Very‐Late‐Onset Corticobasal Degeneration Presenting as Behavioural Variant Frontotemporal Dementia: An Autopsy, Biochemical and Ultrastructural‐Confirmed Case

Corticobasal degeneration (CBD) is a rare four‐repeat (4R) tauopathy characterised by cognitive, behavioural, motor and psychiatric symptoms, making its clinical diagnosis difficult [1]. A definitive diagnosis requires a postmortem examination [1]. Previous studies have reported that CBD typically develops between 50 and 70 years old [2, 3, 4]. We encountered a patient with very‐late‐onset CBD who developed prominent behavioural and personality changes in her early 90s.

The female patient had no history of psychiatric or neurological diseases. She completed compulsory education, worked until her mid‐60s, and lived independently with occasional family support before symptom onset. In her early 90s, increasing frailty and a fall at home necessitated nursing home admission. Several months later, she developed behavioural and personality changes, including disinhibition, irritability and hyperorality. She made insulting remarks, shouted, grabbed other residents and often forcibly took their belongings and food. She showed executive dysfunction, requiring assistance for toileting and medication management, which she frequently resisted. Within 1 year after symptom onset, she fell and broke her left femoral neck, necessitating wheelchair dependence, and was referred to a psychiatrist due to her severe manifestations. Parkinsonism or other extrapyramidal signs were not documented. A Mini‐Mental State Examination was attempted, but she refused to complete it (3/30, all points obtained on naming). Head computed tomography revealed mild left‐dominant frontotemporal atrophy, bilateral basal ganglia calcifications and mild periventricular white matter hypodensities (Figure 1A–D). Shortly thereafter, her oral intake declined, leading to dehydration and hypernatremia, and she died without evidence of other physical causes. Retrospectively, her progressive behavioural disinhibition with socially inappropriate behaviours and hyperorality, along with functional decline, was consistent with probable bvFTD [5].

FIGURE 1.

Neuroimaging, neuropathological and biochemical findings. (A–D) Head computed tomography at admission to the psychiatric hospital showing slightly left‐dominant mild frontotemporal atrophy, bilateral basal ganglia calcifications and mild periventricular white matter hypodensities. (E, F) Convexity and basal views of the cerebral hemispheres showing greater atrophy in the left frontal and temporal lobes than in the right. (G) Formalin‐fixed left cerebral hemisphere and left cerebellar hemisphere. (H) Horizontal section of the midbrain demonstrating severe depigmentation of the substantia nigra (SN). (I) Microscopic section of the SN showing severe neuronal loss, gliosis and free melanin, stained with haematoxylin and eosin (H and E). (J) Anti‐phosphorylated tau (AT8) immunostaining in the SN demonstrating numerous pretangles and threads. (K) H&E staining of the left frontal cortex showing a relatively preserved cortical layered structure. Roman numerals I–VI indicate the approximate positions of the cortical layers. (L) AT8 immunostaining showing pretangles and threads distributed in the left frontal cortex. (M) AT8 immunostaining demonstrating pretangles (arrowhead) and an astrocytic plaque (arrow) in the left frontal cortex. (N, O) AT8 immunostaining (N) and Gallyas–Braak (GB) staining (O) highlighting an astrocytic plaque in the left frontal cortex. (P) AT8 immunostaining of the left globus pallidus demonstrating numerous pretangles and threads. (Q) GB staining demonstrating argyrophilic threads in the fibres of the left putamen. (R) AT8 immunostaining showing subpial thorn‐shaped astrocytes in the left medial temporal lobe, consistent with ageing‐related tau astrogliopathy. (S) AT8 immunostaining showing argyrophilic grains in the left dentate gyrus and neuronal cytoplasmic inclusions in dentate granule cells. (T) An ultrastructural analysis using the TauC antibody (5‐nm gold labelling) revealing characteristic twisted ribbon‐like tau filaments with approximately 140‐nm periodicity. (U) A Western blot analysis with the anti‐tau antibody T46 showing the CBD‐characteristic 37‐kDa C‐terminal doublet and, in the temporal cortex of the present case, 64‐ and 68‐kDa 4R‐tau bands together with a 60‐kDa 3R‐tau band. Lanes 1 and 2 correspond to the frontal and temporal cortex of the present case, respectively and Lanes 3 and 4 correspond to a progressive supranuclear palsy (PSP) case and another CBD case, respectively, both serving as 4R tauopathy controls. Scale bars: 1 cm (E–H); 200 μm (K, L); 100 μm (I, R); 50 μm (J, M–Q, S); 100 nm (T).

