortex and cerebellum when analysed semi-quantitatively. Repeat FDG-PET imaging performed three months later revealed normalisation of striatal hypermetabolism. Previous case reports have described striatal hypermetabolism and/or cortical hypometabolism in patients with VGKCC encephalitis. However, most of these descriptions were based on qualitative analyses only and may represent the relative change in cortical metabolism compared with striatal metabolism. We recommend semi-quantitative analysis of cerebral FDG-PET, in addition to reporting the qualitative FDG-PET images.

Uncommon mutation in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS).

A 26-year-old man presented to the emergency department with new-onset generalised tonic-clonic seizures. His clinical picture suggested either autoimmune or infectious encephalitis while his brain imaging raised the possibility of a stroke. A detailed developmental and childhood medical history added suspicion of a mitochondrial defect to the differential. After several molecular genetic analyses, an uncommon mitochondrial mutation was confirmed, unequivocally consistent with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome.

Visual encoding, consolidation, and retrieval in amyotrophic lateral sclerosis: executive function as a mediator, and predictor of performance.

OBJECTIVE: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). METHODS: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. RESULTS: Patients and controls significantly differed on the Copy trial (p < 0.0001: ω2 = 0.317) immediate recall (p < 0.0001: ω2 = 0.272) and delayed recall (p < 0.0001: ω2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). CONCLUSIONS: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT.

Identifying behavioural changes in ALS: Validation of the Beaumont Behavioural Inventory (BBI).

OBJECTIVE: Behavioural changes are an important part of amyotrophic lateral sclerosis (ALS). However, most tools do not account for the influence of motor impairment. Furthermore, they do not fully measure the broad range of behavioural changes specific to ALS. This study aimed to develop and validate an ALS specific behavioural inventory, the Beaumont Behavioural Inventory (BBI). METHODS: The BBI was validated in a cohort of ALS patients (n = 85) and 78 age-, gender-, and education-matched controls. The scale was validated against the Frontal Systems Behaviour Scale (FrSBe) and The Frontal Assessment Battery (FAB) for convergent validity, and against other non-behavioural measures to assess discriminant validity. Reliability was assessed with Cronbach's alpha. RESULTS: The instrument showed high internal consistency (Cronbach's alpha value =0.891). BBI scores highly correlated with the FrSBe and moderately with the FAB. However, the measure was independent from non-behavioural measures. Using a cut-off score of 7 for mild behavioural changes, the BBI displayed high sensitivity and specificity (87.9% and 78.85%, respectively). The cut-off score for moderate changes, consistent with a diagnosis of ALS-FTD, is set at 22.5, showing 90% sensitivity and 96% specificity. DISCUSSION: The BBI is a sensitive and specific tool to assess the entire behavioural spectrum of ALS.

Screening for cognitive dysfunction in ALS: validation of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) using age and education adjusted normative data.

BACKGROUND: Cognitive and behavioural changes are an important aspect in Amyotrophic Lateral Sclerosis (ALS). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) briefly assesses these changes in ALS. OBJECTIVE: To validate the ECAS against a standardised neuropsychological battery and assess its sensitivity and specificity using age and education adjusted cut-off scores. METHOD: 30 incident ALS cases were assessed on both, ECAS and neuropsychological battery. Age and education adjusted cut-off scores were created from a sample of 82 healthy controls. RESULTS: ECAS composite scores (Total, ALS Specific and Non-Specific) were highly correlated with battery composite scores. High correlations were also observed between ECAS and full battery cognitive domains and subtests. The ECAS Total, ALS Specific and Non-Specific scores were highly sensitive to cognitive impairment. ECAS ALS-Specific cognitive domains also evidenced high sensitivity. Individual subtest sensitivity was medium to low, suggesting that caution should be used when interpreting these scores. Low positive predictive values indicated the presence of false positives. CONCLUSIONS: Psychometric properties of the ECAS using age and education adjusted norms indicate that the ECAS, when used as an overall measure of cognitive decline, is highly sensitive. Further comprehensive assessment is required for patients that present as impaired on the ECAS.

Measurement of Social Cognition in Amyotrophic Lateral Sclerosis: A Population Based Study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Executive dysfunction is common in patients with ALS, with up to 50% of patients performing within an impaired range. There is evidence that social cognitive deficits associated with ALS are a function of deficits in executive function. The 'Reading the Mind in the Eyes' Test is a recognized test of social cognitive function, although the reliability of this instrument remains to be established. METHODOLOGY: Patients with ALS (n = 106), and age and IQ matched controls (n = 50) were recruited and asked to perform the Reading the Mind in the Eyes Test as part of an on-going population-based study of cognitive function. ALS patients were sub-stratified based on the presence, and/or extent of executive dysfunction. RESULTS: Cronbach's Alpha of .73 was observed, indicating good reliability on this measure. Split-half reliability analysis further confirms these findings (p = 0.826). The Reading the Mind in the Eyes test had excellent psychometric properties when discriminating between ALS patients who are cognitively intact, and those who have executive impairment, with an overall medium difficulty. There was a large magnitude significant difference between patients and controls (p< 0.001; η2 = .19). Post-hoc analysis revealed that controls performed significantly higher than patients with executive impairment (p< 0.001), and patients with single executive deficits (p = 0.002). CONCLUSION: Executive dysfunction impacts on social cognitive performance. This study contributes not only to the psychometric knowledge of this measure, but also to the usability, efficacy, and reliability of social cognitive assessment in ALS. Using population-specific normative data, we confirm the Reading the Mind in the Eyes Test is a reliable measure of social cognitive processes in ALS.

