Background
The Muro district covers the mountainous areas of the southern coast of the Kii peninsula in Japan. Amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) endemic to residents in this area is referred to as “Muro disease”. An epidemiological survey of the prevalence rates of amyotrophic lateral sclerosis (ALS) conducted in this area in the 1950s found very dense accumulation in two villages in particular, Hohara and Kozagawa. The prevalence rates in these villages were approximately 100 times those in other areas of Japan. Neuropathological features of ALS patients in this area (Kii ALS) were similar to those observed in the Chamorro people of Guam [
1], and were characterized by a combination of neurofibrillary tangles (NFTs) in the brain and the changes of ALS [
2]. Parkinsonism-dementia complex (PDC) is characterized clinically by progressive parkinsonism and dementia. This disorder is frequently superimposed with ALS clinically and neuronal loss with abundant NFTs in the temporal lobe, frontal lobe and brainstem without accompanying senile plaques was neuropathological hallmark [
3,
4].
Neuroradiological study with Kii ALS/PDC showed hypometabolism of frontotemporal lobes, with or without frontotemporal atrophy, resembling that of the frontotemporal lobar degeneration (FTLD), but different from Alzheimer’s disease (AD) [
5]. Although neuroradiological study of Kii ALS/PDS was similar to FTLD, it is uncertain whether clinical features, especially in the characteristics of dementia, of Kii ALS/PDC are same as that of FTLD. Previous reports showed the clinical characteristics of Kii ALS/PDC were abulia and amnesia [
6]. In the present study, we revealed abulia-apathy, hallucination, impairment of orientation, deterioration of recent memory and/or frontal executive dysfunction and bradyphreniaof patients with Kii ALS/PDC compared with patients with other types of dementia disorders, and used brain magnetic resonance imaging (MRI) and brain regional perfusion as assessed by single photon emission computed tomography (SPECT) to reveal the structural and functional abnormality linked to cognitive dysfunction in these patients.
Discussion
The present study revealed that the core neuropsychological symptoms of patients with Kii ALS/PDC were abulia-apathy, hallucination, impairment of orientation, deterioration of recent memory and/or frontal executive dysfunction and bradyphrenia.
AD is a progressive neurodegenerative disorder that is characterized by the presence of amyloid deposits and NFTs together with the loss of cortical neurons and synapses [
23]. The most profound and earliest cognitive deficits seem to be impairment of episodic memory and the ability to recall events that are specific to a time and place [
24]. AD is characterized by deficits in attentional and executive functions [
25]. Depression is the main psychiatric correlate of abulia-apathy in AD. Several studies have demonstrated a significant association between apathy and reduction in metabolic activity of the frontal lobes, and more severe parkinsonism suggesting that neuropathological changes in specific brain areas may underlie the high frequency of apathy in AD [
26]. A recent study has shown that apathy is a behavioral marker of more aggressive dementia characterized by faster progression of cognitive impairment [
27]. Delusions, and in particular paranoid delusions, are more common than hallucinations in AD [
28].
PSP is one of the most common atypical parkinsonian syndromes. PSP pathology is characterized by the abnormal accumulation of tau protein accompanied by neuronal loss and gliosis, mainly in subcortical structures [
29]. The striato-frontal dysfunction leads to dramatic deficits in planning, monitoring and recall, which evolves into dementia in PSP patients [
30,
31]. The cognitive impairment of PSP patients has been considered the archetype of subcortical dementia. The striking features are severe bradyphrenia, impaired verbal fluency, and difficulty with sequential actions or shifting from one task to another [
32]. Cognitive tests that depend on visual performance are especially affected. Dementia is less severe than might be suggested by dysarthria, bradyphrenia, poor eye contact, and loss of facial expression. Abulia-apathy and disinhibition are common. Emotional incontinence is dominated by inappropriate weeping or, less frequently, laughing.
