Determinantes genéticos del fenotipo clínico y neuropatológico en el espectro demencia frontotemporal – esclerosis lateral amiotrófica

Programa de Doctorat en Medicina i Recerca Translacional[spa] La demencia frontotemporal (DLFT) y la esclerosis lateral amiotrófica (ELA) son un grupo de enfermedades clínica, neuropatológica y genéticamente muy heterogéneas. Esta enorme heterogeneidad conlleva importantes dificultades en el diagnóstico y tratamiento de esta enfermedad. Los posibles futuros tratamientos modificadores de la enfermedad tendrán que ir dirigidos específicamente a los mecanismos fisiopatológicos subyacentes a cada uno de los distintos subtipos moleculares de DFT y/o ELA. Es por ello que, la identificación en vida de cada uno de estos subtipos moleculares es de vital importancia. A día de hoy, esto solo es posible en aquellos casos con una mutación patogénica demostrada. En este sentido, las DFT y la ELA genéticamente predeterminada son un importante modelo de enfermedad. El estudio de sujetos portadores de mutaciones abre la puerta a la identificación de biomarcadores clínicos, bioquímicos y de imagen específicos para cada grupo molecular. Además, la identificación de portadores presintomáticos de mutaciones patogénicas permite estudiar los primeros cambios fisiopatológicos propios de la enfermedad. La presente tesis doctoral pretende estudiar y describir las relaciones genotipo – fenotipo en la DLFT y la ELA. El estudio de los fenotipos clínicos, de neuroimagen y neuropatológicos de la DLFT y la ELA y su relación con los diferentes determinantes genéticos causantes de la enfermedad puede ser de gran utilidad para conocer mejor los mecanismos fisiopatológicos subyacentes a estas enfermedades. Así mismo, conocer las correlaciones genotipo – fenotipo, permitirá mejorar el diagnóstico de estas enfermedades y dirigir adecuadamente el asesoramiento genético a los afectos y sus familiares

Determinantes genéticos del fenotipo clínico y neuropatológico en el espectro demencia frontotemporal – esclerosis lateral amiotrófica

[spa] La demencia frontotemporal (DLFT) y la esclerosis lateral amiotrófica (ELA) son un grupo de enfermedades clínica, neuropatológica y genéticamente muy heterogéneas. Esta enorme heterogeneidad conlleva importantes dificultades en el diagnóstico y tratamiento de esta enfermedad. Los posibles futuros tratamientos modificadores de la enfermedad tendrán que ir dirigidos específicamente a los mecanismos fisiopatológicos subyacentes a cada uno de los distintos subtipos moleculares de DFT y/o ELA. Es por ello que, la identificación en vida de cada uno de estos subtipos moleculares es de vital importancia. A día de hoy, esto solo es posible en aquellos casos con una mutación patogénica demostrada. En este sentido, las DFT y la ELA genéticamente predeterminada son un importante modelo de enfermedad. El estudio de sujetos portadores de mutaciones abre la puerta a la identificación de biomarcadores clínicos, bioquímicos y de imagen específicos para cada grupo molecular. Además, la identificación de portadores presintomáticos de mutaciones patogénicas permite estudiar los primeros cambios fisiopatológicos propios de la enfermedad. La presente tesis doctoral pretende estudiar y describir las relaciones genotipo – fenotipo en la DLFT y la ELA. El estudio de los fenotipos clínicos, de neuroimagen y neuropatológicos de la DLFT y la ELA y su relación con los diferentes determinantes genéticos causantes de la enfermedad puede ser de gran utilidad para conocer mejor los mecanismos fisiopatológicos subyacentes a estas enfermedades. Así mismo, conocer las correlaciones genotipo – fenotipo, permitirá mejorar el diagnóstico de estas enfermedades y dirigir adecuadamente el asesoramiento genético a los afectos y sus familiares

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Proteïna TDP-43; Esclerosi lateral amiotròfica; Demència frontotemporalProteína TDP-43; Esclerosis lateral amiotrófica; Demencia frontotemporalTDP-43 protein; Amyotrophic lateral sclerosis; Frontotemporal dementiaCognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3 (grant no. 20141610 to EG and no. 20143710 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI15/01618 to RRG). AA is funded by Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). JG is recipient of the Instituto de Salud Carlos III-FEDER grants (PI16/01673 and PI19/00593

Bioenergetic and Autophagic Characterization of Skin Fibroblasts from C9orf72 Patients.

