Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case

Abstract

We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.

Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss

“…To date, cases of FTLD with ubiquitin-positive, tau-negative inclusions (previously called as FTLD-U) showing CST degeneration but lacking both LMN loss and Bunina bodies have been reported not only from our institution but from other institution in Japan [28,31]. The disease duration of these two cases was 9 years [28] and 11 years [31], respectively.…”

“…The CST is involved in various brain diseases such as cerebrovascular diseases or degenerative diseases, and the latter is not limited to MND [17][18][19][28][29][30][31][32]. In contrast to the cerebrovascular diseases, CST degeneration in the degenerative diseases is often more severe at lower than at higher levels, and is thought to arise from axonopathy with peripheral "dying back" [29,33,34].…”

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

“…They also show that unlike neurons the quantitative assessment of these inclusions may be a neuropathological marker of disease duration. The presence of ubiquitin-positive tau-negative intraneuronal inclusions within the cerebral cortex and subcortical structures has been long considered as a key neuropathological feature of MND with dementia [16,45] or FTD with MND [3,5,7,9,11,17,23,27,31,39,42,46]. Despite several contributions based on small series, the presence of ubiquitin-related pathology within the cerebral cortex is still considered a rare phenomenon in typical FTD cases [2,6,15,18,21,22,24,34,35,40,47,48].…”

“…Although a global understanding of the molecular background of FTD is far from being achieved, one can schematically consider that this group includes a large but poorly defined subgroup of typical FTD cases characterized by nonspecific histopathological changes (such as neuronal loss, spongiosis and gliosis), two tauopathies [Pick's disease and FTD and parkinsonism linked to chromosome 17 (FTDP-17)], and one ubiquitinrelated disorder, FTD with motor neuron disease (MND) [8,30,41]. This latter form is characterized clinically by the presence of MND with dementia and neuropathologically by the formation of ubiquitin-positive and tau-negative intraneuronal inclusions in hippocampus and subcortical structures [3,7,9,11,27,31,42,46]. However, ubiquitin-positive intraneuronal inclusions and dendrites have also been reported in familial [6,20,24,35] and in a few sporadic FTD cases in the absence of MND [2,15,18,21,22,36,40,47,48] as well as in FTDP-17 cases [17,28,35].…”

Primary lateral sclerosis, hereditary spastic paraplegia, and mutations in thealsingene: Historical background for the first International Conference

“…Mochizuki et al (73) reported a 57-year-old man who had dysarthria at age 57 and was anarthric by age 60. Emotional lability was prominent and movements of the tongue were slow.…”