Deformation based morphometry study of longitudinal MRI changes in behavioral variant frontotemporal dementia

Manera, Ana Laura; Dadar, Mahsa; Collins, D. Louis; Ducharme, Simon; Initiative, Frontotemporal Lobar Degeneration Neuroimaging

doi:10.1016/j.nicl.2019.102079

Cited by 51 publications

(39 citation statements)

References 32 publications

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“…However, these are likely to be artefacts caused by the proximity of these ROIs to the enlarged lateral ventricles, which can cause signal contamination due to partial volume effects, imperfect normalization and smoothing used in tensor-based morphometry analysis. 25 This is illustrated in Supplementary Fig. 1 , which shows the ventricles of the normalized subjects extending slightly beyond the ventricle ROIs of the atlas; the image registration was otherwise very good.…”

Section: Resultsmentioning

confidence: 86%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Lin

Kim

Ahmed

et al. 2021

Brain Communications

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Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

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Section: Resultsmentioning

confidence: 86%

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Lin

Kim

Ahmed

et al. 2021

Brain Communications

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“…3 T rather than 1.5 T), yielding images with better contrast. All the image-processing tools used in this study have been developed and extensively validated for use in multi-centre studies involving different MRI systems and have been used in numerous such studies ( Zeighami et al , 2015 ; Dadar et al , 2018 b ; Misquitta et al , 2018 ; Dadar et al , 2019 ; Manera et al , 2019 ; Sanford et al , 2019 ). In addition, all analyses included ‘centre’ as a categorical random effect to ensure that any residual variability across centres would not bias the results.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the mean DBM values were calculated for the corticospinal tract mask obtained from Yeh et al (2018) , as well as the frontal lobe, frontotemporal lobe, precentral gyrus and dorsolateral prefrontal cortex masks obtained from a grey matter atlas for the Montreal Neurological Institute-International Consortium for Brain Mapping 152 template ( Manera et al , 2019 ). The average values were used in the following region-of-interest analyses:

where clinical measure indicates either categorical dichotomized scores [e.g.…”

Section: Methodsmentioning

confidence: 99%

Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43

Dadar

Manera

Zinman

et al. 2020

Brain Communications

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Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in amyotrophic lateral sclerosis cross-sectionally and longitudinally, and to compare the findings with a recently proposed disease-staging model of amyotrophic lateral sclerosis pathology. Deformation-based morphometry was used to identify the patterns of brain atrophy associated with amyotrophic lateral sclerosis and to assess their relationship with clinical symptoms. Longitudinal T1-weighted magnetic resonance imaging data and clinical measures were acquired at baseline, 4 months, and 8 months, from 66 patients and 43 age-matched controls who participated in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. Whole brain voxel-wise mixed-effects modelling analysis showed extensive atrophy patterns differentiating patients from the normal controls. Cerebral atrophy was present in the motor cortex and corticospinal tract, involving both grey matter and white matter, and to a lesser extent in non-motor regions. More specifically, the results showed significant bilateral atrophy in the motor cortex, the corticospinal tract including the internal capsule and brainstem, with an overall pattern of ventricular enlargement; along with significant progressive longitudinal atrophy in the precentral gyrus, frontal and parietal white matter, accompanied by ventricular and sulcal enlargement. Atrophy in the precentral gyrus was significantly associated with greater disability as quantified with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (p < 0.0001). The pattern of atrophy observed using deformation based morphometry was consistent with the Brettschneider’s four stage pathological model of the disease. Deformation based morphometry provides a sensitive indicator of atrophy in Amyotrophic lateral sclerosis, and has potential as a biomarker of disease burden, in both gray and white matter.

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“…Therefore, DBM is more sensitive for subtle changes in brain tissue composition than VBM. Additionally, data from multiple studies, imaging equipment and research centers can be processed without bias [ 197 ].…”

Section: Novel Methods Applications Of Imaging Techniques and Biomentioning

confidence: 99%

Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

Oostveen

Lange

2021

IJMS

112

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Background. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death. Introduction. In AD, pathological changes occur many years before disease onset. Since disease-modifying therapies may be the most beneficial in the early stages of AD, biomarkers for the early diagnosis and longitudinal monitoring of disease progression are essential. Multiple imaging techniques with associated biomarkers are used to identify and monitor AD. Aim. In this review, we discuss the contemporary early diagnosis and longitudinal monitoring of AD with imaging techniques regarding their diagnostic utility, benefits and limitations. Additionally, novel techniques, applications and biomarkers for AD research are assessed. Findings. Reduced hippocampal volume is a biomarker for neurodegeneration, but atrophy is not an AD-specific measure. Hypometabolism in temporoparietal regions is seen as a biomarker for AD. However, glucose uptake reflects astrocyte function rather than neuronal function. Amyloid-β (Aβ) is the earliest hallmark of AD and can be measured with positron emission tomography (PET), but Aβ accumulation stagnates as disease progresses. Therefore, Aβ may not be a suitable biomarker for monitoring disease progression. The measurement of tau accumulation with PET radiotracers exhibited promising results in both early diagnosis and longitudinal monitoring, but large-scale validation of these radiotracers is required. The implementation of new processing techniques, applications of other imaging techniques and novel biomarkers can contribute to understanding AD and finding a cure. Conclusions. Several biomarkers are proposed for the early diagnosis and longitudinal monitoring of AD with imaging techniques, but all these biomarkers have their limitations regarding specificity, reliability and sensitivity. Future perspectives. Future research should focus on expanding the employment of imaging techniques and identifying novel biomarkers that reflect AD pathology in the earliest stages.

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Deformation based morphometry study of longitudinal MRI changes in behavioral variant frontotemporal dementia

Cited by 51 publications

References 32 publications

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia

Cerebral atrophy in amyotrophic lateral sclerosis parallels the pathological distribution of TDP43

Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

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