Discordant performance on the 'Reading the Mind in the Eyes' Test, based on disease onset in amyotrophic lateral sclerosis.

Executive dysfunction is a core feature of amyotrophic lateral sclerosis (ALS) and is associated with brain atrophy in cortical and subcortical regions. Social cognitive deficits may also be a prominent feature of ALS. This study investigated executive, and social cognitive performance, in a population based cohort of patients with ALS, stratified by disease onset. Participants were recruited as part of a population based study investigating cognitive decline in ALS. Patients carrying pathogenic C9orf72 hexanucleotide repeat were excluded. Participants were stratified based on bulbar (n = 20) or spinal (n = 39) disease onset (n = 59). Matched healthy controls were used to generate culturally specific comparative data for within-patient analyses (n = 59). Results showed that ALS patients performed significantly worse than controls on a number of measures of executive function. When sub-stratified by disease onset, there was a significant difference between bulbar- and spinal-onset patients with respect to the 'Reading the Mind in the Eyes' Test scores (p < 0.001). Conversely, standardized scores of executive function did not differ between the patient groups. In conclusion, patients performed significantly worse than matched controls on measures of executive function. Bulbar-onset ALS patients evidenced more social-affective deficits compared to spinal-onset patients, with matched performance on measures of executive function.

Survival analysis of geospatial factors in the Irish ALS cohort.

Variations in environmental risk factors potentially influence incidence and progression in complex multifactorial diseases. Few studies have examined the association of survival in amyotrophic lateral sclerosis (ALS) with environmental geospatial variables. Here we use data from the Irish ALS cohort to perform such an analysis. Geographic data sources were used to generate small area values for four geospatial variables (population density, social deprivation, distance to coast, and distance to ALS multidisciplinary (MDT) clinic) for each ALS case on the Irish ALS register. These were combined with follow-up data and used as covariates in Royston-Parmar regression survival analysis including age of onset, site of onset, diagnostic delay, riluzole prescription and MDT clinic attendance as covariates. One thousand, two hundred and thirty-two patients with median survival of 2.31 years from disease onset were included. After addition of the individual geospatial variables in turn, none of the four variables was found to be associated with survival with a p-value <0.05. The results may reflect the public healthcare system that provides riluzole prescription and access to the MDT to all patients free of charge, and is also congruent with our recent finding that social deprivation is not associated with ALS incidence in Ireland.

The selective anatomical vulnerability of ALS: 'disease-defining' and 'disease-defying' brain regions.

A large multiparametric MRI study has been undertaken to evaluate anatomical patterns of basal ganglia, white matter and cortical grey matter involvement in ALS. Unaffected brain regions are mapped in patients with significant disability. Multiple white matter diffusivity measures, cortical grey matter density alterations, basal ganglia volumes and subcortical grey matter atrophy patterns are evaluated. Results demonstrated a strikingly selective anatomical vulnerability pattern in ALS that preferentially affects specific grey matter structures, commissural white matter tracts and basal ganglia regions, suggestive of networkwise neurodegeneration in ALS. In conclusion, ALS pathology exhibits predilection for selective and inter-connected anatomical sites that can be comprehensively characterized in vivo by multiparametric neuroimaging. The systematic characterization of unaffected brain regions in ALS has implications for the development of classifier analyses and elucidation of disease biology. The involvement and sparing of contiguous brain regions raises important pathophysiological, phylogenetic and ontogenetic questions regarding ALS pathogenesis and disease spread.

The Utility of the Addenbrooke's Cognitive Examination Version Three in Early-Onset Dementia.

BACKGROUND/AIMS: Early-onset dementia (EOD) is defined as functionally relevant cognitive decline with age of onset at less than 65 years. The aim of this study was to investigate the utility of the recently validated third version of the Addenbrooke's Cognitive Examination (ACE-III) in predicting dementia diagnoses in EOD. METHODS: ACE-III scores of EOD patients were compared to those of healthy controls (HC) and individuals with subjective memory impairment (SMI). RESULTS: The study included 71 EOD patients (Alzheimer's disease, n = 31; primary progressive aphasia, n = 11; behavioural-variant frontotemporal dementia, n = 18, and posterior cortical atrophy, n = 11); there were 28 HC and 15 individuals with SMI. At a cut-off score of 88/100, the ACE-III displayed high sensitivity and specificity in distinguishing EOD from HC (91.5 and 96.4%) and SMI (91.5 and 86.7%). CONCLUSIONS: The ACE-III is a reliable cognitive screening tool in EOD.