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Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72.

ABSTRACT: Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age-matched controls (age: 62.5(10.4) years), using an automated segmentation of T1-weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA-NOS), and 8 with associated motor neurone disease (FTD-MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP-43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16-33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28-38%), TDP-43 type A (47%), tau-CBD (44%), and FTD-MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10-20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers.

SUBMITTER: Bocchetta M

PROVIDER: S-EPMC7267940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder associated with frontal and temporal atrophy. Subcortical involvement has been described as well, with early thalamic atrophy most commonly associated with the C9orf72 expansion. However thalamic involvement has not been comprehensively investigated across the FTD spectrum.MethodsWe investigated thalamic volumes in a sample of 341 FTD patients (age: mean(standard deviation) 64.2(8.5) years; disease duration: 4.6(2.7) years) compared with 99 age-matched controls (age: 61.9(11.4) years). We performed a parcellation of T1 MRIs using an atlas propagation and label fusion approach to extract left and right thalamus volumes, which were corrected for total intracranial volumes. We assessed subgroups stratified by clinical diagnosis (141 behavioural variant FTD (bvFTD), 76 semantic dementia (SD), 103 progressive nonfluent aphasia (PNFA), 7 with associated motor neurone disease (FTD-MND) and 14 primary progressive aphasia not otherwise specified (PPA-NOS), genetic diagnosis (24 with MAPT, 24 with C9orf72, and 15 with GRN mutations), and pathological diagnosis (40 tauopathy, 61 TDP-43opathy, 3 FUSopathy). We assessed the diagnostic accuracy based on thalamic volume.ResultsOverall, FTD patients had smaller thalami than controls (8% difference in volume, p < 0.0005, ANCOVA). Stratifying by genetics, C9orf72 group had the smallest thalami (14% difference from controls, p < 0.0005). However, the thalami were also smaller than controls in the other genetic groups: GRN and MAPT groups showed a difference of 11% and 9% respectively (p < 0.0005). ROC analysis showed a relatively poor ability to separate C9orf72 from MAPT (AUC = 0.651, p = 0.073) and from GRN cases (AUC = 0.644, p = 0.133) using thalamic volume. All clinical subtypes had significantly smaller thalami than controls (p < 0.0005), with the FTD-MND group having the smallest (15%), followed by bvFTD (9%), PNFA (8%), PPA-NOS (7%), and lastly SD (5%). In the pathological groups, the TDP-43opathies had an 11% difference from controls, and tauopathies 9%, while the FUSopathies showed only 2% of difference from controls (p < 0.0005). GRN, PPA-NOS and SD were the subgroups showing the highest asymmetry in volumes.ConclusionsThe thalamus was most affected in C9orf72 genetically, TDP-43opathies pathologically and FTD-MND clinically. However, thalamic atrophy is a common feature across all FTD groups.

Project description:The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson's disease. However, the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear. To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex, a model of Parkinson's disease was established by injecting 8 µg 6-hydroxydopamine into the substantia nigra compacta of rats. After 1 or 3 weeks, 0.3 µg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain. At 3 or 5 weeks after the initial injury, neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically. The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining. Results demonstrated that after injury, the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats. Compared with normal medial prefrontal cortical neurons, at 3 and 5 weeks after substantia nigra compacta injury, the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge, with an increased discharge interval. The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge, but the discharge interval was only higher at 3 weeks. At 3 weeks after the combined lesions, the discharge frequency, discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex. These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex. The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal cortex neurons after substantia nigra compacta injury. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Xi'an Jiaotong University, China (approval No. XJTULAC2017-067) on August 26, 2017.

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Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72.

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