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Neuroradiologic and clinical abnormalities in dementia of diffuse neurofibrillary tangles with calcification (Kosaka–Shibayama disease)
Journal of the Neurological Sciences 209 (2003) 105 – 109 www.elsevier.com/locate/jns
Short communication
Neuroradiologic and clinical abnormalities in dementia of diffuse neurofibrillary tangles with calcification (Kosaka–Shibayama disease) Yasuhiro Ito a,b,*,1, Takashi Kato c, Tomomi Suzuki d, Yuki Yokokawa a, Ikuko Aiba a, Yutaka Arahata b, Eiichi Ito a, Kengo Ito c, Takeshi Yasuda a, Gen Sobue b a
Department of Neurology, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, Nagoya 465-8620, Aichi, Japan b Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan c Department of Biofunctional Research, National Institute for Longevity Science, Ohbu, Aichi, Japan d Department of Rehabilitation, Higashinagoya National Hospital, Nagoya, Aichi, Japan Received 21 October 2002; accepted 6 December 2002
Abstract We describe a characteristic dementia patient diagnosed as diffuse neurofibrillary tangles with calcification (DNTC). Neuropsychologically, dementia, including a decline in memory retention and intelligence, and anomic aphasia were recognized. Imaging revealed circumscribed temporal dominant atrophy and calcification of the basal ganglia and cerebellum. SPECT and FDG-PET revealed a remarkable reduction of blood flow and metabolism in the temporal lobes; however, there is no reduction in the basal ganglia and cerebellum, and FDOPA-PET also disclosed no abnormalities. This suggests that calcification and neuronal degeneration occur independently in DNTC. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Diffuse neurofibrillary tangles with calcification; Dementia; Circumscribed atrophy; Positron emission tomography; Neuropsychological evaluation; Kosaka – Shibayama disease
1. Introduction Senile dementia has, in recent times, been classified in greater detail. In addition to Alzheimer’s disease (AD), frontotemporal dementia including Pick’s disease (PiD) and Lewy body dementia are now recognized clinically and pathologically as discrete illness [1]. Actually, there are also other atypical dementias. One dementia, diffuse neurofibrillary tangles with calcification (DNTC), in particular has attracted recent attention in Japan [2– 7]. This disease is rare, but neuropathologically a discrete disease entity. The pathological observations include circumscribed atrophy centered in the temporal lobes and prominent calcification of the basal ganglia and cerebellum. Furthermore, it is
* Corresponding author. Department of Neurology, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, Nagoya 465-8620, Aichi, Japan. Tel.: +81-52-801-1151; fax: +81-52-801-1160. E-mail address: [email protected] (Y. Ito). 1 Present address: Institute fu¨r Klinische Neurobiologie, University of Wu¨rzburg, Josef-Schneider-Strasse 11, Wu¨rzburg 97080, Germany. Tel.: +49-931-201-49645; fax: +49-931-201-49788.
characterized microscopically by diffuse neurofibrillary tangles and the absence of senile plaques. Prior diagnosis of DNTC was mostly performed by autopsy and there are few clinical reports precisely evaluated neuroradiologically and neuropsychologically. Here we describe a patient diagnosed as DNTC.
2. Case report A 76-year-old woman with no remarkable past and family history was admitted to our facility with pneumonia. Mycobacterium tuberculosis was detected in the sputum, and administration of Isoniazid and Rifampicin was initiated. Shortly thereafter, abnormal behavior was observed, including eating of ointments, wandering, and stuffing of soiled diapers and snacks together in bags. The patient had graduated from a senior high school, was right-handed, and had participated actively in social activities, but 8 years previously, she had become shut in at home. Approximately 6 years previously, her house had become unkempt, and neighbors complained repeatedly about its unsanitary state. The patient also showed trash-hoarding behavior. Though a
0022-510X/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0022-510X(02)00468-9
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Table 1 Patient’s scores in neuropsychological tests Test
Scores
Mini-Mental State Test WAIS-R Verbal IQ Performance IQ Full IQ Raven Coloured Progressive Matrices Test Wechsler Memory Scale-Revised General memory Verbal memory Visual memory Attention/concentration Digit span (forwards/backwards) Ray Auditory Verbal Learning Test Recall trials 1 – 5 Recall of List B Recall of List A (after B) Recognition of List A Rey – Osterrieth Complex Figure Test Copy score Reproduction Word fluency (animals/vegetables/household) Letter fluency (Ah/Ka/Sa) Wisconsin Card Sorting Test Scroop Test Trail Making Test WAB Content Fluency Auditory comprehension Repetition Naming Reading Writing
17/30 64 71 64 24/36 < index 50 < 50 65 63 5/2 0–3–2–2–1 1 0 0 32/36 2/36 2/7/5 2/4/3 not achieveda not achieveda not achieveda AQ 75.7 5/10 9/10 8.6/10 8.4/10 6.9/10 5.2/10 5/10
a Our patient could not understood these tests and therefore could not be performed.
