Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in <i>Mapt</i> Mutation Carriers

Chen, Qin; Boeve, Bradley F.; Tosakulwong, Nirubol; Lesnick, Timothy G.; Brushaber, Danielle; Dheel, Christina; Fields, Julie A.; Forsberg, Leah K.; Gavrilova, Ralitza H.; Gearhart, Debra; Haley, Dana; Gunter, Jeffrey L.; Graff‐Radford, Jonathan; Jones, David T.; Knopman, David S.; Graff‐Radford, Neill R.; Kraft, Ruth; Lapid, Maria I.; Rademakers, Rosa; Wszołek, Zbigniew K.; Rosen, Howie; Boxer, Adam L.; Kantarci, Kejal

doi:10.1111/jon.12642

Cited by 9 publications

(9 citation statements)

References 35 publications

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“…An elevation in myoinositol (mI) or mI to creatine (mI/Cr) and a decrease in the neuronal integrity marker NAA or NAA/Cr have been found in symptomatic patients with FTLD (83), while only elevated mI/Cr in the posterior cingulate gyrus has been reported in asymptomatic MAPT mutation carriers (8). During longitudinal follow-up in MAPT mutation carriers who converted from the asymptomatic to symptomatic disease, serial 1 H MRS from the posterior cingulate voxel demonstrated that metabolite ratio changes, characterized by increasing mI/Cr and decreasing NAA/mI ratios, begin to accelerate ∼2 years prior to symptom onset (40).…”

Section: Proton Magnetic Resonance Spectroscopymentioning

confidence: 99%

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Chen

Kantarci

2020

Front. Neurol.

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Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral changes, language abnormality, as well as executive function deficits and motor impairment. In about 30-50% of FTLD patients, an autosomal dominant pattern of inheritance was found with major mutations in the MAPT, GRN, and the C9orf72 repeat expansion. These mutations could lead to neurodegenerative pathology years before clinical symptoms onset. With potential disease-modifying treatments that are under development, non-invasive biomarkers that help determine the early brain changes in presymptomatic FTLD patients will be critical for tracking disease progression and enrolling the right participants into the clinical trials at the right time during the disease course. In recent years, there is increasing evidence that a number of imaging biomarkers show the abnormalities during the presymptomatic stage. Imaging biomarkers of presymptomatic familial FTLD may provide insight into the underlying neurodegenerative process years before symptom onset. Structural magnetic resonance imaging (MRI) has demonstrated cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers. In addition, diffusion tensor imaging (DTI) has shown the loss of white matter microstructural integrity in the presymptomatic stage of familial FTLD. Furthermore, proton magnetic resonance spectroscopy ( 1 H MRS), which provides a non-invasive measurement of brain biochemistry, has identified early neurochemical abnormalities in presymptomatic MAPT mutation carriers. Positron emission tomography (PET) imaging with [ 18 F]-fluorodeoxyglucose (FDG) has demonstrated the glucose hypometabolism in the presymptomatic stage of familial FTLD. Also, a novel PET ligand, 18 F-AV-1451, has been used in this group to evaluate tau deposition in the brain. Promising imaging biomarkers for presymptomatic familial FTLD have been identified and assessed for specificity and sensitivity for accurate prediction of symptom onset and tracking disease progression during the presymptomatic stage when clinical measures are not useful. Furthermore, identifying imaging biomarkers for the presymptomatic stage is important for the design of disease-modifying trials. We review the recent progress in imaging biomarkers of the presymptomatic phase of familial FTLD and discuss the imaging techniques and analysis methods, with a focus on the potential implication of these imaging techniques and their utility in specific mutation types.

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Section: Proton Magnetic Resonance Spectroscopymentioning

confidence: 99%

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Chen

Kantarci

2020

Front. Neurol.

