Aims

To explore stepwise functional connectivity (SFC) rearrangements in patients affected by frontotemporal lobar degeneration (FTLD) variants.

Methods

Patients with behavioral variant of frontotemporal dementia (bvFTD, n=26), nonfluent (nfvPPA, n=11) or semantic variant of primary progressive aphasia (svPPA, n=14) underwent clinical evaluation and 3T MRI scan. For each subgroup, cortical thickness was assessed, in order to identify the peak of atrophy (here considered as the disease epicenter), when compared with 37 age- and sex-matched healthy controls. These areas were used as seed regions for the subsequent SFC analyses.

Results

The selected seed regions were the right orbitofrontal cortex for bvFTD, left supplementary motor area for nfvPPA, and left temporal pole for svPPA. Compared with controls, all three patient groups showed decreased SFC in widespread regions with direct/intermediate connections with the respective seed regions. bvFTD and nfvPPA patients also showed increased SFC within the brain regions closest to the respective seed region and homologous contralateral cortices at one link-step. At further link-steps, SFC increase was also observed in the posterior cerebellum of bvFTD and nfvPPA patients, and the superior frontal cortex of svPPA patients.

Conclusions

Our findings indicate an increase in the short-range direct connectivity around the disease epicenters of FTLD, probably as a compensation for neurodegeneration, in contrast with widespread functional rearrangements that characterize each phenotype across different link-steps. This was the first study exploring SFC in FTLD, opening promising perspectives to understand the physiopathological underpinnings of these presentations and model disease evolution.

Supported by: European Research Council (StG-2016_714388_NeuroTRACK).

Aims

To investigate the relationship between emotion processing and resting state-functional connectivity (RS-FC) in healthy controls and in patients with frontotemporal lobar degeneration (FTLD).

Methods

We recruited 80 FTLD (26 bvFTD, 10 PSP, 12 PPA, and 32 ALS) and 65 healthy controls. Participants underwent a RS-functional MRI (RS-fMRI) and the Comprehensive Affect Testing System. In each group, correlation models were performed between each emotion construct and RS-FC changes.

Results

A high performance at the emotion naming was related in controls with decreased RS-FC of the right inferior temporal gyrus within the right frontoparietal-network; and in FTLD patients with increased RS-FC of the frontal regions within salience, frontoparietal and executive-control networks. Furthermore, a high performance at the emotion differentiation was related in healthy controls with decreased RS-FC of the right middle temporal gyrus within the salience-network; and in FTLD patients with increased RS-FC of the left inferior and medial-orbitofrontal gyri, and right thalamus within the subcortical-network. Finally, a high performance at the emotion matching was related in both healthy controls and FTLD groups with increased RS-FC of precuneus and vermis within the visual-network, and with further increased RS-FC of bilateral lingual, middle temporal and calcarine gyri in FTLD group only.

Conclusions

In FTLD compared to controls, RS-FC associated with emotional performance involves a larger number of brain regions, which are linked to the disease development and progression. These findings offer new potential markers for detecting functional vulnerability linked to social interactions.

Funding: Italian Ministry of Health (GR-2013-02357415); European Research Council (StG-2016_714388_NeuroTRACK).

Aims

Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized by inclusions of tau (FTLD-Tau) or TDP43 (FTLD-TDP). Cerebrospinal fluid (CSF) biomarkers are needed for the diagnosis of FTD and its pathological subtypes. Our CSF proteomics study showed increased Apolipoprotein L1 (APOL1), involved in lipid metabolism, in FTD with stronger levels in FTLD-Tau. Here, we aimed to characterize APOL1 in FTLD post-mortem brain tissue with definite pathology and validate its potential as a FTD biomarker.

Methods

APOL1 levels were analyzed in frontal cortex of FTLD (n=62, including 23 FTLD-Tau and 29 FTLD-TDP) and non-demented controls (n=18) either by immunohistochemistry, western blot or our in-house ELISA. The association of APOL1 immunoreactivity with phosphorylated Tau (pTau) and TDP-43 (pTDP43) was assessed. CSF APOL1 was measured in FTD patients (n=27, including 12 FTLD-Tau and 15 FTLD-TDP) and controls (n=15) by ELISA

Results

APOL1 levels were significantly increased in the frontal cortex of FTLD cases using three different technologies. No differences between FTLD pathological subtypes were detected. APOL1 immunoreactivity was observed in neuronal and glia cells. No association with the main FTLD proteinopathies (pTau or pTDP43) was detected. In CSF, the levels of APOL1 were comparable between FTD patients and controls, and between FTLD pathological subtypes.

Conclusions

We show increases of APOL1 in FTLD pathology irrespective of the subtypes. APOL1 changes were not detected in CSF using the current immunoassay, therefore, novel assays need to be developed. Future research should also explore the specific role APOL1 plays within FTLD pathogenesis.

