Reconfigured metabolism brain network in asymptomatic microtubule-associated protein tau mutation carriers: a graph theoretical analysis

BackgroundStudies exploring topologic properties of the metabolic network in the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce, which may be important for understanding brain function and disease pathogenesis. This study aimed to explore FTD‐specific patterns of metabolism topology reconfiguration in asymptomatic microtubule‐associated protein tau (MAPT) mutation carriers.MethodSix asymptomatic carriers of MAPT P301L mutation were compared with 12 non‐carriers who were all from the same large family of FTD. For comparison, we included 32 behavioral‐variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and hybrid PET/MRI scan. Voxel‐wise gray matter volume and standardized uptake value ratio were calculated and compared for structural MRI and FDG‐PET, separately. The sparse inverse covariance estimation (SICE) method was applied to topologic properties and metabolic connectomes of brain functional networks derived from 18F‐fluorodeoxyglucose PET/MRI data. Independent component analysis was used to explore metabolic connectivity in the salience (SN) and default mode networks (DMN).ResultThe mean estimated years from symptom onset was 8.33 ± 1.875 years in the mutation carrier group. The asymptomatic MAPT carriers show no significant differences in cognitive tests, gray matter volume and FDG uptake compared to non‐carriers. They also retained normal global parameters of metabolism network, but not for bvFTD patients. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers, which is consistent with the findings in bvFTD patients. Similarly, significant differences in local parameters of these nodes were observed in asymptomatic carriers. The reduction in connectivity was marked in lost hub regions during the asymptomatic stage. Functional connectivity within the SN and DMN was enhanced in asymptomatic carriers, while reduced in bvFTD patients.ConclusionOur findings showed that asymptomatic MAPT carriers were initially involved in medial prefrontal areas and actively compensated in task‐related regions. Topologic properties of the metabolic network may contribute to further investigations and monitoring of the earliest stages of FTD in individuals with genetic backgrounds.

Flortaucipir (AV-1451) and pyridinyl-butadienyl-benzothiazole 3 (PBB3) are newly developed and commonly used positron emission tomography (PET) tracers to detect tau deposition in tauopathies, including frontotemporal dementia (FTD). [18F]PM-PBB3, as a second-generation compound, has not been described in FTD so far. We aim to explore the in vivo performance of [18F]PM-PBB3 tau PET in an FTD case caused by microtubule-associated protein tau (MAPT) mutation and compare the binding to different tau strains between AV-1451 and PBB3. We reported the clinical and FDG, [18F]AV45 amyloid and [18F]PM-PBB3 tau PET findings in a patient with FTD of P301L MAPT mutation. Based on our results and published data, we summarized and compared the different utilities of tau PET tracers of AV-1451 and PBB3 in FTD with MAPT mutation. The patient demonstrated slightly diffuse [18F]PM-PBB3 tau deposition in cerebral lobes especially in the left frontal lobe overlapping with the hypometabolic region detected by FDG PET. From our analysis of 35 FTD patients with MAPT mutation who underwent tau PET, AV-1451 was positive in all (n = 11) patients with mutations known to cause three and four repeat (3R/4R) tau deposition and in 14.3% (n = 2/14) of 4R tauopathies, while positive PBB3 retention was found in all patients with both 3R/4R (n = 2) and 4R (n = 8) tau. [18F]PM-PBB3 tau PET assisted the diagnosis of FTD with P301L MAPT mutation, and might be useful in the in vivo detection of both 3R/4R and 4R tau domains in the brain of FTD with MAPT mutation.

To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.

The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n=21), GRN mutations (n=11), C9ORF72 repeat expansions (n=11) or sporadic FTD (n=15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS

To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation. MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging. We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET. Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article.In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick's disease (K257T), corticobasal degeneration (S305S, IVS10‰+‰16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10‰+‰16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models.

BackgroundMutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls.Methods(18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient’s FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference.ResultOn review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1).On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2).ConclusionHypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes.

Investigating brain metabolic networks is crucial for understanding the pathogenesis and functional alterations in Creutzfeldt-Jakob disease (CJD). However, studies on presymptomatic individuals remain limited. This study aimed to examine metabolic network topology reconfiguration in asymptomatic carriers of the PRNP G114V mutation. Seven asymptomatic PRNP G114V mutation carriers from a familial genetic CJD (gCJD) cohort, 43 CJD patients, and 35 healthy controls were included. All participants underwent neuropsychological assessments, genetic testing, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI scans. Voxel-based gray matter volume and FDG PET standardized uptake value ratios (SUVRs) were analyzed between asymptomatic PRNP G114V mutation carriers and healthy controls and between CJD patients and controls. Graph theory and sparse inverse covariance estimation (SICE) were used to assess the whole-brain metabolic connectomes and topological properties. Spatial independent component analysis (ICA) was used to evaluate subnetworks, including the default mode network (DMN), salience network (SN), and central executive network (CEN). With respect to global properties, assortativity was significantly increased in asymptomatic carriers, which was consistent with the findings in CJD patients. We revealed lost hubs in the right anterior cingulate, left ventral prefrontal lobe, left parahippocampal gyrus, and left lingual gyrus and reconfigured hubs in prefrontal lobes, including right ventromedial prefrontal cortex, right anterior prefrontal cortex, and right middle frontal gyrus of the orbit in asymptomatic carriers compared with healthy controls, which overlapped with the comparisons between CJD patients and controls. Alterations in the local parameters and metabolic connectivity in the left parahippocampal gyrus were most pronounced. Among the subnetworks, asymptomatic carriers presented higher assortativity and lower hierarchy in the SN, whereas the global parameters of the DMN and CEN were not significantly altered. The DMN and SN showed partial hypoconnectivity and hyperconnectivity, whereas the CEN mainly showed significantly enhanced connectivity in asymptomatic PRNP carriers. This study revealed altered brain metabolic topology and connectomics in asymptomatic PRNP G114V mutation carriers, which could be detected before gray matter or regional metabolic changes, suggesting that metabolism topology reconfiguration may serve as a sensitive imaging biomarker for investigating early CJD pathological changes.

BackgroundIn patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms.MethodsMagnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas).ResultsIntra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers.ConclusionsThese simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Familial forms of frontotemporal dementia (FTD) are in 10–43% of patients, caused by mutations in the gene encoding the microtubule associated protein tau (MAPT) located at chromosome 17q21. Neuropathologically, these patients are characterized by tau-positive depositions in brain. However, autosomal dominant forms of FTD without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. One such form is FTD linked to 17q21, with tau-negative but ubiquitine-positive neuronal inclusions or FTD-U. We previously reduced the candidate chromosomal region to 4.8 cM in a Dutch FTD-U family, 1083. A mutation in MAPT was excluded by genomic sequencing. More recently, we identified three Belgian FTD families of which two, DR2 and DR8, showed linkage to the 17q21 region. Both families shared a common haplotype in an 8.04 cM region, indicating that they are genetically related to a common founder. In the third family, DR7, we obtained an autopsy confirmation of the characteristic ubiquitin-positive, tau-negative neuronal inclusions. Currently, there are 11 FTD families linked to 17q21 that do not segregate a MAPT mutation, of which five are conclusively linked (LOD score > 3). Together the data suggest that FTD-U could represent an important subtype of FTD, and that identification of the underlying gene defect might significantly contribute to our understanding of the pathomechanism leading to neurodegeneration in this dementia subtype.

Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.

PHENOCONVERSION FROM ASYMPTOMATIC TO MINIMALLY SYMPTOMATIC FTLD: PRELIMINARY DATA IN THE LEFFTDS COHORT