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Figure 1.
Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) images of the brain in patient 1 with amyotrophic lateral sclerosis (Table 1). At age 67 years, she had an 8-year history of bulbar palsy and tetraparesis but no dementia or parkinsonism. There is slight atrophy of the frontal lobe within normal limits for age on the T1-weighted (A) and T2-weighted (B) axial MRIs. A decrease in cerebral blood flow of the frontal and temporal lobes is seen on SPECT (C).

Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) images of the brain in patient 1 with amyotrophic lateral sclerosis (Table 1). At age 67 years, she had an 8-year history of bulbar palsy and tetraparesis but no dementia or parkinsonism. There is slight atrophy of the frontal lobe within normal limits for age on the T1-weighted (A) and T2-weighted (B) axial MRIs. A decrease in cerebral blood flow of the frontal and temporal lobes is seen on SPECT (C).

Figure 2.
Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) images of the brain in patient 1 with parkinsonism–dementia complex (Table 1). At age 73 years, she had a 7-year history of parkinsonism and dementia, followed by development of amyotrophic lateral sclerosis features. There is severe atrophy of the frontal and temporal lobes on the T1-weighted axial MRIs (A, B, and C) and FLAIR coronal MRI (D). A marked decrease in cerebral blood flow of the frontal and temporal lobes is seen on SPECT (E).

Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) images of the brain in patient 1 with parkinsonism–dementia complex (Table 1). At age 73 years, she had a 7-year history of parkinsonism and dementia, followed by development of amyotrophic lateral sclerosis features. There is severe atrophy of the frontal and temporal lobes on the T1-weighted axial MRIs (A, B, and C) and FLAIR coronal MRI (D). A marked decrease in cerebral blood flow of the frontal and temporal lobes is seen on SPECT (E).

Table 1. 
Clinical Summary of the Patients
Clinical Summary of the Patients3
Table 2. 
Neuroradiological Findings
Neuroradiological Findings
1.
Shiraki  HYase  Y Amyotrophic lateral sclerosis in Japan.  In: Vinken  PJ, Bruyn  GW, Klawans  HL, eds. Handbook of Clinical Neurology. Vol 22. Amsterdam, the Netherlands: North Holland Publishing Co; 1975:353-419.
2.
Kuzuhara  SKokubo  YNarita  YSasaki  R Continuing high incidence rates and familial occurrence of amyotrophic lateral sclerosis and parkinsonism–dementia complex of the Kii peninsula of Japan [abstract]. Neurology.1998;50(suppl 4):A173.
3.
Kuzuhara  SKokubo  YSasaki  R  et al Familial amyotrophic lateral sclerosis and parkinsonism–dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis. Ann Neurol.2001;49:501-511.
PubMed
4.
Hirano  AMalamud  NElizan  TSKurland  LT Amyotrophic lateral sclerosis and parkinsonism–dementia complex on Guam: further pathologic studies. Arch Neurol.1966;15:35-51.
PubMed
5.
World Federation of Neurology Research Group on Motor Neuron Diseases El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.  In: Consensus conference held at Airlie House; April 2-4, 1998; Warrenton, Va. Available at: http://www.wfnals.org. Accessed March 1, 2002.
6.
Kokubo  YKuzuhara  S Neurological and neuropathological study of amyotrophic lateral sclerosis/parkinsonism–dementia complex in the Kii peninsula of Japan [in Japanese]. Rinsho Shinkeigaku.2001;41:769-774.
PubMed
7.
Petersen  RCWaring  SCXu  YCJack Jr  CRKurland  LT Magnetic resonance volumetric measurements of the hippocampus in the parkinsonism–dementia complex of Guam [abstract]. Ann Neurol.1995;38:324.
8.
Peppard  RFMartin  WRWGuttman  M  et al Cerebral glucose metabolism in Parkinson's disease and the PD complex of Guam.  In: Crossman  AR, Sambrook  MA, eds. Current Problems in Neurology Series. Vol 9. London, England: John Libbey Medical Publishing; 1989:445-452.
9.
Snow  BJPeppard  RFGuttman  M  et al Positron emission tomographic scanning demonstrates a presynaptic dopaminergic lesion in Lytico-Bodig: the amyotrophic lateral sclerosis–parkinsonism–dementia complex of Guam. Arch Neurol.1990;47:870-874.
PubMed
10.
Boccardi  MLaakso  MPBresciani  L  et al The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia. Neurobiol Aging.2003;24:95-103.
PubMed
11.
Lojkowska  WRyglewicz  DJedrzejczak  T  et al SPECT as a diagnostic test in the investigation of dementia. J Neurol Sci.2002;203-204:215-219.
PubMed
12.
van Swieten  JCStevens  MRosso  SM  et al Phenotypic variation in hereditary FTD with tau mutation. Ann Neurol.1999;46:617-626.
PubMed
13.
Jagust  WJEberling  JL MRI, CT, SPECT, PET: their use in diagnosing dementia. Geriatrics.1991;46:28-35.
PubMed
14.
Soliveri  PMonza  DParidi  DSP  et al Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy. Neurology.1999;53:502-507.
PubMed
15.
Testa  DSavoiardo  MFetoni  V  et al Multiple system atrophy: clinical and MR observations on 42 cases. Ital J Neurol Sci.1993;14:211-216.
PubMed
16.
Shiozawa  ZShindo  KOhta  EOhushi  KNagamatsu  MNagasaka  T A concise overview of recent breakthroughs in imaging of ALS. Amyotrophic Lateral Sclerosis Other Motor Neuron Disord.2000;1(suppl 2):S3-S6.
Original Contribution
September 2003

