Genetic testing in motor neuron disease and frontotemporal dementia: a 5-year multicentre evaluation.

INTRODUCTION: Motor neuron disease (MND) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum. Genetic testing and counselling is complex in MND/FTD owing to incomplete penetrance, variable phenotype and variants of uncertain significance. Affected patients and unaffected relatives are commonly referred to clinical genetics to consider genetic testing. However, no consensus exists regarding how such genetic testing should best be undertaken and on which patients. OBJECTIVE: We sought to ascertain UK clinical genetics testing practice in MND/FTD referrals, with the aim of helping inform guideline development. METHODS: MND/FTD clinical genetics referrals comprising both affected patients and unaffected relatives between 2012 and 2016 were identified and a standardised proforma used to collate data from clinical records. RESULTS: 301 referrals (70 affected, 231 unaffected) were reviewed across 10 genetics centres. Previously identified familial variants were known in 107 cases and 58% subsequently underwent testing (8 of 8 diagnostic and 54 of 99 predictive). The median number of genetic counselling appointments was 2 for diagnostic and 4 for predictive testing. Importantly, application of current UK Genomic Test Directory eligibility criteria would not have resulted in detection of all pathogenic variants observed in this cohort. CONCLUSION: We propose pragmatic MND/FTD genetic testing guidelines based on appropriate genetic counselling.

Improving follow up after predictive testing in Huntington's disease: evaluating a genetic counselling narrative group session.

Recently updated Huntington's disease (HD) predictive testing guidelines emphasise clinicians' responsibility to facilitate emotional support following testing, regardless of the result. Yet models of post-test counselling support are poorly defined. Moreover, it is unclear how these might be best delivered. In this project, a genetic counsellor and clinical psychologist developed standalone group sessions using collective narrative practices for individuals post-predictive testing. Here we present an evaluation of the experiences of one group of six people who have tested mutation positive for HD and remain pre-symptomatic. Two partners also attended the session. Observations, evaluation forms and telephone interviews were used in data collection. Interview data was available from five mutation-positive individuals and one partner. Qualitative data were analysed using a thematic framework approach. Responses were overwhelmingly positive, emphasising the importance of a specifically arranged time and space to share experiences in a structured way. This was typically the first time participants had spoken openly with someone in their situation. Narrative facilitation of discussion encouraged participants to re-discover their strengths and resiliences, with similar experiences being discovered through connections with others. The evaluation was successful in implementing group narrative interventions as part of the predictive test counselling support for Huntington's disease. Participants suggested that the approach could be extended and adopted for other genetic conditions.

Genetic Counselling and Narrative Practices: A Model of Support following a "Negative" Predictive Test for Huntington's Disease.

BACKGROUND: Predictive testing for Huntington's disease (HD) has been available for individuals at risk of HD by direct mutation analysis since 1993. International Predictive test guidelines recommend that support is offered following the result regardless of test outcome. However, there is lack of an evidence base regarding what this support should look like and how it might work in practice. OBJECTIVE: A service improvement initiative looked at the feasibility of offering a narrative group session co-facilitated by a genetic counsellor and clinical psychologist, to individuals who had tested mutation negative for HD. The narrative session was evaluated from the perspective of group participants. METHODS: Individuals who tested mutation negative at a genetic centre in the North of England over a 5-year period were invited to attend a narrative group session. 52 people were contacted and 9 people agreed to participate. Participants completed standardised questionnaires (PHQ-9 and GAD-7) before and after the session and a detailed written evaluation. Participants' comments were analysed thematically. RESULTS: Participants were overwhelmingly positive about the narrative session finding it a safe and enjoyable way to explore difficult life experiences. Reported benefits included feeling less isolated, being inspired by other people's stories and connecting as a group. All 9 participants said they would recommend the narrative session to anyone impacted by HD. CONCLUSIONS: The narrative group session was considered an interesting and useful approach to facilitating adaptation following a negative predictive test result for HD.

Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

OBJECTIVE: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. BACKGROUND: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. METHODS: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. RESULTS: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. CONCLUSIONS: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.