daughter made efforts to clean, the patient became angry and directed her to stop cleaning. Approximately 2 years previously, the patient no longer spoke the names of her grandchildren and would only address her daughter and son as ‘sister’ and ‘brother’. Neurologic examination showed generalized hyperreflexia but no focal signs. Neither parkinsonism nor cerebellar ataxia was recognized. Neuropsychologically, good deportment was maintained and cooperation was good, but there was strong disorientation and absolutely no awareness of illness. Speech was fluent and copious, but paraphemia, verbal paraphasia, circumlocution, and preservation were observed. Mild impairment of comprehension was recognized. The results of further neuropsychological tests are shown in Table 1. The aphasia index in the WAB aphasia test
was 75.7, classified as anomic aphasia. Preservation was often shown, however, frontal disturbance sign was, in general, mild. There was no impairment of construction, apraxia, or agnosia. The EEG was a 9– 10 Hz slow a basic rhythm with sporadic 7 – 8 Hz activity, nearly normal for this age group. Cranial CT revealed distinct, symmetrical calcification of the periventricular deep white matter, basal ganglia primarily in globus pallidus and putamen, pulvinar thalami, and the cerebellum (Fig. 1A). Cranial MRI indicated symmetrical atrophy of frontal and temporal lobes. Atrophy was particularly dominant at the temporal tip, and the atrophied area extended over the entire temporal lobe, including the superior, middle, and inferior temporal gyrus, the hippocampus, and the parahippocampal gyrus (Fig. 1B). SPECT showed a marked reduction in blood flow centered in the temporal lobes (Fig. 2A). Imaging by [18F]6-fluoro-deoxyglucose (FDG)-PET revealed a dramatic reduction in glucose metabolism in the temporal lobes, and a notable reduction in the frontal lobes as well (Fig. 2B). Blood flow and metabolism in the basal ganglia, parietal, occipital lobes, and cerebellum were normal. In [ 18F]6-fluoro- L-DOPA (FDOPA)-PET, uptake in the basal ganglia showed no abnormalities (Fig. 2C). Blood biochemistry observations were also free from abnormalities, including Ca and P values. Parathyroid hormone, calcitonin, cAMP, lactic acid, pyruvic acid, and blood lead values were also completely normal.
3. Discussion Diffuse neurofibrillary tangles with calcification (DNTC) is characterized in some pathologic findings [2– 6]. Circumscribed cerebral atrophy is one hallmark of this disease. Atrophy is most severe in the temporal lobes, followed by the frontal lobes as shown in this patient. Pick’s disease (PiD) is well known for its circumscribed atrophy of frontotemporal lobes. However, PiD differs from DNTC in that half of PiD patients show laterality, the superior temporal gyrus are well preserved, and hippocampus does not atrophy until the end of stage [3]. One other characteristic is bilaterally symmetrical calcinosis predominantly in the basal ganglia and cerebellum [2– 6]. Hypoparathyroidism, pseudoparathyroidism, mitochondria encephalopathy, and lead poisoning also present cerebral calcification closely resembling the distribution in calcinosis [8]. We could exclude these diseases by hormonal and blood examination. Fahr’s disease shows similar idiopathic cerebral calcification. However, it also presents no obvious circumscribed atrophy [4].
Fig. 2. (A) 123I-IMP SPECT reveals a distinct reduction in blood flow centered in the temporal lobes and a notable reduction in the frontal lobes. (B) [18F]6fluoro-deoxyglucose (FDG)-PET indicates a dramatic reduction in glucose metabolism in the anterioinferior portion of the temporal lobes, and a notable reduction in the frontal lobes as well. The blood flow and metabolism in the basal ganglia and cerebellum are normal. (C) [18F]6-fluoro-L-DOPA (FDOPA)-PET shows no abnormalities in basal ganglia.
Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109
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Fig. 1. (A) Cranial CT reveals symmetrical calcification of the cerebellum, basal ganglia, pulvinar thalami, and periventricular deep white matter. (B) Coronal T1-weighted MRI indicates symmetrical atrophy of the temporal and frontal lobes. Atrophy was particularly distinct at the temporal tip, and entire temporal lobe was involved.
Fig. 2.
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The calcinosis is characterized histologically by a primary component of calcium species binding Ca, Fe, and the like on an acidic mucopolysaccharide substrate, and presence in the neuropil and vascular walls of the white matter and cortex [5]. Of great interest is the pathological finding of mild degeneration and loss of neurons in the basal ganglia and cerebellum, despite distinct calcinosis in these areas [5,6]. Clinically, too, cerebellar ataxia and subcortical dementia symptoms were hardly observed. Our SPECT, FDG-, and FDOPA-PET studies revealed reduced blood flow and a dramatic reduction in glucose metabolism in atrophied portion; however, blood flow and metabolism in basal ganglia and cerebellum remained virtually normal. This finding shows that cellular function was maintained despite of severe calcification, strongly indicating that calcification and neuronal degeneration occur independently in DNTC. In histopathological observation, diffuse manifestation of neurofibrillary tangles (NFT) in many of the remaining neurons is characteristic [2– 6]. The strong correlation between region of prolific NFT and regions of intense neuronal loss and atrophy in DNTC suggests that NFTs are the primary component of the pathology. Clinical characteristics of this disease are not precisely clarified yet because there are few patients reported neuroradiologically and neuropsychologically [9,10]. This disease usually first manifests by reduced memory retention, and progresses to cortical dementia. There are no genetic factors. Therefore, patients with this disease are often misdiagnosed as suffering from Alzheimer’s disease [3 –5]. Shibayama et al. [4] pointed out that the early stages resemble Alzheimer’s disease (AD) in that the personality is maintained and accessibility is good, but the course entails an accrual of Pick’s disease (PiD)-like symptoms of frontotemporal dementia such as apathy, disinhibited behavior, and personal change, and the disease is characterized by a mixture of both sets of symptoms. Our patient resembled AD in a decline in memory retention and good deportment was maintained. At the same time, abnormal unhygienic behavior and aphasia resembled PiD. However, no apraxia and agnosia were recognized from the neuropsychological test, and these findings are compatible with other reports [4,5]. Our SPECT and FDG-PET studies also showed no abnormalities in parietal area. These results may be a great distinction between DNTC and AD. Names suggested for this illness include diffuse neurofibrillary tangles with calcification (DNTC) [3], Kosaka – Shibayama disease (KSD) [2], dementia with cerebral calcification and tangles (DCCT) [5], and non-Alzheimer, non-Pick dementia with Fahr’s syndrome (NANPDF) [4]. Prior diagnosis of DNTC was exclusively performed by autopsy; however, clinical symptoms and characteristic image-based observations suggest a potential for clinical diagnosis, as in the present and other cases [9,10]. Considering these circumstances, we find that the name diffuse neurofibrillary tangles with calcification (DNTC) is oriented toward only the pathological findings and impractical for
clinicians. We believe that next to Alzheimer’s disease and Pick’s disease, the name Kosaka –Shibayama disease (KSD) is more appropriate [2]. While only about 20 cases of DNTC have now been reported worldwide, all but two have been Japanese [5, 11,12]. Furthermore, its gender ratio is 1:4 in favor of woman. Racial, environmental, and hormonal factors are potentially related to the incidence and pathology of DNTC; however, it is wholly conceivable that cases may exist in other ethnic populations. We look forward to study in other geographic regions and also hope that the clinical, neuroradiological, and pathological diagnostic criteria for this disease are established. As a conclusion, DNTC is a discrete disease entity. It has also characteristic neuroradiological and clinical abnormalities. Prior diagnosis of DNTC was exclusively performed by autopsy, however, we think it is possible to perform clinical diagnosis by image-based observations and clinical symptoms. Our SPECT, FDG-, and FDOPA-PET studies showed a dramatic reduction in blood flow and glucose metabolism at atrophied portion, however, blood flow and metabolism remained normal in portions with severe calcification including basal ganglia and cerebellum. These findings show that cellular function was maintained despite of severe calcification, strongly indicating that calcification and neuronal degeneration occur independently in DNTC.
Acknowledgements This study was supported by the grants from the Ministry of Health, Sports and Welfare of Japan.
