Cheryl L. Stopford

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.

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 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.

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.

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.

The age distribution of the Ε4 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 Ε4 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 Ε4 allele was later than that in those EOAD cases without Ε4 allele, whereas in LOAD mean age at onset in cases bearing APOE Ε4 allele was earlier than in those without Ε4 allele. When analysed by decade, it was observed that 37% of the total number of APOE Ε4 allele bearers, and 43% of total number of cases with APOE Ε4/Ε4 genotype fell into the 60–69 years age class. Hence, APOE Ε4 allele frequency, at 0.44, was highest in the 60–69 years age class, progressively decreasing either side of this age group. APOE Ε4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.