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Recently Kosaka reviewed 16 cases of slowly progressive presenile cortical dementia thought to be a clinicopathological entity with pathological features characterised by circumscribed lobar atrophy, diffuse neurofibrillary tangles, and calcification of the Fahr type and named diffuse neurofibrillary tangles with calcification.1 However, the pathogenesis and biochemical findings of this new entity are not known in detail. Herein, we report on a patient with presenile dementia, intracranial calcification, and M-proteinaemia, which may play some part in the development of intracranial calcification with dementia.
A 66 year old man was admitted with dementia, which had been apparent since about 60 years of age. At the age of 62 he started to lose spontaneity and at the age of 66 gait disturbance occurred. In addition he showed slurred dysarthria, mild muscle rigidity, bilateral pyramidal signs, and mild truncal ataxia. Dementia slowly progressed and his dementia scales were as follows. Hasegawa’s dementia rating scale revised was 16/30 points, mini mental state examination was 20/30 points, the Japanese Wechsler adult intelligence scale revised showed verbal IQ 83, performance IQ 67, and total IQ 74. His routine laboratory investigations were normal. In particular, serum calcium and phosphorus were within the normal range. Twenty four hour urinary calcium and phosphorus were also within the normal range. Serum pyruvate, lactate, vitamins, including 1.25-(OH)2-vitamin D, and analysis of amino acids were within normal limits. Wasserman’s test, rheumatoid arthritis test, antinuclear antibodies, and DNA antibodies were all non-reactive. Endocrinological tests showed a slightly low concentration of parathyroid hormone (173 pg/ml; normal range 180–560 pg/ml), other tests, including the Ellsworth Howard test and thyroid function, gave normal results. Immunoelectrophoresis showed the presence of IgG λ M-protein in serum. Bence-Jones protein was not detected in urine. Routine CSF tests were normal for cell counts and protein concentrations. The concentrations of amyloid β (Aβ) 1–40 and Aβ1–42 in CSF measured by enzyme linked immunosorbent assay (ELISA)2 were 1659 fmol/ml and 179.1 fmol/ml respectively, which were within the normal ranges. The concentration of tau protein in CSF measured by a sandwich ELISA (Innogenetics, Belgium) was raised at 457 pg/ml. Bone marrow was normal. Chest radiography and CT showed calcification of the aorta, pleura, pericardium, and diaphragm. Brain CT and MRI (figure) disclosed calcification in the basal ganglia, the floor of the cortices, subcortical white matter, and cerebellum. Magnetic resonance angiography showed no evidence of arteriosclerosis. The cerebral blood flow measured by 123I-IMP SPECT showed hypoperfusion in the frontotemporal lobes (figure). Neurophysiological tests including auditory brainstem responses, sensory evoked potentials, and peripheral nerve conduction velocities were normal.
Diffuse neurofibrillary tangles with calcification is a presenile dementia as proposed by Kosaka1 and its clinical characteristics are (a) presenile onset, (b) slowly progressive cortical dementia, (c) more common temporofrontal focal signs rather than parietooccipital signs, (d) atrophy of the frontotemporal lobes on CT or MRI, (e) calcification of the bilateral globus pallidus and dentate nucleus, (f) hypoperfusion in the frontotemporal lobes on SPECT or PET, (g) normal serum calcium and phosphorus concentrations .
Our present case showed presenile slowly progressive cortical dementia and loss of spontaneity. Brain CT and MRI disclosed symmetric non-arteriosclerotic, intracranial severe calcification. Although parathyroid hormone was slightly low, other hormones measured and serum calcium and phosphorus were within normal limits, suggesting that intracranial calcification was idiopathic. The CSF study of Aβ and tau protein is considered a biological diagnostic marker for Alzheimer’s disease.3-5 Decreased Aβ1–42 and increased tau protein are specific for diagnosis of Alzheimer’s disease. The CSF concentration of Aβ1–42 was within the normal range and the CSF concentration of tau protein was high which may indicate the absence of deficits in Aβ metabolism but the presence of neurofibrillary tangles. Besides, our patient had IgG λ M-proteinaemia without Bence-Jones protein. The study of bone marrow indicated no malignancy. The gammopathy was considered to be monoclonal gammopathy with undetermined significance. Previously Nishiyamaet al 6 reported a 41 year old woman with idiopathic intracranial calcification associated with M-proteinaemia, followed by multiple myeloma. Her symptoms were dystonia, gait and speech disturbance, and dementia. This case suggested an association between M proteinaemia and dementia with intracranial calcification. Tentolouris et al 7 reported three cases of familial calcification of the aorta and calcific aortic valve disease associated with a monoclonal λ-chain gammopathy. They indicated that immunological abnormalities were associated with calcifications, but they did not assess the CNS.
Without the pathological evidence, clinically this case appeared to be consistent with the criteria for diffuse neurofibrillary tangles with calcification and CSF studies may indicated the presence of neurofibrillary tangles. At present, little is known about the biological and pathogenetic findings in diffuse neurofibrillary tangles with calcification. The present case suggests that M-proteinaemia may play a part in the development of dementia with intracranial calcification such as diffuse neurofibrillary tangles with calcification. Further biochemical studies are necessary in patients with dementia and intracranial calcifications.