The postmortem interval was 21 min. Her brain weighed 1030 g. Macroscopically, the left frontal and temporal lobes were more atrophic than the right (Figure 1E–G). Formalin‐fixed left‐hemisphere tissue was examined microscopically, and frozen right‐hemisphere tissue was used for ultrastructural and Western blot analyses using previously described methods [6]. The substantia nigra showed severe depigmentation and neuronal loss, and anti‐phosphorylated tau (AT8) immunostaining demonstrated numerous pretangles and threads (Figure 1H–J). Moderate AT8‐positive pretangles and threads, as well as AT8‐ and Gallyas–Braak–positive astrocytic plaques, were distributed in the cortex and subcortical white matter of the frontal gyrus and temporal gyrus. However, the layered structure of the cortex was relatively preserved (Figure 1K–O) with mild neuronal loss and gliosis, and ballooned neurons were rarely identified. Widespread pretangles and numerous threads with neuronal loss and gliosis were also observed in the basal ganglia (Figure 1P,Q), most prominently involving the globus pallidus, followed by the subthalamic nucleus and the putamen. In the cerebellar dentate nucleus, a small number of AT8‐positive pretangles and threads were observed with mild neuronal loss, but no grumose degeneration was detected. Ageing‐related tau astrogliopathy was observed particularly in the perivascular, subpial and subependymal regions of the medial temporal lobe and brainstem (Figure 1R). Argyrophilic grains (AGs) were observed in the hippocampus (Figure 1S), insula and hypothalamus, corresponding to Saito Stage III. Alzheimer's disease neuropathological change was ‘low’ (A1B2C0). Vascular changes were minimal. Vascular wall calcification was observed in the putamen and globus pallidus. Cerebral amyloid angiopathy and apparent myelin pallor were absent. pTDP‐43‐positive inclusions, p‐α‐synuclein‐positive inclusions, tufted astrocytes, or trauma‐related pathological changes were not detected. Ultrastructural analyses using the TauC antibody (5‐nm gold labelling) revealed twisted ribbon‐like filaments characteristic of CBD with periodicity of 140 nm (Figure 1T). A Western blot analysis with the anti‐tau antibody T46 detected a CBD‐characteristic 37‐kDa C‐terminal doublet, and the temporal cortex showed 64‐ and 68‐kDa 4R‐tau bands with a 60‐kDa 3R‐tau band (Figure 1U), consistent with CBD accompanied by low Alzheimer's disease neuropathological change.

In previous reports of CBD cohorts, the age at onset typically ranges between 50 and 70, and death beyond the late 80s is uncommon [2, 3, 4]. This case demonstrates that CBD with minimal age‐related co‐pathology can present as bvFTD around age 90. Severe nigral degeneration and basal ganglia involvement may have contributed to recurrent falls. The dementia manifestations were attributable to frontal and temporal cortical involvement, while relatively mild neuronal loss and gliosis were consistent with the short disease duration. Parietal involvement was mild, in line with the lack of overt posterior cortical signs. A clinical diagnosis of CBD would have been difficult because of her advanced age, which was not within the typical age range of CBD onset and lack of the full typical symptoms of CBD. The clinical diagnostic criteria for CBD have been reported to have limited sensitivity and specificity [1, 7] and the symptoms of bvFTD in elderly patients are milder than those of early‐onset patients [5]. Previously reported CBD cases dying in their 80s presented with corticobasal syndrome or unclassified phenotypes [4], whereas the clinical features of CBD in very elderly patients remain poorly understood, highlighting the importance of autopsy studies to further understand the phenotypic variability of CBD.

Funding

This work was supported by the Japan Agency for Medical Research and Development (JP25wm0625126) and the Japan Society for the Promotion of Science (JP19K17059 and JP22K07595).

Ethics Statement

After the patient's death, written consent for publication was obtained from the patient's proxy. This study was approved by the Ethics Review Committee of the Nagoya University Graduate School of Medicine. The autopsy was performed in accordance with the Corpse Autopsy and Preservation Law.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy and ethical restrictions.