References [1] Terry RD, Katzman R, Bick KL, Sisodia SS, editors. Alzheimer disease. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999. [2] Yamada K, Takeda A. Atypical dementia: circumscribed brain atrophy with neurofibrillary tangles and calcification and absence of senile plaque. Igaku no ayumi 1991;158:851 [Japanese]. [3] Kosaka K. Diffuse neurofibrillary tangles with calcification: a new presenile dementia. J Neurol Neurosurg Psychiatry 1994;57:594 – 6. [4] Shibayama H, Kobayashi H, Nakagawa M, Yamada K, Iwata H, Iwai K, et al. Non-Alzheimer non-Pick dementia with Fahr’s syndrome. Clin Neuropathol 1992;11:237 – 50. [5] Ujihira N, Hashizume Y. Dementia with cerebral calcification and tangles. Neurol Med 1998;49:407 – 15 [Japanese]. [6] Tsuchiya K, Nakayama H, Iritani S, Arai T, Niizato K, Haga C, et al. Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases. Acta Neuropathol (Berlin) 2002;103:555 – 64. [7] Jellinger KA, Bancher C. Senile dementia with tangles (tangle dominant form of senile dementia). Brain Pathol 1998;8:367 – 76. [8] Grossman CB. Hydrocephalus and atrophic and degenerative disorders. In: Grossman CB, editor. Magnetic resonance imaging and computed tomography of the head and spine. 2nd ed. Baltimore: Williams & Wilkins; 1996. p. 417 – 58.
Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109 [9] Li F, Nishimura T, Iseki E, Kosaka K. A clinical case of diffuse neurofibrillary tangles with calcification. Seishinigaku 1996;38:91 – 3 [Japanese]. [10] Narita K, Murata T, Ito T, Murata I, Fukutani Y, Tsuji Y, et al. A case of diffuse neurofibrillary tangles with calcification. Psychiatry Clin Neurosci 2002;56:117 – 20.
109
[11] Tariska I. Circumscribed cerebral atrophy in Alzheimer’s disease. A pathological study. In: Wolstenholme GEW, O’Connor M, editors. Alzheimer’s disease. London: Churchill; 1970. p. 51 – 73. [12] Langlois NE, Grieve JH, Best PV. Changes of diffuse neurofibrillary tangles with calcification (DNTC) in a woman without evidence of dementia. J Neurol Neurosurg Psychiatry 1995;59:103.
Short communication
Neuroradiologic and clinical abnormalities in dementia of diffuse neurofibrillary tangles with calcification (Kosaka–Shibayama disease) Yasuhiro Ito a,b,*,1, Takashi Kato c, Tomomi Suzuki d, Yuki Yokokawa a, Ikuko Aiba a, Yutaka Arahata b, Eiichi Ito a, Kengo Ito c, Takeshi Yasuda a, Gen Sobue b a
Department of Neurology, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, Nagoya 465-8620, Aichi, Japan b Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan c Department of Biofunctional Research, National Institute for Longevity Science, Ohbu, Aichi, Japan d Department of Rehabilitation, Higashinagoya National Hospital, Nagoya, Aichi, Japan Received 21 October 2002; accepted 6 December 2002
Abstract We describe a characteristic dementia patient diagnosed as diffuse neurofibrillary tangles with calcification (DNTC). Neuropsychologically, dementia, including a decline in memory retention and intelligence, and anomic aphasia were recognized. Imaging revealed circumscribed temporal dominant atrophy and calcification of the basal ganglia and cerebellum. SPECT and FDG-PET revealed a remarkable reduction of blood flow and metabolism in the temporal lobes; however, there is no reduction in the basal ganglia and cerebellum, and FDOPA-PET also disclosed no abnormalities. This suggests that calcification and neuronal degeneration occur independently in DNTC. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Diffuse neurofibrillary tangles with calcification; Dementia; Circumscribed atrophy; Positron emission tomography; Neuropsychological evaluation; Kosaka – Shibayama disease
1. Introduction Senile dementia has, in recent times, been classified in greater detail. In addition to Alzheimer’s disease (AD), frontotemporal dementia including Pick’s disease (PiD) and Lewy body dementia are now recognized clinically and pathologically as discrete illness [1]. Actually, there are also other atypical dementias. One dementia, diffuse neurofibrillary tangles with calcification (DNTC), in particular has attracted recent attention in Japan [2– 7]. This disease is rare, but neuropathologically a discrete disease entity. The pathological observations include circumscribed atrophy centered in the temporal lobes and prominent calcification of the basal ganglia and cerebellum. Furthermore, it is
* Corresponding author. Department of Neurology, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, Nagoya 465-8620, Aichi, Japan. Tel.: +81-52-801-1151; fax: +81-52-801-1160. E-mail address: [email protected] (Y. Ito). 1 Present address: Institute fu¨r Klinische Neurobiologie, University of Wu¨rzburg, Josef-Schneider-Strasse 11, Wu¨rzburg 97080, Germany. Tel.: +49-931-201-49645; fax: +49-931-201-49788.
