Ian Coyle-Gilchrist

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

BACKGROUND Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. METHODS We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. FINDINGS Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). INTERPRETATION Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. FUNDING Centres of Excellence in Neurodegeneration.

Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes

Objectives: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. Methods: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. Results: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation. Conclusions: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinsons disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinsons disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinsons disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinsons disease, the individual patients response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016.

Atomoxetine restores the response inhibition network in Parkinson’s disease

Impairments in response inhibition in Parkinson’s disease may reflect loss of noradrenaline and impaired fronto-subcortical connectivity. Rae et al. show that the noradrenaline reuptake inhibitor atomoxetine can restore functional connectivity in the inhibition network. Individual treatment responses depend on disease severity, plasma drug concentration and anatomical connectivity within the network.

Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease

Both progressive supranuclear palsy and Parkinson’s disease cause impulsivity and impair executive function. Using a saccadic Go/No-Go paradigm and hierarchical Bayesian models, Zhang et al. show differential decision-making deficits in the two disorders, and that model parameters are better than common behavioural measures for single-patient classification of the diseases.

Research paper does not show causal link between benzodiazepine use and diagnosis of dementia

The prospective population based study by Billioti de Gage and colleagues shows an association between benzodiazepine use and the subsequent diagnosis of dementia but it does not show causality.1 Sleep disturbance is a common feature of many neurodegenerative diseases and may precede dementia by years.2 For example, the 10 year risk of a …

Neurophysiological signatures of Alzheimer’s disease and frontotemporal lobar degeneration: pathology versus phenotype

Sami et al. identify characteristic neurophysiological signatures of five neurodegenerative diseases, including two variants of Alzheimer’s disease and three forms of frontotemporal lobar degeneration. Disorders that share a common underlying pathology have a similar spectral signature of altered connectivity, regardless of phenotype.

In vivo assay of cortical microcircuitry in frontotemporal dementia: a platform for experimental medicine studies

The analysis of neural circuits can provide critical insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioural variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to non-invasive human magnetoecphalography can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case-control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.

CEREBRAL PERFUSION AS AN IMAGING BIOMARKER OF PRESYMPTOMATIC GENETIC FRONTOTEMPORAL DEMENTIA: PRELIMINARY RESULTS FROM THE GENETIC FRONTOTEMPORAL DEMENTIA INITIATIVE (GENFI)

Background Frontotemporal dementia (FTD) is a common cause of early onset dementia. While three genetic mutations are responsible for the majority of genetic FTD, imaging biomarkers that predict symptom onset are needed1. Recent work shows volumetric changes several years before the predicted age at disease onset2. Herein, we extend on this work by investigating whether perfusion patterns derived from non-invasive arterial spin labeling (ASL) MRI can be used as an early functional neuroimaging biomarker of presymptomatic genetic FTD. Methods Data were drawn from the GENetic Frontotemporal dementia Initiative (GENFI)2. From the first GENFI data freeze (n=220), 168 subjects had 3T ASL from which this analysis considers only the presymptomatic carriers and controls (n=144, Table 1). Cerebral blood flow (CBF)-maps were scaled to a mean grey matter (GM) CBF of 50 mL/100g/min per ASL sequence (four different ASL sequences were used) and registered to SPM12 3D T1 GM segmentations that were registered to MNI using DARTEL. In pre-selected ROIs associated with FTD, we investigated the effects of mutation status and years to expected age of disease onset on CBF, accounting for gender and family membership as fixed and random covariates. ROI CBF-values were corrected for partial volume fractions. Results Years to expected age of disease onset (p 0.1), there was an interaction effect between mutation carrier status and years to expected age of disease onset on CBF (Table 2). This interaction effect was significant for all ROIs except for the parietal and occipital cortices, anterior cingulate and putamen with the strongest effects being seen in the insula and the caudate nucleus (Figure 1). Conclusions CBF decreased as individuals approached the expected age of disease onset and this CBF decrease was accelerated in the presymptomatic mutation carriers compared to controls, in key regions implicated in FTD. These preliminary findings demonstrate the potential utility of non-invasive perfusion MRI as an early biomarker for genetic FTD. References 1. Montine et al., Neurology 2014 2. Rohrer et al., Lancet Neurol 2015