Aims

To define and compare the neuropsychological presentation at diagnosis in early-onset patients (<65 years) with Alzheimer's disease (EOAD) and behavioral variant of Frontotemporal Dementia (bvFTD).

Methods

We included 167 subjects according to their clinical status and cerebrospinal fluid (CSF) AD biomarker levels: 46 controls (age: 57.4±4.7; MMSE: 28.7±1.6), 96 EOAD (age: 59.8±4.1; MMSE: 22.7±3.9) and 25 bvFTD (age: 58.1±4.5; MMSE: 23.8±5.4). All subjects completed a comprehensive neuropsychological battery that included the assessment of five cognitive domains: memory, language, praxis, visual perception and executive functions. Cognitive performance was compared between groups using ANCOVA, adjusting for age and years of education.

Results

There were no differences between EOAD and bvFTD in terms of age, years of education or the MMSE score. As expected, the EOAD group showed lower levels of Aβ₄₂ and higher levels of total tau and phosphorylated tau in CSF than the control and bvFTD groups (p<0.01).

Controls performed better than EOAD and bvFTD in all tests, except for the constructional praxis subtest where there were no differences between controls and bvFTD. The EOAD group performed worse than the bvFTD in verbal (learning and free delayed recall; p<0.05) and visual memory (p<0.01), constructional praxis (p<0.01), visuoperceptive function (p<0.05) and psychomotor speed (p<0.01). The bvFTD group performed worse than the EOAD group in language (naming and commands comprehension; p<0.05) and verbal fluency tasks (p<0.05).

Conclusions

Neuropsychological assessment allows characterizing the cognitive profile of patients with early-onset dementias and could help on the differential diagnosis between EOAD and bvFTD.

Aims

The anterior cingulate gyrus is a focal point of neurodegeneration in behavioural variant Frontotemporal Dementia (bvFTD). Studies have identified a hemispheric asymmetry in healthy individuals, such that a paracingulate gyrus is more prevalent in the left hemisphere. In schizophrenia a lack of this asymmetry is found. The current study aim is to identify if a reduced prevalence of paracingulate sulcation (i.e. paracingulate gyrus) is also found in bvFTD.

Methods

The study population consisted of a sporadic bvFTD group (N = 106, mean age 67 years), individuals with Alzheimer’s disease (AD, N=94, mean age 71.3) and a healthy control group (HC, N=110, mean age 60.7). Individual whole brain magnetic resonance images were analyzed by 1 blinded rater. Paracingulate sulcation was identified in hemispheres of each subject as “present” or “absent” in accordance with established criteria.

Results

Contrary to our hypothesis, no difference in left hemisphere paracingulate sulcal frequency was observed between groups: a frequency of 0.69, 0.71 and 0.60 was observed respectively in the bvFTD, AD and HC groups, (Chi-squared = 2.8439, df = 2, p-value = 0.2412). Similar results were found in the right hemisphere. In the bvFTD group there was a significant impact of right hemispheric paracingulate sulcation on age at onset, where the mean age of subjects with an “absent” PCS was 60.46 versus 63.93 where a PCS was “present “ (t = -2.1237, df = 88.276, p-value = 0.03649).

Conclusions

These findings suggest that right paracingulate sulcation impacts upon age at diagnosis, suggesting an influence on disease expression in bvFTD.

Aims

The aim was to unravel structural/functional MRI connectomic features of motor neuron disease (MND) and behavioral variant of frontotemporal dementia (bvFTD).

Methods

115 MND (including amyotrophic lateral sclerosis [ALS] and primary lateral sclerosis), 35 bvFTD patients and 61 controls underwent clinical/cognitive and MRI evaluations. MND patients were divided in 79 pure-motor (MNDpm), 36 cognitive/behavioral impaired (MNDci/bi). A sub-analysis was performed on ALS patients only (54 ALSpm, 21 ALSci/bi and 8 ALS-FTD). Graph analysis and connectomics assessed structural/functional topological network properties at global, lobar and regional level.

Results

Globally, bvFTD showed altered structural and functional network properties compared to all other groups. Particularly, bvFTD showed altered structural and functional network properties within the frontotemporal and basal ganglia areas relative to all groups. Structural alterations in the parietal lobe discriminated bvFTD from controls and MNDpm only. MND groups showed altered graph metrics within the sensorimotor and basal ganglia areas relative to controls. At regional level, bvFTD showed widespread structural damage and decreased functional connecivity (FC) relative to all groups. MND showed disrupted structural architecture and enhanced FC within sensorimotor, basal ganglia and frontotemporal areas relative to controls. Structural and functional patterns have been replicated in ALS sub-analysis.

