Shigeki Kuzuhara

An update of the endemic parkinsonism–dementia complex (PDC) frequently associated with amyotrophic lateral sclerosis (ALS) in the high prevalence ALS focus of the Kii peninsula of Japan is presented. The initial symptom was parkinsonian gait or hypobulia/amnesia, which was followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and finally by akinetic mutism. In several years, most of the patients developed ALS symptoms such as muscle atrophy, bulbar palsy, and upper motor neuron signs. Magnetic resonance imaging and computed tomography of the brain showed marked atrophy of the temporal and frontal lobes and the cerebral blood flow reduction on single-photon emission computed tomography. Marked loss of nerve cells associated with abundant neurofibrillar tangles (NFTs) in the entire central nervous system, most predominantly in the brainstem and temporal lobe was characteristic. Concomitant ALS pathology involving the upper and lower motor neurons was common, and senile plaques were absent in most cases. NFTs consisted of twisted tubules on electron microscopy. Western blot of tau protein showed three bands consisting of six tau isoforms, similar to those of Alzheimer's disease. A family history of ALS/PDC was recorded in more than 70% of patients, but no abnormal mutation or polymorphism was found in the genes of SOD1, tau, and apolipoprotein E. Familial nature and continuing morbidity of Kii ALS/PDC suggest that genetic factors may be more likely in its pathogenesis. © 2005 Movement Disorder Society

This review article deals with the cardinal features to differentiate various conditions which present with parkinsonism other than Parkinson's disease. Special attention is paid to the distinctive clinical features, laboratory data and neuroimaging findings of frequent diseases as well as important ones including multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body disease, drug-induced parkinsonism, vascular pseudo-parkinsonism, normal pressure hydrocephalus and manganese intoxication due to parenteral nutrition. MRI is useful to diagnose MSA, vascular pseudo-parkinsonism and manganese intoxication. Benzamide derivatives including sulpiride and metoclopramide are the main causes of drug-induced parkinsonism in recent years in Japan.

Research from JAMA Neurology — Neuroradiological Study of Patients With Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex on the Kii Peninsula of Japan

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula (Kii ALS/PDC) is a neurodegenerative disorder endemic to natives in the southern coast area of the Kii peninsula of Japan. The disorder closely resembles Guamanian ALS/PDC clinically and neuropathologically. The characteristic neuropathological finding is abundant neurofibrillary tangles (NFTs) without amyloid deposition. To elucidate the biochemical properties of hyperphosphorylated tau protein, the major component of the NFTs, we examined Kii ALS/PDC brains by immunoblotting and immunohistochemical analysis using well-characterized anti-tau antibodies specific to phosphorylation-dependent or -independent epitopes. Hyperphosphorylated tau in Kii ALS/PDC had phosphorylated epitopes common to tau of paired helical filaments (PHFs) in Alzheimer disease (AD); immunoblot showed triplet bands composed of 6 tau isoforms. Ultrastructurally, NFTs revealed a twisted filamentous shape similar to PHF of AD. The biochemical properties of its phosphorylated tau protein and the ultrastructural characteristics of the NFTs of Kii ALS/PDC are very similar, if not identical, to PHF tau in AD, although they are different taupopathies.

We report transient dementia in a 71-year-old woman, that was caused by hyperthyroidism of painless thyroiditis. Her friends, who found her very forgetful and performing abnormal behavior, brought her to our hospital. She looked alert and cooperative. There was neither goiter nor pain of the thyroid. Neurological examination revealed impairment of recent memory with a low score of memory test (MMSE: 20/30) indicating mild dementia. EEG showed slow alpha waves (8 Hz) with random theta and delta waves in the frontotemporal regions bilaterally. MRI showed mild diffuse atrophy of the brain, and SPECT revealed diffuse decrease in the cerebral blood flow most predominantly in the frontotemporal regions bilaterally. Abnormal findings included low levels of thyroid stimulating hormone (TSH), high levels of free triiodothyronine and free thyroxine. Antithyrogloblin antibody was positive and TSH receptor antibody was negative, while CRP was normal. Radioactive Tc uptake of the thyroid gland was low. A diagnosis of painless thyroiditis was made. Thyroid function turned to euthyroid state spontaneously in four weeks without antithyroid therapy, and subsequently memory disturbance and abnormal behavior disappeared. SPECT after clinical recovery showed improvement in the cerebral blood flow of the frontotemporal lobes. To our knowledge, dementia-like symptoms secondary to hyperthyroidism of painless thyroiditis have not been reported previously, and should be kept in mind as one of the causes of treatable dementia.

Psychotic symptoms develop in 20–30 % of patients with Parkinson's disease (PD) receiving chronic anti-PD medications, and visual hallucinations with or without delirium and paranoid delusions are the most frequent symptoms. Psychotic symptoms disturb ADL and QOL of PD patients and tax caregivers far more than the motor disabilities do, and good management of drug-induced psychotic symptoms is potentially important. Withdrawal of anti-PD drugs relieves the patients from psychotic side effects, but worsens the parkinsonian motor symptoms. The first step of treatment is to eliminate triggering factors other than anti-PD drugs, such as infections, metabolic disorders, subdural hematoma, and hallucinogenic drugs. The second step is to eliminate anti-PD drugs in the following order; first anticholinergics, amantadine and selegiline, second dopamine agonists, and finally levodopa/carbidopa. Anti-PD medications should be reduced to the point of improving psychotic side effects without drastically worsening parkinsonian motor symptoms. When the above adjustments fail to sufficiently alleviate psychotic side effects, the third step is consideration of antipsychotic drugs although they have potential capacity to antagonize dopamine D2 receptors and worsen parkinsonism. Atypical antipsychotics such as clozapine and olanzapine are recommended, though the former is not available in Japan.

We report the first case of neuropathologically verified parkinsonism-dementia complex of the Kii peninsula, together with the patient's brother, who had amyotrophic lateral sclerosis. The propositus woman developed parkinsonism and dementia at 63 years of age and died at 70 without displaying clinical features of amyotrophic lateral sclerosis. The brain exhibited marked atrophy of the frontal and temporal lobes. Microscopically, there were many neurofibrillary tangles in the central nervous system, most markedly in the mesial temporal lobe and deep nuclei, as well as changes of amyotrophic lateral sclerosis but no senile plaques or Lewy bodies. Neurofibrillary tangles exhibited twisted tubule structures on electon microscopic examination, and an analysis of insoluble tau protein extracted from the fresh brain revealed a 60-, 64-, 68-kD triplet. The tau gene exhibited no mutations. Her brother developed progressive bulbar palsy-type amyotrophic lateral sclerosis at 45 years of age and died at 49 without presenting with dementia or parkinsonism. Neuropathological examination revealed not only pathologic features of amyotrophic lateral sclerosis but also a moderate number of neurofibrillary tangles in the temporal cortex and deep nuclei. The siblings were neuropathologically similar despite their different clinical manifestations. These findings suggest that amyotrophic lateral sclerosis and parkinsonism-dementia complex of this family may be phenotypic variants of a tauopathy caused by genetic abnormalities.