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“…Pre-symptomatic MAPT mutation carriers exhibit evidence of insidious radiological involvement, typically beginning in the medial temporal lobes, extending to the insula and accelerating 2-years before symptom onset (Rohrer et al, 2015 ; Panman et al, 2019 ; Jiskoot et al, 2019 ; Dopper et al, 2016 ; Chen et al, 2019a ). Multimodal MRI based classification models suggest that individual radiological changes may not detectable until a few years before phenoconversion (Feis et al, 2019 ; McKenna et al, 2022 ).…”

Section: C9orf72mentioning

confidence: 99%

“…MR spectroscopy studies have suggested a relatively stereotyped sequence of events, beginning with increased mI/Cr ratio (indicators of glial activity), followed by decreased NAA/mI ratio (markers of loss of neuronal integrity) and subsequent atrophy (Christidi et al, 2022 ). MRS studies of presymptomatic MAPT mutation carriers are predominantly single voxel studies focusing on different regions of interests (ROIs) such as the posterior cingulate gyrus inferior precuneus (Chen et al, 2019a ; Kantarci et al, 2010 ) or medial frontal lobe (Chen et al, 2019c ). Similar to structural findings, these radiological changes accelerate in the 2-years preceding symptom onset (Chen et al, 2019a ).…”

Section: C9orf72mentioning

confidence: 99%

“…MRS studies of presymptomatic MAPT mutation carriers are predominantly single voxel studies focusing on different regions of interests (ROIs) such as the posterior cingulate gyrus inferior precuneus (Chen et al, 2019a ; Kantarci et al, 2010 ) or medial frontal lobe (Chen et al, 2019c ). Similar to structural findings, these radiological changes accelerate in the 2-years preceding symptom onset (Chen et al, 2019a ). Cross-sectional studies have reported divergent results of NAA/Cr ratios: some studies have demonstrated decreased NAA/Cr ratios in the medial frontal lobe (Chen et al, 2019c ); and other studies have shown no difference in the posterior cingulate gyrus inferior precuneus (Kantarci et al, 2010 ).…”

Section: C9orf72mentioning

confidence: 99%

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Pre-symptomatic radiological changes in frontotemporal dementia: propagation characteristics, predictive value and implications for clinical trials

McKenna

Lope

Tan

et al. 2022

Brain Imaging and Behavior

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Computational imaging and quantitative biomarkers offer invaluable insights in the pre-symptomatic phase of neurodegenerative conditions several years before clinical manifestation. In recent years, there has been a focused effort to characterize pre-symptomatic cerebral changes in familial frontotemporal dementias using computational imaging. Accordingly, a systematic literature review was conducted of original articles investigating pre-symptomatic imaging changes in frontotemporal dementia focusing on study design, imaging modalities, data interpretation, control cohorts and key findings. The review is limited to the most common genotypes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) genotypes. Sixty-eight studies were identified with a median sample size of 15 (3–141) per genotype. Only a minority of studies were longitudinal (28%; 19/68) with a median follow-up of 2 (1–8) years. MRI (97%; 66/68) was the most common imaging modality, and primarily grey matter analyses were conducted (75%; 19/68). Some studies used multimodal analyses 44% (30/68). Genotype-associated imaging signatures are presented, innovative study designs are highlighted, common methodological shortcomings are discussed and lessons for future studies are outlined. Emerging academic observations have potential clinical implications for expediting the diagnosis, tracking disease progression and optimising the timing of pharmaceutical trials.

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“…Some studies also reported cerebral metabolite changes in extra-motor regions. Previous studies performed in asymptomatic genetic carriers of mutations associated with FTLD using MRS-derived markers exhibit an encouraging discriminatory ability to identify patients from healthy controls; however, more data are needed to determine their ability to assist with the diagnosis in early stages and in distinguishing from disease mimics ( 232 – 239 ).…”

Section: Biomarkersmentioning

confidence: 99%

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

et al. 2022

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.

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Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

Cited by 9 publications

References 35 publications

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

Pre-symptomatic radiological changes in frontotemporal dementia: propagation characteristics, predictive value and implications for clinical trials

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

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