Conclusions

The disruption of the structural architecture in MND worsens in relation with cognitive deficits. Functional changes are characterized by enhanced FC in presence of exclusive motor impairment that intensifies with the occurrence of cognitive impairment in MND. The comorbidity of ALS and FTD leads to decreased FC similarly to bvFTD.

Funding:The Italian Ministry of Health(GR-2011-02351217;GR-2013-02357415;RF-2011-02351193) and AriSLA(ConnectALS).

Aims

To assess longitudinal patterns of atrophy shown by magnetic resonance imaging (MRI) in the cortical and subcortical GM of patients affected by different clinical variants of the FTLD spectrum.

Methods

Fifty-nine patients, including 26 with behavioral variant of frontotemporal dementia (bvFTD), 10 non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA), 12 semantic variant of PPA (svPPA), and 11 MND, in the absence of known pathogenic mutations, underwent MRI on a 3T scanner at 6-month intervals for one year. Thirty-three healthy controls underwent the same protocol. 3D T1-weighted MRI sequences were analyzed using voxel-based morphometry to assess the longitudinal evolution of GM atrophy in patients, compared with HC.

Results

At baseline, severe diffuse atrophy of frontotemporal cortical regions and basal ganglia was found in bvFTD, nfvPPA and svPPA groups, whereas MND did not show significant GM atrophy. At 6-month follow-up, bvFTD and PPA showed progression of atrophy in the insular (bvFTD, nfvPPA and svPPA) and anterior cingulate cortices (bvFTD and nfvPPA), bilaterally, as well as in the left caudate nucleus and middle temporal cortex (svPPA). At 12-month follow-up, similar patterns of atrophy progression were found, with the additional involvement of the superior frontal cortical gyri in nfvPPA, and right hippocampus in svPPA. No significant progression of atrophy was found in MND.

Conclusions

Atrophy of insular and anterior cingulate cortical regions closely reflects the progression of neurodegeneration across the behavioral and linguistic presentations of FTD, in contrast with a substantial sparing of GM in MND.

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

Aims

Pathogenic LOF and missense mutations in the TBK1 gene are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, we report on the prevalence and phenotype of TBK1 mutation carriers in the Flanders-Belgian population.

Methods

We screened the Flanders-Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) cohorts for mutations in the TBK1 gene. We identified 19 carriers of pathogenic mutations. We sampled and screened family members. In total, we have a TBK1 carrier cohort of 47 individuals. We collected data on clinical characteristics, biomarkers of disease and neuropathology.

Results

Overall, the TBK1 mutation frequency was 2.0%, with 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS patients. Among the 47 carriers, 30 are affected: FTD (n = 10, 33.3%), ALS (n = 10, 33.3%), unspecified dementia (n = 6, 20.0%), FTD-ALS (n = 2, 6.7%), mild cognitive impairment (n = 1, 3.3%) and Alzheimer’s disease (n = 1, 3.3%). In the FTD group, the behavioral variant FTD (bvFTD) was the most common phenotype but non-fluent variant primary progressive aphasia (nvf-PPA) was also reported. Mean onset age and disease duration were 63.2 and 6.1 years (ranges 41-86 and 0-24 years). Neuropathology confirmed FTLD-TDP type B.

Conclusions

Pathogenic mutations in TBK1 are a frequent cause of FTD, ALS and particularly of FTD plus ALS in the Flanders-Belgian population. The most common phenotypes were FTD (mostly bvFTD, less common nfv-PPA), ALS and unspecified dementia. Brain autopsy revealed FTLD-TDP type B neuropathology.

Aims

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

Methods

We recruited 80 FTLD (26 bvFTD, 10 PSP, 12 PPA, and 32 ALS) and 65 HC. 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 HC 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 HC 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 HC 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 HC, RS-FC associated with emotional performances involved 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.

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

Aims

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterized by motor and cognitive disturbances. By histology, astrocytic plaques are diagnostic of CBD; by SDS–PAGE, so too are detergent-insoluble, 37 kDa fragments of tau. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats. This distinguishes such ‘4R’ tauopathies from Pick’s disease (3R tauopathies) and from Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) (3R+4R tauopathies). We previously reported different tau filament structures from AD, Pick’s disease and CTE, but tau filament structures of 4R tauopathies remained unknown.

Methods

We extracted the tau filaments from the brains of three individuals with CBD and used cryo-electron microscopy to analyse the structures of the tau filaments.

Results

These filaments from CBD were identical between cases, but distinct from those seen in AD, Pick’s disease and CTE. The core of a CBD filament comprises residues 274 to 380 of tau, spanning the last residue of the R1 repeat, all of the R2, R3 and R4 repeat, and 12 residues after R4 repeat. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

Conclusions

Our determination of the CBD fold opens up 4R tauopathies to structural analysis. It supports the hypothesis that distinct conformers of filamentous tau define different tauopathies.