Neuroradiological Study of Patients With Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex on the Kii Peninsula of Japan

Author Affiliations

From the Department of Neurology, Mie University School of Medicine, Tsu, Mie-ken, Japan.

Arch Neurol. 2003;60(9):1257-1261. doi:10.1001/archneur.60.9.1257
Abstract

Background  The Kii peninsula of Japan, together with Guam and West New Guinea, has one of the highest incidences of amyotrophic lateral sclerosis (ALS) and parkinsonism–dementia complex (PDC) in the world.

Objective  To perform neuroimaging studies on patients with ALS and PDC on the Kii peninsula.

Methods  Results of computed tomography, magnetic resonance imaging, and single-photon emission computed tomography were studied in 4 patients with ALS and in 10 patients with PDC from the Hohara village on the Kii peninsula of Japan.

Results  In patients with PDC, there was mild to severe atrophy of the frontal and temporal lobes on computed tomography and magnetic resonance imaging and a marked decrease in cerebral blood flow on single-photon emission computed tomography. In contrast, in patients with ALS, there was a decrease in cerebral blood flow of the frontal and temporal lobes, although the patients did not show signs of clinical dementia or obvious brain atrophy on computed tomography or magnetic resonance imaging.

Conclusion  The finding of an obvious decrease in cerebral blood flow of the frontal and temporal lobes in patients with PDC and ALS with or without cerebral atrophy supports the concept that the 2 conditions are different manifestations of a single frontotemporal tauopathy.

THE KII peninsula of Japan, together with Guam and West New Guinea, has one of the highest incidences of amyotrophic lateral sclerosis (ALS) in the world.1 Recently, a continuing high incidence of ALS and parkinsonism–dementia complex (PDC) on the Kii peninsula has been reported,2 as well as the first neuropathologically verified case of PDC in a family with ALS-PDC.3 Features of ALS and PDC are commonly seen in the same individual and in the same family, and similar neuropathologic findings, characterized by widely distributed neurofibrillary tangles, are seen in the central nervous system in patients with both conditions. On the Kii peninsula and Guam, ALS and PDC are regarded as different clinical manifestations of a single disease entity.4 Although many investigations on the clinical features and neuropathologic findings of patients with ALS-PDC have been done on Guam and on the Kii peninsula, few neuroimaging findings have been reported so far. The present study reports the findings of computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) in 4 patients with ALS and in 10 patients with PDC on the Kii peninsula.

METHODS

Four patients with ALS and 10 patients with PDC were included in the study. All of the patients were natives of the Hohara village on the Kii peninsula, which has a high incidence of ALS-PDC. A family history of ALS, PDC, or both was positive in 2 of the 4 patients with ALS and in 8 of the 10 patients with PDC. The diagnosis of ALS was based on the presence of clinical symptoms of classic ALS.5 None of the patients with ALS demonstrated abnormalities in cognitive functions on the Mini-Mental State Examination. The diagnosis of PDC was made based on the findings of levodopa-unresponsive parkinsonism and dementia, frequently accompanied by amyotrophy. The clinical features of the patients are summarized in Table 1. A CT scanner (X-lead; Toshiba, Tokyo, Japan), an MRI scanner (FLEXART 0.5T; Toshiba), and a SPECT scanner (model GCA-901A; Toshiba) using a tracer technetium Tc 99m ethyl cysteinate dimer were used for the study.

REPORT OF CASES
PATIENT 1 WITH ALS

The patient was a 65-year-old female native of Hohara. She had no family history of ALS or PDC. She developed dysarthria at age 57, and a diagnosis of ALS was made at age 59 when she developed atrophy of the tongue and small hand muscles. An electromyogram revealed neuropathic changes indicative of lower motor neuron involvements in the muscles of the tongue and extremities. Gradually, she developed bulbar palsy, muscle atrophy of the extremities, and pyramidal tract signs. A neuroradiological study was done at age 65 when she exhibited tetraparesis and aphonia due to severe bulbar palsy, but without cognitive impairments or respiratory dysfunction. Results of CT and MRI revealed slight frontal lobe atrophy within normal limits for age. In contrast, SPECT showed an obvious decrease in cerebral blood flow (CBF) of the frontal and temporal lobes (Figure 1).

PATIENT 1 WITH PDC

The patient was a 73-year-old female native of Hohara. Her father and 3 siblings had died of PDC, and a nephew had ALS. She developed parkinsonian gait at age 66, and the parkinsonism gradually worsened without response to levodopa. A diagnosis of PDC was made at age 67 when she developed dementia, atrophy of the intrinsic hand muscles, and pyramidal tract signs. Neuroradiological studies were done at age 73 when she showed severe memory disturbance, disorientation, abulia, apathy, bradykinesia, rigidity, gait disturbance, hand muscle atrophy with fasciculation, and pyramidal tract signs. Computed tomography and MRI revealed marked atrophy of the frontal and temporal lobes, and SPECT showed a marked decrease in CBF of the frontal and temporal lobes (Figure 2).

RESULTS

The neuroradiological findings are summarized in Table 2.

PATIENTS WITH ALS

Among patients with ALS, the results of CT and MRI of the brain were unremarkable, without brain atrophy or abnormal signal intensity of the corticospinal tract. A low signal intensity of the motor cortex on T2-weighted images was confirmed in patient 2, who showed mild parkinsonism from the early stage of the illness. In contrast, SPECT showed a decrease in CBF of the frontal lobe in all patients, and of the temporal lobe in 3 of the 4 patients. The decrease in CBF did not correlate with severity or duration of the illness.

PATIENTS WITH PDC

The results of CT and MRI of the brain showed moderate to severe atrophy of the frontal and temporal lobes, without remarkable changes of the putamen, corticospinal tract, or motor cortex in 7 patients with advanced-stage PDC, and atrophy of the entire brainstem in patient 7 with terminal-stage PDC. Findings on SPECT revealed a decrease in CBF of the frontal and temporal lobes in all the patients, including patients 8, 9, and 10 with early-stage PDC, who showed mild clinical symptoms. A decrease in CBF of the parietal lobe was detected in patients 4 and 8.

COMMENT

A continuing high incidence of ALS has been reported in Hohara since 1980.2 We recently described the clinical spectrum and neuropathologic findings in 3 patients with ALS and in 19 patients with PDC examined during 1996 and 1999.6 The clinical manifestations of ALS consisted of amyotrophy, pyramidal tract signs, and bulbar palsy, but without dementia or parkinsonism, and were similar to those of classic ALS. In contrast, the major symptoms of PDC consisted of cognitive impairment and parkinsonism, frequently accompanied by amyotrophy and pyramidal tract signs. In this geographic region, the clinical manifestations of ALS and PDC thus appear to differ. However, the 2 conditions share common neuropathologic features of widely distributed neurofibrillary tangles in the central nervous system and pathologic findings consistent with ALS.3

Some neuroradiological investigations have been performed in patients with ALS and PDC on Guam. Petersen et al7 studied volumetric MRI measurements of the hippocampus in patients with PDC on Guam and reported that hippocampal formation volumes were significantly reduced and correlated clinically with memory function and neuropathologically with the site of intense neurofibrillary tangle deposition. There was no description of the size of the frontal and temporal lobes. In our patients with PDC on the Kii peninsula, hippocampal atrophy was obvious early on and progressed as the disease advanced, as shown in Figure 2, although volumetric MRI was not performed in the present study.

Peppard et al8 assessed regional cerebral glucose metabolism in 8 patients with PDC on Guam using positron emission tomography with 18F-2-fluoro-2-deoxyglucose. They reported decreased regional cerebral glucose metabolism in all cortical and subcortical areas in the brains of these patients.

Snow et al9 performed positron emission tomography using 18F-6-fluorodopa in patients with ALS, patients with PDC, and clinically normal residents on Guam and compared the findings with those of control subjects at the University of British Columbia, Vancouver. The striatal 18F-6-fluorodopa uptake was significantly reduced in all the patients with PDC. The uptake was also significantly reduced in the patients with ALS, but was intermediate between that observed in the group with PDC and the Vancouver control subjects. Two of the clinically normal subjects on Guam showed reduced striatal 18F-6-fluorodopa uptake, suggesting early asymptomatic dopaminergic lesions. Position emission tomography was not performed in the present study, and the blood flow of the striatal area could not be assessed precisely because of the low resolution of our SPECT system.

To our knowledge, systematic neuroradiological studies on the brain have not been done in patients with ALS and PDC on the Kii peninsula, and the present study is the first to clarify the characteristic neuroradiological features of ALS-PDC in this region. The important findings were as follows: First, patients with PDC showed progressive atrophy of the frontal and temporal lobes on CT and MRI that became marked at the terminal stage, and a decrease in CBF of the frontal and temporal lobes was obvious from the early stage of the disease. Second, brain atrophy was absent or minimal in patients with ALS on the Kii peninsula, even in those at the advanced stage, but SPECT showed an obvious decrease in CBF of the frontal and temporal lobes. A decrease in CBF of the frontal and temporal lobes from the early stage of the disease was common to ALS and PDC, even when the patients had no obvious dementia clinically or cerebral atrophy on CT or MRI. This may be a functional manifestation of the background abnormalities common to patients with ALS and PDC in this region.

The present study revealed neuroradiological findings unique to ALS-PDC in this geographic region and distinct from other neurodegenerative diseases. Results of CT, MRI, and SPECT of patients with ALS-PDC on the Kii peninsula showed hypometabolism of the frontotemporal lobes, with or without frontotemporal atrophy, resembling that of the frontotemporal dementia syndrome,1012 but different from Alzheimer disease, characterized by hypometabolism of the association cortex of the temporoparieto-occipital lobes.13 Furthermore, the neuroradiological findings of patients with ALS-PDC on the Kii peninsula were distinct from those observed in the following studies: midbrain atrophy and a decrease in CBF of the frontal lobe in progressive supranuclear palsy,14 atrophy and abnormal intensity of the striatum in an MRI study of striatal nigral degeneration,15 asymmetric pericentral cortical atrophy and a decrease in CBF in corticobasal degeneration,14 and abnormal signal intensity of the pyramidal tract on MRI in classic ALS.16 From the viewpoint of neuropathologic and neuroimaging findings, ALS and PDC on the Kii peninsula can be considered a single disease entity of Kii ALS-PDC, as in Guamanian ALS-PDC.4 Furthermore, Kii ALS-PDC is a manifestation of a single tauopathy of frontotemporal degeneration.

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Article Information

Corresponding author and reprints: Shigeki Kuzuhara, MD, Department of Neurology, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie-ken 514-8507, Japan (e-mail: kuzuhara@clin.medic.mie-u.ac.jp).

Accepted for publication April 22, 2003.

Author contributions: Study concept and design (Drs Kokubo and Kuzuhara); acquisition of data (Dr Kokubo); analysis and interpretation of data (Dr Kokubo); drafting of the manuscript (Dr Kokubo); critical revision of the manuscript for important intellectual content (Dr Kuzuhara); obtained funding (Drs Kokubo and Kuzuhara); administrative, technical, and material support (Dr Kokubo); study supervision (Dr Kuzuhara).