characterized microscopically by diffuse neurofibrillary tangles and the absence of senile plaques. Prior diagnosis of DNTC was mostly performed by autopsy and there are few clinical reports precisely evaluated neuroradiologically and neuropsychologically. Here we describe a patient diagnosed as DNTC.
2. Case report A 76-year-old woman with no remarkable past and family history was admitted to our facility with pneumonia. Mycobacterium tuberculosis was detected in the sputum, and administration of Isoniazid and Rifampicin was initiated. Shortly thereafter, abnormal behavior was observed, including eating of ointments, wandering, and stuffing of soiled diapers and snacks together in bags. The patient had graduated from a senior high school, was right-handed, and had participated actively in social activities, but 8 years previously, she had become shut in at home. Approximately 6 years previously, her house had become unkempt, and neighbors complained repeatedly about its unsanitary state. The patient also showed trash-hoarding behavior. Though a
0022-510X/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0022-510X(02)00468-9
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Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109
Table 1 Patient’s scores in neuropsychological tests Test
Scores
Mini-Mental State Test WAIS-R Verbal IQ Performance IQ Full IQ Raven Coloured Progressive Matrices Test Wechsler Memory Scale-Revised General memory Verbal memory Visual memory Attention/concentration Digit span (forwards/backwards) Ray Auditory Verbal Learning Test Recall trials 1 – 5 Recall of List B Recall of List A (after B) Recognition of List A Rey – Osterrieth Complex Figure Test Copy score Reproduction Word fluency (animals/vegetables/household) Letter fluency (Ah/Ka/Sa) Wisconsin Card Sorting Test Scroop Test Trail Making Test WAB Content Fluency Auditory comprehension Repetition Naming Reading Writing
17/30 64 71 64 24/36 < index 50 < 50 65 63 5/2 0–3–2–2–1 1 0 0 32/36 2/36 2/7/5 2/4/3 not achieveda not achieveda not achieveda AQ 75.7 5/10 9/10 8.6/10 8.4/10 6.9/10 5.2/10 5/10
a Our patient could not understood these tests and therefore could not be performed.
daughter made efforts to clean, the patient became angry and directed her to stop cleaning. Approximately 2 years previously, the patient no longer spoke the names of her grandchildren and would only address her daughter and son as ‘sister’ and ‘brother’. Neurologic examination showed generalized hyperreflexia but no focal signs. Neither parkinsonism nor cerebellar ataxia was recognized. Neuropsychologically, good deportment was maintained and cooperation was good, but there was strong disorientation and absolutely no awareness of illness. Speech was fluent and copious, but paraphemia, verbal paraphasia, circumlocution, and preservation were observed. Mild impairment of comprehension was recognized. The results of further neuropsychological tests are shown in Table 1. The aphasia index in the WAB aphasia test
was 75.7, classified as anomic aphasia. Preservation was often shown, however, frontal disturbance sign was, in general, mild. There was no impairment of construction, apraxia, or agnosia. The EEG was a 9– 10 Hz slow a basic rhythm with sporadic 7 – 8 Hz activity, nearly normal for this age group. Cranial CT revealed distinct, symmetrical calcification of the periventricular deep white matter, basal ganglia primarily in globus pallidus and putamen, pulvinar thalami, and the cerebellum (Fig. 1A). Cranial MRI indicated symmetrical atrophy of frontal and temporal lobes. Atrophy was particularly dominant at the temporal tip, and the atrophied area extended over the entire temporal lobe, including the superior, middle, and inferior temporal gyrus, the hippocampus, and the parahippocampal gyrus (Fig. 1B). SPECT showed a marked reduction in blood flow centered in the temporal lobes (Fig. 2A). Imaging by [18F]6-fluoro-deoxyglucose (FDG)-PET revealed a dramatic reduction in glucose metabolism in the temporal lobes, and a notable reduction in the frontal lobes as well (Fig. 2B). Blood flow and metabolism in the basal ganglia, parietal, occipital lobes, and cerebellum were normal. In [ 18F]6-fluoro- L-DOPA (FDOPA)-PET, uptake in the basal ganglia showed no abnormalities (Fig. 2C). Blood biochemistry observations were also free from abnormalities, including Ca and P values. Parathyroid hormone, calcitonin, cAMP, lactic acid, pyruvic acid, and blood lead values were also completely normal.
3. Discussion Diffuse neurofibrillary tangles with calcification (DNTC) is characterized in some pathologic findings [2– 6]. Circumscribed cerebral atrophy is one hallmark of this disease. Atrophy is most severe in the temporal lobes, followed by the frontal lobes as shown in this patient. Pick’s disease (PiD) is well known for its circumscribed atrophy of frontotemporal lobes. However, PiD differs from DNTC in that half of PiD patients show laterality, the superior temporal gyrus are well preserved, and hippocampus does not atrophy until the end of stage [3]. One other characteristic is bilaterally symmetrical calcinosis predominantly in the basal ganglia and cerebellum [2– 6]. Hypoparathyroidism, pseudoparathyroidism, mitochondria encephalopathy, and lead poisoning also present cerebral calcification closely resembling the distribution in calcinosis [8]. We could exclude these diseases by hormonal and blood examination. Fahr’s disease shows similar idiopathic cerebral calcification. However, it also presents no obvious circumscribed atrophy [4].
Fig. 2. (A) 123I-IMP SPECT reveals a distinct reduction in blood flow centered in the temporal lobes and a notable reduction in the frontal lobes. (B) [18F]6fluoro-deoxyglucose (FDG)-PET indicates a dramatic reduction in glucose metabolism in the anterioinferior portion of the temporal lobes, and a notable reduction in the frontal lobes as well. The blood flow and metabolism in the basal ganglia and cerebellum are normal. (C) [18F]6-fluoro-L-DOPA (FDOPA)-PET shows no abnormalities in basal ganglia.
Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109
107
Fig. 1. (A) Cranial CT reveals symmetrical calcification of the cerebellum, basal ganglia, pulvinar thalami, and periventricular deep white matter. (B) Coronal T1-weighted MRI indicates symmetrical atrophy of the temporal and frontal lobes. Atrophy was particularly distinct at the temporal tip, and entire temporal lobe was involved.
Fig. 2.
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Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109
The calcinosis is characterized histologically by a primary component of calcium species binding Ca, Fe, and the like on an acidic mucopolysaccharide substrate, and presence in the neuropil and vascular walls of the white matter and cortex [5]. Of great interest is the pathological finding of mild degeneration and loss of neurons in the basal ganglia and cerebellum, despite distinct calcinosis in these areas [5,6]. Clinically, too, cerebellar ataxia and subcortical dementia symptoms were hardly observed. Our SPECT, FDG-, and FDOPA-PET studies revealed reduced blood flow and a dramatic reduction in glucose metabolism in atrophied portion; however, blood flow and metabolism in basal ganglia and cerebellum remained virtually normal. This finding shows that cellular function was maintained despite of severe calcification, strongly indicating that calcification and neuronal degeneration occur independently in DNTC. In histopathological observation, diffuse manifestation of neurofibrillary tangles (NFT) in many of the remaining neurons is characteristic [2– 6]. The strong correlation between region of prolific NFT and regions of intense neuronal loss and atrophy in DNTC suggests that NFTs are the primary component of the pathology. Clinical characteristics of this disease are not precisely clarified yet because there are few patients reported neuroradiologically and neuropsychologically [9,10]. This disease usually first manifests by reduced memory retention, and progresses to cortical dementia. There are no genetic factors. Therefore, patients with this disease are often misdiagnosed as suffering from Alzheimer’s disease [3 –5]. Shibayama et al. [4] pointed out that the early stages resemble Alzheimer’s disease (AD) in that the personality is maintained and accessibility is good, but the course entails an accrual of Pick’s disease (PiD)-like symptoms of frontotemporal dementia such as apathy, disinhibited behavior, and personal change, and the disease is characterized by a mixture of both sets of symptoms. Our patient resembled AD in a decline in memory retention and good deportment was maintained. At the same time, abnormal unhygienic behavior and aphasia resembled PiD. However, no apraxia and agnosia were recognized