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Predicting disease progression in behavioral variant frontotemporal dementia
Get PDFIntroduction: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline.Methods: One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models.Results: We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models.Discussion: Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model
Predicting disease progression in behavioral variant frontotemporal dementia
No full textAbstract Introduction The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. Methods One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups (“fast progressors” vs. “slow progressors”), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models. Results We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models. Discussion Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model
Criminal behavior in frontotemporal dementia: A multimodal MRI study
Get PDFThe behavioral variant of frontotemporal dementia (bvFTD) is related to a variety of social misbehaviors, including criminal behavior (CB) due to deep changes in cognition, behavior, and personality. Recent work suggests that impairment in emotional processing, along with disinhibition, constitutes the necessary elements for CB in bvFTD. However, the underlying neurobiological mechanisms are still unclear. Therefore, we aim at investigating structural and functional brain changes related to CB in bvFTD using magnetic resonance imaging (MRI) with the German Consortium for Frontotemporal Lobar Degeneration (FTLD). Our study comprised 87 patients with bvFTD and 26 healthy controls recruited within different locations of the FTLD Consortium. A subset of 21 patients with bvFTD showed CB, including theft, physical violence, sexual assault, drug abuse, and violations against traffic law. Voxel-based morphometry was performed, generating gray matter density (GMD) images obtained from high-resolution T1-weighted MR images. In addition, surface-based morphometry was performed by reconstruction of cortical thickness using a projection-based thickness approach. Both GMD and cortical thickness were further analyzed in order to detect group differences between bvFTD with and without CB. Resting-state functional MRI was available for a subgroup of 56 patients with bvFTD, including 16 patients showing CB. On a behavioral level, CB in bvFTD was associated with a higher frequency of disinhibition, lower frequency of apathy, and better performance in verbal fluency. Comparing bvFTD with and without CB, we obtained reduced GMD and reduced cortical thickness in the temporal lobe, predominantly in the left hemisphere. Impairment in brain structure was correlated with the Frontal Systems Behavior Scale, particularly with disinhibition, in the left superior temporal gyrus in interaction with CB in bvFTD. Investigating functional MRI data, CB was associated with significant functional brain dysconnectivity, particularly between the left anterior superior temporal gyrus and widely distributed cortical regions, including areas in the vicinity of the precentral sulcus and the inferior frontal junction, related to executive functions. Our study revealed structural and functional brain differences between bvFTD with and without CB, showing CB-related reduced GMD and cortical thickness in the left temporal lobe, indicating disinhibition as the main driver for CB. Interestingly, brain degeneration in the temporal lobe is discussed with CB in bvFTD in the current literature, dominantly affecting the right hemisphere. Our study investigates specifically the neural correlates of CB in bvFTD with MRI, modifying this view. Further work is necessary to shed more light on the role of the temporal lobe in bvFTD with CB
Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia
Get PDFBehavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing
Criminal Behavior in Frontotemporal Dementia: A Multimodal MRI Study
No full textABSTRACT The behavioral variant of frontotemporal dementia (bvFTD) is related to a variety of social misbehaviors, including criminal behavior (CB) due to deep changes in cognition, behavior, and personality. Recent work suggests that impairment in emotional processing, along with disinhibition, constitutes the necessary elements for CB in bvFTD. However, the underlying neurobiological mechanisms are still unclear. Therefore, we aim at investigating structural and functional brain changes related to CB in bvFTD using magnetic resonance imaging (MRI) with the German Consortium for Frontotemporal Lobar Degeneration (FTLD). Our study comprised 87 patients with bvFTD and 26 healthy controls recruited within different locations of the FTLD Consortium. A subset of 21 patients with bvFTD showed CB, including theft, physical violence, sexual assault, drug abuse, and violations against traffic law. Voxel‐based morphometry was performed, generating gray matter density (GMD) images obtained from high‐resolution T1‐weighted MR images. In addition, surface‐based morphometry was performed by reconstruction of cortical thickness using a projection‐based thickness approach. Both GMD and cortical thickness were further analyzed in order to detect group differences between bvFTD with and without CB. Resting‐state functional MRI was available for a subgroup of 56 patients with bvFTD, including 16 patients showing CB. On a behavioral level, CB in bvFTD was associated with a higher frequency of disinhibition, lower frequency of apathy, and better performance in verbal fluency. Comparing bvFTD with and without CB, we obtained reduced GMD and reduced cortical thickness in the temporal lobe, predominantly in the left hemisphere. Impairment in brain structure was correlated with the Frontal Systems Behavior Scale, particularly with disinhibition, in the left superior temporal gyrus in interaction with CB in bvFTD. Investigating functional MRI data, CB was associated with significant functional brain dysconnectivity, particularly between the left anterior superior temporal gyrus and widely distributed cortical regions, including areas in the vicinity of the precentral sulcus and the inferior frontal junction, related to executive functions. Our study revealed structural and functional brain differences between bvFTD with and without CB, showing CB‐related reduced GMD and cortical thickness in the left temporal lobe, indicating disinhibition as the main driver for CB. Interestingly, brain degeneration in the temporal lobe is discussed with CB in bvFTD in the current literature, dominantly affecting the right hemisphere. Our study investigates specifically the neural correlates of CB in bvFTD with MRI, modifying this view. Further work is necessary to shed more light on the role of the temporal lobe in bvFTD with CB
Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging
Get PDFAlien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia.The structure–function relationship of alien/anarchic limb was investigated in multi-centric structural magnetic resonance imaging (MRI) data. Whole-group and single-subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns.Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions.We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture
Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases
Get PDFAccurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer’s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins—neurofilament medium and myelin basic protein—showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.Open access funding provided by Royal Institute of Technology.Royal Institute of Technolog
Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems
Get PDFAside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.Maps of fractional amplitude of low frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 female) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 female). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Further, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.Patients displayed significantly reduced fALFF in fronto-temporal and fronto-parietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b, 5-HT2a), dopamine (D2), and γ-aminobutyric acid (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with D2 and NET was associated with cognitive symptoms and disease severity of bvFTD.Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD
Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration – A transdiagnostic study cross‐validating atrophy and fluid biomarkers
Get PDFIntroduction: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging.Methods: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry.Results: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects.Discussion: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy.Highlights: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy
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