Neuropsychiatry and White Matter Microstructure in Huntington's Disease.

BACKGROUND: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population. OBJECTIVE: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD. METHODS: DTI data were collected from 39 premanifest and 45 early-HD participants in the Track-HD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO). RESULTS: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain. CONCLUSIONS: We demonstrate that white matter changes associated with both depression and irritability in HD occur at different stages of disease progression concomitant with their clinical presentation.

Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Longitudinal evaluation of neuropsychiatric symptoms in Huntington's disease.

A group of 111 patients with Huntington's disease (HD) underwent a minimum of three annual neuropsychiatric assessments, using the Problem Behaviors Assessment for Huntington's Disease (PBA-HD). Longitudinal prevalence of neuropsychiatric symptoms was notably higher than baseline prevalence, suggesting that previous studies may have underestimated the extent of this clinical problem. Moreover, apathy, irritability, and depression were each associated with distinct longitudinal profiles. Apathy progressed over time and across disease stages. Irritability also increased significantly, but only in early stages of HD. Depression did not increase significantly at any stage of disease. The neuropsychiatric syndrome of apathy appears to be intrinsic to the evolution and progression of HD.

Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.

The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.

Cognitive phenotypes in Alzheimer's disease and genetic variants in ACE and IDE.

Alzheimer's disease (AD) is generally considered to be a disorder primarily affecting memory. It is increasingly recognized that the clinical presentation or "cognitive phenotype" is variable. The apolipoprotein E ε4 (APOE ε4) allele has been associated with an amnestic presentation, but does not appear to fully explain the high prevalence of family history within this group. We examined polymorphisms in the genes ACE and IDE in relation to cognitive phenotype. In this study 276 participants with AD were categorized into 1 of 4 cognitive phenotype classifications: typical, amnestic, language, and posterior. Family history and possession of the APOE ε4 allele were most prevalent in the amnestic group. Of the 10 genetic variants of IDE, and the 3 genetic variants of ACE studied, only ACErs4291 and ACErs1800764 were nominally associated with the amnestic presentation.

Working memory, attention, and executive function in Alzheimer's disease and frontotemporal dementia.

Working memory deficits are a recognised feature of Alzheimer's disease (AD). They are commonly ascribed to central executive impairment and assumed to relate to frontal lobe dysfunction. Performance failures on standard tests of attention and executive function reinforce this interpretation. Nevertheless, early-onset AD patients do not show the frank behavioural changes indicative of frontal lobe dysfunction, and the characteristic functional neuroimaging changes are in posterior hemispheres rather than frontal lobes. We explored this anomaly through a comparison of working memory, attention and executive test performance in patients with AD (a 'typical' early-onset group with deficits in memory, language and perceptuospatial function and an 'amnesic' group) and frontotemporal dementia (FTD). Typical-AD and FTD patients both showed impaired performance, whereas amnesic-AD patients performed well. Despite similar quantitative performance measures, typical-AD and FTD patients showed qualitatively distinct performance profiles. Impairments in FTD patients were interpreted in 'frontal' executive terms as deficits in attention, set shifting and response inhibition. AD patients' performance appeared to be influenced by information load and was interpreted in terms of working memory capacity. In keeping with these different interpretations, neuroimaging showed characteristic frontal lobe abnormalities in FTD and temporoparietal change in typical-AD. The findings highlight the importance of the posterior hemispheres in working memory and point to a need for caution in the automatic attribution of working memory, attention and executive test failures to frontal lobe failure. They underline also the phenotypic variation within AD.

The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships.

Accuracy of clinical diagnosis of dementia is increasingly important for therapeutic and scientific investigations. In this study, we examine diagnostic accuracy in a consecutive series of 228 patients referred to a specialist early-onset dementia clinic, whose brains were subsequently examined at post-mortem. Diagnosis was based on structured history, neurological examination and neuropsychological assessment, with emphasis on qualitative as well as quantitative aspects of performance. Neuroimaging provided support for but did not alter the clinical diagnosis. We set out the principles that guided diagnosis: (i) time course of illness; (ii) weighting of physical, behavioural and cognitive symptoms and signs; (iii) 'anterior' versus 'posterior' hemisphere character of cognitive change; and (iv) specificity of deficit, paying attention to the differentiation between syndromes of frontotemporal lobar degeneration and focal forms of Alzheimer's disease. Forty-two per cent of the patients had clinical diagnoses of one of the syndromes of frontotemporal lobar degeneration, the high proportion reflecting the research interests of the group. Forty-six per cent were diagnosed with Alzheimer's disease and the remaining patients, dementia with Lewy bodies, Creutzfeldt-Jakob disease, vascular or unclassified dementia. Frontotemporal lobar degeneration was identified with 100% sensitivity and 97% specificity and Alzheimer's disease with 97% sensitivity and 100% specificity. Patients with other pathologies were accurately identified on clinical grounds. Examination of subsyndromes of frontotemporal lobar degeneration showed a relatively predictable relationship between clinical diagnosis and pathological subtype. Whereas the behavioural disorder of frontotemporal dementia was associated with tau, transactive response DNA binding protein 43 and fused-in-sarcoma pathology, cases of frontotemporal dementia with motoneuron disease, semantic dementia and, with one exception, progressive non-fluent aphasia were associated with transactive response DNA binding protein 43 pathology, distinguished by ubiquitin subtyping (types B, C and A, respectively). Clinical diagnoses of progressive apraxia, corticobasal degeneration and progressive supranuclear palsy were, with one exception, associated with Pick, corticobasal and progressive supranuclear palsy subtypes of tau pathology, respectively. Unanticipated findings included Alzheimer pathology in two patients presenting with the behavioural syndrome of frontotemporal dementia and corticobasal pathology in four others with clinical frontotemporal dementia. Notwithstanding such anomalies, which serve as a reminder that there is not an absolute concordance between clinical phenotype and underlying pathology, the findings show that dementias can be distinguished in life with a high level of accuracy. Moreover, careful clinical phenotyping allows prediction of histopathological subtype of frontotemporal lobar degeneration. The principles guiding diagnosis provide the foundation for future prospective studies.

Variability in cognitive presentation of Alzheimer's disease.

The aim of the present study was to explore the nature and prevalence of phenotypic variations in Alzheimer's disease (AD). Neuropsychological profiles of a large cross-sectional cohort of patients with a clinical diagnosis of the disease were examined. All tests distinguished the AD group from controls confirming their sensitivity to the presence of early AD. Factor analysis of test scores revealed five factors, reflecting the discrete cognitive domains of memory, language, perceptuospatial abilities, executive skills, and praxis. Cluster analysis revealed distinct performance profiles that could not be accounted for by disease severity. Some patients showed an accentuation of memory impairment relative to other domains, whereas others showed relative sparing. Cognitive deficits other than memory were the salient presenting feature in a relatively high proportion of patients. A subset of the cohort (22%) showed grossly disproportionate impairments in one cognitive domain. The findings emphasise variability in presentation and indicate that distinct phenotypic variations appear to lie on a continuum rather than representing discrete forms of disease.

Cognitive phenotypes in Alzheimer's disease and genetic risk.

Variation in the clinical characteristics of patients with Alzheimer's disease (AD) is increasingly recognised, although the factors underlying variation are not fully understood. The study examined the cognitive characteristics of 523 AD patients at the time of their presentation to a neurological dementia clinic and explored the relationship to family history and apolipoprotein E (APOE) genotype. Distinct profiles were identified, which were mirrored by topographical differences on neuroimaging. Clinical distinctions were maintained over time. Two-thirds of patients showed a constellation of deficits at presentation which included memory, language, visuospatial and constructional difficulties. However, a quarter had circumscribed presentations of amnesia, aphasia, perceptuospatial disorder or apraxia. The rare presence of frontal lobe characteristics was associated with a younger age of onset, an increased incidence of myoclonus at presentation, a positive family history but not with possession of APOE epsilon4 allele. An amnestic presentation (severe, yet circumscribed amnesia) was strongly associated with an older age of onset, a positive family history and the presence of APOE epsilon4 allele. Posterior cortical presentations showed a female bias, were typically sporadic, and showed no association with APOE epsilon4. The findings support the notion of phenotypic variation in AD, and show that genetic risk factors can influence clinical presentation. The findings draw attention to the specific association between APOE epsilon4 allele and memory but challenge the commonly held notion that the presence of the epsilon4 allele inevitably reduces onset age. The findings indicate that risk factors other than APOE epsilon4 allele underlie the non-familial, early onset posterior hemisphere presentations of AD.

Distinct memory profiles in Alzheimer's disease.

Memory impairment is a prominent defining feature of Alzheimer's disease (AD), yet the degree to which the profile of memory impairment is uniform across patients is not fully resolved. The study examined patterns of memory impairment in a large cohort of AD patients, with particular attention to the relationship between working and long-term declarative memory. Tests of working memory, visual and verbal recall and recognition, and recent personal memory were administered to 67 AD patients in the early to moderate stages of disease and to 30 age-matched controls. Performance on all measures was significantly poorer in patients than in controls. Factor analysis of test scores delineated five factors representing the domains of working memory, visual recall, verbal recall, recognition, and personal memory, indicating that these aspects of memory can break down separately. Cluster analysis revealed distinct memory profiles. Some patients showed predominant problems in working memory, with relatively superior long term retention, whereas other patients showed the reverse pattern. Qualitatively distinct profiles arose at comparable levels of severity. Problems in working memory, but not long term memory were associated with the presence of language and perceptuospatial deficits. The results reinforce previous findings that both working and long term memory failure contribute to the memory symptoms of AD patients, and demonstrate dissociations in memory breakdown across the cohort. The link between working memory and language performance, together with findings of posterior hemisphere abnormalities on neuroimaging, lead us to reassess the nature of working memory deficits in AD.

Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease.

The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.

Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation.

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration (FTLD). Clinical misdiagnosis rate was low with only 3 patients (4%) failing to show pathological changes consistent with this diagnosis; 1 patient had Alzheimer's disease and 2 had cerebrovascular disease (CVD). In the remaining 67 patients, the most common underlying histological cause was ubiquitin pathology with 24 (36%) cases so affected. In these, ubiquitin-positive inclusions were present in the cerebral cortex as small, rounded or crescent-shaped structures within the cytoplasm of neurones of layer II, together with coiled or curvilinear bodies within neurites, and in the hippocampus as small, solid and more spherical-shaped inclusion bodies within the cytoplasm of dentate gyrus granule cells. In one patient, "cat's eye" or "lentiform" intranuclear ubiquitin inclusions were also present. The second most common histological type was dementia lacking distinctive histology (DLDH), in which neither tau nor ubiquitin inclusions were present, with 16 cases (24%) being affected. Pick-type histology was seen in 14 cases (21%) and tau histological changes associated with frontotemporal dementia (FTD) linked to chromosome 17 (FTDP-17) were present in 11 cases (16%). One case (1%) showed an unusual tau pathology that could not be allocated to any of the other tau groups. Only 1 case (1%) had neuronal intermediate filament inclusion dementia. No cases with ubiquitinated, valosin-containing protein-immunoreactive intranuclear inclusion bodies of the type seen in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia were seen. Clinicopathological correlation showed that any of these histological subtypes can be associated with FTD. However, for FTD with motor neurone disease (FTD+MND), semantic dementia or primary progressive aphasia (PA), the histological profile was either ubiquitin type or DLDH type; Pick-type histology was seen in only 1 case of PA. None of these latter three clinical subtypes was associated with a mutation in tau gene and FTDP-17 type of tau pathology. All cases of progressive apraxia were associated with Pick-type histology. Present data therefore indicate that, although ubiquitin pathology is the most common histological form associated with FTLD, this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.