Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review

Abstract

The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation.

Biogenic Amines in Neurotransmission and Human Disease

“…We have recently demonstrated that the effect of the KARs' activation in this synapse requires protein kinase A (PKA) activation, since the inhibition of this protein by cAMP-Rp suppresses the effect of KA in glutamate release [80], in agreement with previous studies in hippocampus and cortex [87][88][89]. This congruence between mechanisms at different synapses has also been seen through the inhibition of PKA using H-89, which eliminates KARs-mediated facilitation of glutamate release.…”

“…A biphasic action of KARs, activated by the agonist domoate, has been shown previously at PF-PuC synapse, with low agonist concentrations, facilitating synaptic transmission and higher concentrations depressing synaptic transmission [86] in agreement with what has been found in the hippocampus [87][88][89], cortex [90], amygdala [91], and the thalamus [92]. EPSC trial-to-trial fluctuation analysis, failure rates, as well as paired-pulse ratios have shown that these facilitatory and depressive actions of KARs in the cerebellum are mediated by presynaptic KARs [80]. However, the precise mechanism of action by which KARs mediate potentiation (and depression) of synaptic transmission at PF-PuC synapses has remained elusive until very recently [80] (Table 1).…”

“…In neurodegeneration, KARs may have a role in calcification of the brain tissue as it has been found that local application of KA in some areas of the cerebellum produces changes in different ion levels, highly increasing Ca 2+ levels for more than 8 weeks, which mediate calcification [78] (Table 1). KARs have been described as producing increases in intracellular calcium [79,80] and seems to signal increasing intracellular calcium without putting the cell at risk due to excitotoxicity, due to its low conductance in contrast to AMPARs. Due to the lack of knowledge on the subject, further exploration is necessary to determine the KARs' role in cerebellum development and cerebellar alterations.…”

“…EPSC trial-to-trial fluctuation analysis, failure rates, as well as paired-pulse ratios have shown that these facilitatory and depressive actions of KARs in the cerebellum are mediated by presynaptic KARs [80]. However, the precise mechanism of action by which KARs mediate potentiation (and depression) of synaptic transmission at PF-PuC synapses has remained elusive until very recently [80] (Table 1).…”

The spectrum of involuntary vocalizations in humans: A video atlas

“…101 However, it is most commonly reported in TS 66,102 and ASD. [103][104][105][106] Patients with other neurodevelopmental disorders, 15,[107][108][109][110] including fragile X 108,109 and Williams syndrome, 110 and neurodegenerative syndromes (eg, dementia with Lewy bodies, 111 various tauopathies, [112][113][114][115][116][117] HD, 118 Creutzfeldt-Jakob disease (CJD), 119 and chorea-acanthocytosis 73 ) may also present with echolalia. Neurometabolic disorders, such as Niemann-Pick type C (Video 1L) and Wilson's disease 120 or encephalopathic syndromes, [121][122][123] as well as brain lesions due to focal or diffuse cerebrovascular damage, 114,124 carbon monoxide poisoning, 60 and severe head trauma 85 were also associated with echolalic behaviors.…”