Aims

In pure-motor ALS patients, we recently observed that smaller volume of the left pallidum was related with impaired recognition of disgust. In the present study, we investigated the resting-state functional connectivity (RS-FC) of the pallidum in ALS, and the relationship between RS-FC changes and disgust recognition.

Methods

19 pure-motor ALS patients and 52 matched healthy controls underwent RS functional MRI and a neuropsychological assessment including the Comprehensive Affect Testing System (CATS), investigating emotion recognition. A seed-based RS-FC analysis was run between the left and right pallidum and the rest of the brain, and compared between groups. Correlation analyses were assessed between the RS-FC significant changes and patients’ performance in recognizing disgust.

Results

Compared to controls, ALS presented reduced RS-FC between bilateral pallidum and right superior and middle frontal gyri, and increased RS-FC between bilateral pallidum and left superior temporal and postcentral gyri, and left Rolandic operculum. Increased RS-FC was observed between left pallidum and left supramarginal gyrus and between right pallidum and contralateral insula and thalamus. In patients, lower performance in recognizing disgust was related with reduced RS-FC between bilateral pallidum and right middle and superior frontal gyri, and with increased RS-FC between bilateral pallidum and left postcentral gyrus and Rolandic operculum.

Conclusions

Conclusions. In cognitively unimpaired ALS patients, reduced pallidum-frontal RS-FC and increased pallidum-insular-thalamic RS-FC suggest a fronto-striatal functional disconnection, which may contribute to deficits of patients in recognizing disgust.

Funding: Italian Ministry of Health (GR-2013-02357415); European Research Council (StG-2016_714388_NeuroTRACK).

Aims

A hexanucleotide repeat expansion within the C9orf72 gene (C9) is the primary genetic cause of Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD). Toxicity in neurons at least partly results from the production of dipeptide repeat proteins (DPR) which are translated via non canonical non- ATG initiated translation. To try to understand the mechanisms leading to neuronal death we have developed a Drosophila melanogaster model expressing 36 hexanucleotide repeats (36R). This model displays neuronal toxicity and a shortened lifespan. We have carried out a large scale genetic screen and identified a number of suppressors of toxicity. We are now characterising one of these, a monocarboxylate transporter.

Methods

We have carried out lifespans and behavioural assays in Drosophila, together with ELISAs for the different DPRs produced by the expansion to evaluate the effect of the transporter on the health of the C9 model and on the toxic DPRs.

Results

The monocarboxylate transporter we have identified, when over-expressed, leads to a substantial rescue of toxicity and to a reduction in the levels of the toxic peptides associated with the repeats. This transporter can import lactate and pyruvate, two known suppressors of histone deacetylases (HDACs). We have identified significant changes in acetylation patterns following the expression of the transporter.

We are in the process of understanding how this rescue is mediated and whether modulation of HDACs is a mediator of this rescue.

Conclusions

Over-expression of a monocarboxylate transporter can rescue C9 repeat expansion toxicity, possibly by modulating HDAC activation.

Aims

Frontotemporal dementia (FTD) is a rare, early-onset form of dementia, and hexanucleotide repeat expansions in the C9orf72 gene is the most common cause of familial FTD. Scientific evidence suggests a common pathway between C9orf72 and progranulin-mediated disease. Variants of GRN that reduce progranulin levels have been linked to shortened survival after disease onset in C9orf72 repeat expansion carriers. FTD-C9orf72 patients exhibit TDP-43 pathology, and in nonclinical studies progranulin was shown to reverse and protect against TDP-43 pathology, suggesting that increasing progranulin levels may reduce TDP-43 pathology in humans. AL001 is a human monoclonal IgG1 antibody that blocks and downregulates sortilin, a receptor in the key degradation pathway of progranulin, and is being developed by Alector for the treatment of FTD.

Methods

INFRONT-2 is an open-label, Phase 2 study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL001 administered intravenously every four weeks in FTD-C9orf72 and FTD-GRN mutation carriers. Lumbar punctures and MRI scans were performed at baseline and every 6 months. Clinical assessments were done every 3 months. Fluid biomarkers were analyzed in plasma and CSF.

Results

Preliminary results demonstrated that AL001 is generally well tolerated in FTD-C9orf72 participants in INFRONT-2. Chronic dosing led to a sustained increase in progranulin levels throughout treatment. Preliminary data on clinical assessments and biomarkers will be presented for FTD-C9orf72 participants who have received AL001 for up to 12 months.

Conclusions

There is a high unmet need for effective therapies in FTD. AL001 is being developed for the treatment of FTD patients including FTD-C9orf72.

Aims

Methods

Results

Conclusions