Albert Lladó

YNICL Journal 2021 Journal Article

Differential early subcortical involvement in genetic FTD within the GENFI cohort

• Martina Bocchetta
• Emily G. Todd
• Georgia Peakman
• David M. Cash
• Rhian S. Convery
• Lucy L. Russell
• David L. Thomas
• Juan Eugenio Iglesias

BACKGROUND: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. METHODS: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). RESULTS: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). CONCLUSIONS: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.

YNICL Journal 2021 Journal Article

Disease-related cortical thinning in presymptomatic granulin mutation carriers

• Sergi Borrego-Écija
• Roser Sala-Llonch
• John van Swieten
• Barbara Borroni
• Fermín Moreno
• Mario Masellis
• Carmela Tartaglia
• Caroline Graff

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.

YNICL Journal 2021 Journal Article

Longitudinal brain atrophy and CSF biomarkers in early-onset Alzheimer’s disease

• José Contador
• Agnès Pérez-Millán
• Adrià Tort-Merino
• Mircea Balasa
• Neus Falgàs
• Jaume Olives
• Magdalena Castellví
• Sergi Borrego-Écija

There is evidence of longitudinal atrophy in posterior brain areas in early-onset Alzheimer's disease (EOAD; aged < 65 years), but no studies have been conducted in an EOAD cohort with fluid biomarkers characterization. We used 3T-MRI and Freesurfer 6.0 to investigate cortical and subcortical gray matter loss at two years in 12 EOAD patients (A + T + N + ) compared to 19 controls (A-T-N-) from the Hospital Clínic Barcelona cohort. We explored group differences in atrophy patterns and we correlated atrophy and baseline CSF-biomarkers levels in EOAD. We replicated the correlation analyses in 14 EOAD (A + T + N + ) and 55 late-onset AD (LOAD; aged ≥ 75 years; A + T + N + ) participants from the Alzheimer's disease Neuroimaging Initiative. We found that EOAD longitudinal atrophy spread with a posterior-to-anterior gradient and beyond hippocampus/amygdala. In EOAD, higher initial CSF NfL levels correlated with higher ventricular volumes at baseline. On the other hand, higher initial CSF Aβ42 levels (within pathological range) predicted higher rates of cortical loss in EOAD. In EOAD and LOAD subjects, higher CSF t-tau values at baseline predicted higher rates of subcortical atrophy. CSF p-tau did not show any significant correlation. In conclusion, posterior cortices, hippocampus and amygdala capture EOAD atrophy from early stages. CSF Aβ42 might predict cortical thinning and t-tau/NfL subcortical atrophy.

YNICL Journal 2019 Journal Article

Hippocampal atrophy has limited usefulness as a diagnostic biomarker on the early onset Alzheimer's disease patients: A comparison between visual and quantitative assessment

• Neus Falgàs
• Raquel Sánchez-Valle
• Núria Bargalló
• Mircea Balasa
• Guadalupe Fernández-Villullas
• Beatriz Bosch
• Jaume Olives
• Adrià Tort-Merino

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD.

YNICL Journal 2019 Journal Article

Mechanisms of functional compensation, delineated by eigenvector centrality mapping, across the pathophysiological continuum of Alzheimer’s disease

• Stavros Skouras
• Carles Falcon
• Alan Tucholka
• Lorena Rami
• Raquel Sanchez-Valle
• Albert Lladó
• Juan D. Gispert
• José Luís Molinuevo

BACKGROUND: Mechanisms of functional compensation throughout the progression of Alzheimer's disease (AD) remain largely underspecified. By investigating functional connectomics in relation to cerebrospinal fluid (CSF) biomarkers across the pathophysiological continuum of AD, we identify disease-stage-specific patterns of functional degradation and functional compensation. METHODS: Data from a sample of 96 participants, comprised of 49 controls, 11 preclinical AD subjects, 21 patients with mild cognitive impairment (MCI) due to AD and 15 patients with mild dementia due to AD, were analyzed. CSF ratio of phosphorylated tau protein over amyloid beta peptide 42 (p-tau/Aβ42) was computed and used as a marker of progression along the AD continuum. Whole-brain, voxel-wise eigenvector centrality mapping (ECM) was computed from resting-state fMRI and regression against p-tau/Aβ42 was performed. Surviving clusters were used as data-derived seeds in functional connectivity analyses and investigated in relation to memory performance scores (delayed free recall and memory alteration) via complementary regression models. To investigate disease-stage-specific effects, the whole-brain connectivity maps of each cluster were compared between progressive groups. RESULTS: Centrality in BA39-BA19 is negatively correlated with the p-tau/Aβ42 ratio and associated to memory function impairment across the AD continuum. The thalamus, anterior cingulate (ACC), midcingulate (MCC) and posterior cingulate cortex (PCC) show the opposite effect. The MCC shows the highest increase in centrality as memory performance decays. In the asymptomatic preclinical group, MCC shows reduced functional connectivity (FC) with the left hippocampus and stronger FC with the precuneus (PCu). Additionally, BA39-BA19 show reduced FC with the cerebellum, compensated by stronger FC between cerebellum and PCC. In the MCI group, PCC shows reduced FC with PCu, compensated by stronger FC with the left pars orbitalis, insula and temporal pole, as well as by stronger FC of MCC with its anterior and ventral neighboring areas and the cerebellum. In the mild dementia group, extensive functional decoupling occurs across the entire autobiographical memory network and functional resilience ensues in posterior regions and the cerebellum. CONCLUSIONS: Functional decoupling in preclinical AD occurs predominantly in AD-vulnerable regions (e.g. hippocampus, cerebellar lobule VI / Crus I, visual cortex, frontal pole) and coupling between MCC and PCu, as well as between PCC and cerebellum, emerge as intrinsic mechanisms of functional compensation. At the MCI stage, the PCu can no longer compensate for hippocampal decoupling, but the compensatory role of the MCC and PCC ensue into the stage of dementia. These findings shed light on the neural mechanisms of functional compensation across the pathophysiological continuum of AD, highlighting the compensatory roles of several key brain areas.

YNIMG Journal 2019 Journal Article

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

• Enrico Premi
• Vince D. Calhoun
• Matteo Diano
• Stefano Gazzina
• Maura Cosseddu
• Antonella Alberici
• Silvana Archetti
• Donata Paternicò

YNICL Journal 2019 Journal Article

White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

• Carole H. Sudre
• Martina Bocchetta
• Carolin Heller
• Rhian Convery
• Mollie Neason
• Katrina M. Moore
• David M. Cash
• Ione O.C. Woollacott

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.