Buciuc, Marina

AbstractBackgroundGlobular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD).MethodsFor this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed.ResultsTwelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes.ConclusionsFemale sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

Abstract Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

Abstract Aims To assess the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) inclusions in a unique cohort of old‐age patients with genetic frontotemporal lobar degeneration (gFTLD‐TDP) and compare these patients with sporadic old‐age individuals with TDP‐43, either in the presence of Alzheimer's disease (AD‐TDP) or in isolation (pure‐TDP). Methods The brain bank at Mayo Clinic‐Jacksonville was searched for cases ≥75 years old at death with TDP‐43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD‐TDP ( n = 15) with progranulin ( GRN )/ C9ORF72 mutations; (2) AD‐TDP ( n = 10)—cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure‐TDP ( n = 10)—cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP‐43 burden was calculated using digital pathology. Results Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP‐43 burden in gFTLD‐TDP and AD‐TDP, but not pure‐TDP, was limbic‐predominant targeting CA1 and subiculum. Patients with gFTLD‐TDP had higher burden in entorhinal cortex compared to AD‐TDP. TDP‐43 burden in middle frontal cortex did not differ between the three groups. Conclusions In old age it is challenging to clinically and pathologically differentiate gFTLD‐TDP from AD‐TDP and pure‐TDP‐43 based on burden. Like AD‐TDP, old age gFTLD‐TDP have a limbic predominant TDP‐43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP‐43 directly and indirectly targets limbic regions.