Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

Abstract

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…These data reveal vulnerable neuroanatomical structures during the presymptomatic and symptomatic stages, which include ventral and dorsomedial prefrontal cortex, ventral and dorsal insula, anterior cingulate, caudate, and the medial thalamus. These regions are highly anatomically congruent with atrophy patterns found in C9orf72 ‐associated frontotemporal dementia 45, 47, 48, 49, 50. Notably, several studies confirmed that the medial thalamus is a region affected across C9orf72 expansion carriers,50 even during the presymptomatic phase 23, 36, 46.…”

“…In parallel with the ROI analysis, the voxel‐wise analysis showed that certain sparse regions of lower grey matter volumes tended to associate with higher poly(GP), which included regions in the bilateral dorsolateral prefrontal, medial frontal, and lateral temporal cortices. Although higher poly(GP) levels showed a relatively weak association with lower grey matter volumes in our analyses, the regions identified include those atrophied in C9orf72‐ associated FTD patients,45, 47, 48, 49 and show reduced volume in presymptomatic C9orf72 expansion carriers 23, 36…”

Timing and significance of pathological features inC9orf72expansion-associated frontotemporal dementia

“…Spells in Case 1 consisted of altered consciousness, panic, and/or stereotyped behaviours, incapacitating her for hours at a time. Given her pattern of focal atrophy, we hypothesize that these periods of altered awareness reflected perturbed thalamo-cingulo-insular oscillations normally generated by the medial pulvinar thalamus, an emerging major epicentre of C9orf72 disease (Lee et al, 2014;Rohrer et al, 2015). In past decades, this patient might have been diagnosed with socalled 'thalamic dementia', a term applied when strategic vascular or degenerative thalamic lesions produced profound multi-domain cognitive-behavioural impairment (Abbruzzese et al, 1986;Szirmai et al, 2002).…”

“…The most common FTD syndrome in carriers is the behavioural variant (bvFTD) (Karageorgiou and Miller, 2014), and neuroimaging studies reveal bvFTDtypical atrophy involving anterior cingulate, anterior insula, and frontal and temporal cortices, as well as less typical parietal lobe, medial thalamic, and cerebellar involvement (Mahoney et al, 2012;Sha et al, 2012;Lee et al, 2014). Some carriers with bvFTD, however, exhibit slow progression and/or minimal brain atrophy (Boeve et al, 2012;Khan et al, 2012;Suhonen et al, 2015) despite predictable changes in brain connectivity, suggesting that neuronal dysfunction or disconnection leads to clinical deficits prior to overt neurodegeneration (Lee et al, 2014).…”

Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy

“…In bvFTD, breakdown in this afferent system may interfere with generosity by hampering patients’ access to internal emotional cues that typically motivate prosocial behaviors. Recent findings suggest that in at least one subtype of bvFTD, those with mutations in the C9ORF72 gene, the pulvinar is an early site for neurodegeneration (Lee et al., 2014), an atrophy pattern that may help to distinguish this group from other forms of frontotemporal dementia (Bocchetta et al., 2016; Whitwell et al., 2015). …”