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that C9orf72 patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 (p = 0.03). Our results provide new data reinforcing that C9orf72 cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer's disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD

Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity

INTRODUCTIONNeuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential.METHODSWe examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored.RESULTSGal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3.DISCUSSIONOur findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers

Impact of cortical and subcortical atrophy in the diagnosis and prognosis of bvFTD: A multicenter longitudinal study

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) presents with variable patterns of cortical and subcortical atrophy on Magnetic Resonance Imaging (MRI). We aimed to assess the clinical utility of two reproducible measurements of cerebral atrophy (Harper's visual atrophy scale [HVAS], and the Magnetic Resonance Parkinsonism Index [MRPI]) in a large multicenter sample of bvFTD with longitudinal follow‐up.MethodsWe included 466 participants from three centers: 241 bvFTD (according to the International bvFTD Criteria Consortium), and 225 healthy controls (HC). Clinical deterioration was assessed with Mini‐Mental State Examination (MMSE) and the Clinical Deterioration Scale Sum‐of‐boxes (CDR‐sb). bvFTD participants were considered to have an increased certainty of underlying Frontotemporal Lobar Degeneration (+FTLD) when: (i) FTLD was confirmed at autopsy (n=72); (ii) a secondary FTLD‐related phenotype was identified during follow‐up (n=47) or (iii) a FTLD‐related mutation was found (n=49). Six raters blinded to clinical data were first asked to dichotomize participants according to the presence of "a clear pattern of atrophy suggestive of probable bvFTD", and then applied the HVAS (ICC(2,k)=.86 to .96). The MRPI was calculated with a fully automated algorithm.ResultsMean age of bvFTD participants was 63.3 ± 10, 68% were male (MMSE=23 ± 7 and CDR‐sb=6.7 ± 3.5). Blinded raters had 52% sensitivity and 97% specificity for the identification of bvFTD participants (AUC=.74, p=.001). All HVAS measures with the exception of posterior atrophy discriminated between bvFTD and HC (AUC=.77 to .83, p<.001). The composite bvFTD score (average score of orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe and frontal insula regions) showed the best diagnostic accuracy for the differentiation of bvFTD from HC (AUC=.91, p<.001 in +FTLD). This composite score also differentiated between bvFTD participants that were not considered to have a clear pattern of atrophy suggestive of probable bvFTD (blinded raters) and HC (p<.001). We hypothesized that HVAS and MRPI scores may be independent predictors of clinical deterioration and survival in bvFTD (definitive results pending).ConclusionThe combination of HVAS and MRPI may provide valuable diagnostic and prognostic information in the behavioral syndromes verifying bvFTD criteria. These measures represent reliable, reproducible and affordable imaging biomarkers

Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers:a GENFI study

Background and objectives: The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods: We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results: A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion: We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.</p

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration

Can widely available measures of atrophy on magnetic resonance imaging increase diagnostic certainty of underlying frontotemporal lobar degeneration (FTLD) and estimate clinical deterioration in the behavioral variant of frontotemporal dementia (bvFTD)? This diagnostic/prognostic study investigated the clinical utility of 5 validated visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index. When combined, VAS showed excellent diagnostic performance for differentiating between bvFTD with high and low confidence of FTLD and for the estimation of longitudinal clinical deterioration, whereas the Magnetic Resonance Parkinsonism Index was increased in bvFTD with underlying 4-repeat tauopathies. These findings suggest that, in bvFTD, VAS can be used to increase diagnostic certainty of underlying FTLD and estimate longitudinal clinical deterioration. This diagnostic/prognostic study assesses the utility of 6 visual atrophy scales and the Magnetic Resonance Parkinsonism Index in patients with behavioral variant frontotemporal dementia to distinguish those with high vs low confidence of frontotemporal lobar degeneration. The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking. To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI). In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020. The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration. Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001). Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration