Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease

Abstract

Abstract. In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: 1) to identify target regions in different disease stages and 2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages (14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporoparietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease.

Multimodal Brain Analysis of Functional Neurological Disorders: A Functional Stroke Mimic Case Series

“…To increase the homogeneity of neuroimaging and TMS analysis (3 patients with right-side and one with left-side hemiparesis) data were left-right flipped for the latter patient; furthermore, 2 groups of healthy controls (HC) ( n = 23; mean age: 41.1 ± 9.3 years and n = 10, mean age: 38.2 ± 13.8 years) were recruited to compare neuroimaging and TMS findings, respectively [5,6]. Analyses were performed considering age as nuisance (ReHo: permutation test [10,000 permutations] with Statistical NonParametric Mapping [http://warwick.ac.uk/snpm, p < 0.001 uncorrected for multiple comparisons]; TMS: Mann-Whitney U test [SPSS 21.0, assuming a p < 0.05]).…”

“…At the 1-month follow-up, for the persistence of symptoms and for research purposes, brain MRI, including T1 MPRAGE for voxel-based morphometry analysis, FLAIR and T2*-weighted echo planar sensitized to blood oxygen level-dependent (BOLD) contrast for rs-fMRI (ReHo analysis) [5], cervical MRI scan, and TMS (SICI-ICF and short-latency afferent inhibition with different interstimulus intervals, LTP-like plasticity evaluated with a paired associative stimulation protocol, all assessed contralateral to the affected clinical side [6]) were performed. Functional aetiology was confirmed by unremarkable instrumental examinations and on the basis of psychological evaluation (Symptom Distress Scale [8], Minnesota Multiphasic Personality Inventory-2 [9], and the Italian version of the Symptom Rating Test [10]), demonstrating clinical distress with scores above the normative data (traits of hypochondria, hysteria, and mania) with a largely/completely functional aetiology on the Carson scale [3].…”

“…A number of rs-fMRI parameters have been introduced to study brain functional network abnormalities, like regional homogeneity (ReHo), as an index of the coherence of local brain spontaneous low-frequency signal fluctuations at whole-brain level [5]. Furthermore, TMS has been used to test the integrity of corticospinal tracts, resting motor threshold, short-interval intracortical inhibition-facilitation (SICI-ICF), short-latency afferent inhibition (a parameter of sensorimotor integration), and LTP-like plasticity (to evaluate possible mechanisms of maladaptive plasticity) [6].…”

Predementia Brain Changes in Progranulin Mutation: A Systematic Review of Neuroimaging Evidence

“…The sample size of mutation carriers ranged between 5 and 65. Three studies evaluated the same mutation carrier cohort[13, 30, 31]. Only one study had a longitudinal study design[29].…”

“…1). Seven of the 13 studies utilized at least 2 of the 4 neuroimaging modalities[7, 25-30]. The sample size of mutation carriers ranged between 5 and 65.…”