FTLD is the third most common cause of cortical dementia, following AD and DLB [
12]. FTLD encompasses two major pathologic substrates that affect primarily thefrontal or temporal cortex, in some patients asymmetrically. Three prototypic neurobehavioral syndromes can result from FTLD. The most common clinical manifestations of FTLD are changes in character, disordered social conduct, and lack of affect, concern and insight, with relative preservation of memory function [
33,
34]. Cognitive deficits occur in the domains of attention, abstraction, planning, and problem solving, in keeping with a frontal dysexecutive syndrome, whereas primary tools of language, perception, and spatial functions are well preserved. Patients are not clinically amnesic. Two other prototypic clinical syndromes occur in FTLD: progressive non-fluent aphasia and semantic dementia [
33]. The disorder of language occurs in the absence of impairment in other cognitive domains.
DLB was originally defined as a clinicopathologic entity with a specific constellation of clinical features, and a descriptive approach was proposed for assessing neuropathology [
9]. The only neuropathologic requirement for DLB is the presence of Lewy bodies somewhere in the brain of a patient with a clinical history of dementia. Recurrent, complex visual hallucinations continue to be one of the most useful signposts to a clinical diagnosis of DLB. Disability in DLB derives not only from cognitive impairment but also from neuropsychiatric, motor, sleep, and autonomic dysfunction. The cognitive profile of DLB comprises both cortical and subcortical impairments with substantial attentional deficits and prominent executive and visuospatial dysfunction [
35,
36].
In this study, the clinical features of Kii ALS/PDC are abulia-apathy and hallucination, but not alteration of personality and aphasia. The patients with Kii ALS/PDC share some part of symptoms with PSP and DLB patients. In MMSE and PAWLT, the patients with Kii ALS/PDC showed more severe disorientation than those with AD and FTLD, and more severe deterioration of recent memory than those with PSP and FTLD despite the equivalent duration of the cognitive impairment in each group. Recall performance can potentially be impaired as a result of a primary amnesia, or secondarily as a result of poor frontal executive function, therefore it was difficult to discriminate a primary amnesia and poor frontal executive function in the patients with Kii ALS/PDC in this study. RCPM results revealed that the bradyphrenia observed in Kii ALS/PDC patients was even slower than that observed in AD patients and FTLD patients. Although the results of FAB, which was examined only in several selected cases, showed the patients with Kii ALS/PDC might have frontal executive dysfunction, there was a limitation of the study in view of the central importance of assessing frontal lobe functions in this patient group.
Most characteristic cognitive deficit of Kii ALS/PDC was abulia/apathy. Abulia/apathy may reflect neuronal loss and tau pathology especially in the anterior cingulate gyrus in which the decrease of the cerebral blood flow was also detected in SPECT (unpublished data). Visual hallucination may be linked to α-synuclein pathology [
37]. The patients with Kii ALS/PDC lacked the typical symptoms of behavior variant FTD, semantic dementia and non-fluent progressive aphasia, those were personality change, inappropriate social behavior/disinhibition, loss of empathy, loss of insight, abnormal eating behavior and aphasia, except for decrease of extraversion, apathy and reduced speech. Although Kii ALS/PDC showed atrophy and the decrease of the blood flow in the frontal lobe and temporal lobe, the neuropsychological symptoms of patients with Kii ALS/PDC was different from those of the patients with FTLD. Also Kii ALS/PDC showed unique cognitive impairments comparing with AD, PSP, FTLD and DLB.
This study has a limitation in that we could not evaluate focus on frontal function except for FAB, none of tests are specifically designed for patients with ALS. And the motor impairment due to parkinsonism or ALS may affect the results of battery. There is a possibility of the effect to the performance in the test. We have only small cases of Kii ALS/PDC, and statistical comparison also has a limitation. However, the results of clinical symptoms, neuropsychological tests and neuroradiological tests seemed to be mutually related. These results are expected to contribute something to solving Kii ALS/PDC.
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Competing interests
The authors declare no conflicts interest regarding this manuscript.
Authors’ contributions
AS carried out conception and design of study, analysis and interpretation of data, collection and assembly data, and draft of the article. YU carried out the analysis of neuropsychological tests. SK conceived of the study, and participated in its design and coordination and helped to draft the manuscript. YK carried out critical revision of the article for important intellectual content, and final approval of this article. All authors read and approved the final manuscript.