This study was supported in part by a grant from the Mie Medical Research Foundation, Tsu, Japan, and grants from the Research Committee of Central Nervous System Degenerative Diseases, the Ministry of Health and Welfare (grant 1400003), and the Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture (grant 13470132), Tokyo, Japan.

We thank Hisami Akatsuka for her technical assistance in tissue preparation for histopathologic examinations and Kayoko Kihira for her clerical assistance.

References
1.
Shiraki  HYase  Y Amyotrophic lateral sclerosis in Japan.  In: Vinken  PJ, Bruyn  GW, Klawans  HL, eds. Handbook of Clinical Neurology. Vol 22. Amsterdam, the Netherlands: North Holland Publishing Co; 1975:353-419.
2.
Kuzuhara  SKokubo  YNarita  YSasaki  R Continuing high incidence rates and familial occurrence of amyotrophic lateral sclerosis and parkinsonism–dementia complex of the Kii peninsula of Japan [abstract]. Neurology.1998;50(suppl 4):A173.
3.
Kuzuhara  SKokubo  YSasaki  R  et al Familial amyotrophic lateral sclerosis and parkinsonism–dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis. Ann Neurol.2001;49:501-511.
PubMed
4.
Hirano  AMalamud  NElizan  TSKurland  LT Amyotrophic lateral sclerosis and parkinsonism–dementia complex on Guam: further pathologic studies. Arch Neurol.1966;15:35-51.
PubMed
5.
World Federation of Neurology Research Group on Motor Neuron Diseases El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.  In: Consensus conference held at Airlie House; April 2-4, 1998; Warrenton, Va. Available at: http://www.wfnals.org. Accessed March 1, 2002.
6.
Kokubo  YKuzuhara  S Neurological and neuropathological study of amyotrophic lateral sclerosis/parkinsonism–dementia complex in the Kii peninsula of Japan [in Japanese]. Rinsho Shinkeigaku.2001;41:769-774.
PubMed
7.
Petersen  RCWaring  SCXu  YCJack Jr  CRKurland  LT Magnetic resonance volumetric measurements of the hippocampus in the parkinsonism–dementia complex of Guam [abstract]. Ann Neurol.1995;38:324.
8.
Peppard  RFMartin  WRWGuttman  M  et al Cerebral glucose metabolism in Parkinson's disease and the PD complex of Guam.  In: Crossman  AR, Sambrook  MA, eds. Current Problems in Neurology Series. Vol 9. London, England: John Libbey Medical Publishing; 1989:445-452.
9.
Snow  BJPeppard  RFGuttman  M  et al Positron emission tomographic scanning demonstrates a presynaptic dopaminergic lesion in Lytico-Bodig: the amyotrophic lateral sclerosis–parkinsonism–dementia complex of Guam. Arch Neurol.1990;47:870-874.
PubMed
10.
Boccardi  MLaakso  MPBresciani  L  et al The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia. Neurobiol Aging.2003;24:95-103.
PubMed
11.
Lojkowska  WRyglewicz  DJedrzejczak  T  et al SPECT as a diagnostic test in the investigation of dementia. J Neurol Sci.2002;203-204:215-219.
PubMed
12.
van Swieten  JCStevens  MRosso  SM  et al Phenotypic variation in hereditary FTD with tau mutation. Ann Neurol.1999;46:617-626.
PubMed
13.
Jagust  WJEberling  JL MRI, CT, SPECT, PET: their use in diagnosing dementia. Geriatrics.1991;46:28-35.
PubMed
14.
Soliveri  PMonza  DParidi  DSP  et al Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy. Neurology.1999;53:502-507.
PubMed
15.
Testa  DSavoiardo  MFetoni  V  et al Multiple system atrophy: clinical and MR observations on 42 cases. Ital J Neurol Sci.1993;14:211-216.
PubMed
16.
Shiozawa  ZShindo  KOhta  EOhushi  KNagamatsu  MNagasaka  T A concise overview of recent breakthroughs in imaging of ALS. Amyotrophic Lateral Sclerosis Other Motor Neuron Disord.2000;1(suppl 2):S3-S6.
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