from the neuropsychological test, and these findings are compatible with other reports [4,5]. Our SPECT and FDG-PET studies also showed no abnormalities in parietal area. These results may be a great distinction between DNTC and AD. Names suggested for this illness include diffuse neurofibrillary tangles with calcification (DNTC) [3], Kosaka – Shibayama disease (KSD) [2], dementia with cerebral calcification and tangles (DCCT) [5], and non-Alzheimer, non-Pick dementia with Fahr’s syndrome (NANPDF) [4]. Prior diagnosis of DNTC was exclusively performed by autopsy; however, clinical symptoms and characteristic image-based observations suggest a potential for clinical diagnosis, as in the present and other cases [9,10]. Considering these circumstances, we find that the name diffuse neurofibrillary tangles with calcification (DNTC) is oriented toward only the pathological findings and impractical for
clinicians. We believe that next to Alzheimer’s disease and Pick’s disease, the name Kosaka –Shibayama disease (KSD) is more appropriate [2]. While only about 20 cases of DNTC have now been reported worldwide, all but two have been Japanese [5, 11,12]. Furthermore, its gender ratio is 1:4 in favor of woman. Racial, environmental, and hormonal factors are potentially related to the incidence and pathology of DNTC; however, it is wholly conceivable that cases may exist in other ethnic populations. We look forward to study in other geographic regions and also hope that the clinical, neuroradiological, and pathological diagnostic criteria for this disease are established. As a conclusion, DNTC is a discrete disease entity. It has also characteristic neuroradiological and clinical abnormalities. Prior diagnosis of DNTC was exclusively performed by autopsy, however, we think it is possible to perform clinical diagnosis by image-based observations and clinical symptoms. Our SPECT, FDG-, and FDOPA-PET studies showed a dramatic reduction in blood flow and glucose metabolism at atrophied portion, however, blood flow and metabolism remained normal in portions with severe calcification including basal ganglia and cerebellum. These findings show that cellular function was maintained despite of severe calcification, strongly indicating that calcification and neuronal degeneration occur independently in DNTC.
Acknowledgements This study was supported by the grants from the Ministry of Health, Sports and Welfare of Japan.
References [1] Terry RD, Katzman R, Bick KL, Sisodia SS, editors. Alzheimer disease. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999. [2] Yamada K, Takeda A. Atypical dementia: circumscribed brain atrophy with neurofibrillary tangles and calcification and absence of senile plaque. Igaku no ayumi 1991;158:851 [Japanese]. [3] Kosaka K. Diffuse neurofibrillary tangles with calcification: a new presenile dementia. J Neurol Neurosurg Psychiatry 1994;57:594 – 6. [4] Shibayama H, Kobayashi H, Nakagawa M, Yamada K, Iwata H, Iwai K, et al. Non-Alzheimer non-Pick dementia with Fahr’s syndrome. Clin Neuropathol 1992;11:237 – 50. [5] Ujihira N, Hashizume Y. Dementia with cerebral calcification and tangles. Neurol Med 1998;49:407 – 15 [Japanese]. [6] Tsuchiya K, Nakayama H, Iritani S, Arai T, Niizato K, Haga C, et al. Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases. Acta Neuropathol (Berlin) 2002;103:555 – 64. [7] Jellinger KA, Bancher C. Senile dementia with tangles (tangle dominant form of senile dementia). Brain Pathol 1998;8:367 – 76. [8] Grossman CB. Hydrocephalus and atrophic and degenerative disorders. In: Grossman CB, editor. Magnetic resonance imaging and computed tomography of the head and spine. 2nd ed. Baltimore: Williams & Wilkins; 1996. p. 417 – 58.
Y. Ito et al. / Journal of the Neurological Sciences 209 (2003) 105–109 [9] Li F, Nishimura T, Iseki E, Kosaka K. A clinical case of diffuse neurofibrillary tangles with calcification. Seishinigaku 1996;38:91 – 3 [Japanese]. [10] Narita K, Murata T, Ito T, Murata I, Fukutani Y, Tsuji Y, et al. A case of diffuse neurofibrillary tangles with calcification. Psychiatry Clin Neurosci 2002;56:117 – 20.
109
[11] Tariska I. Circumscribed cerebral atrophy in Alzheimer’s disease. A pathological study. In: Wolstenholme GEW, O’Connor M, editors. Alzheimer’s disease. London: Churchill; 1970. p. 51 – 73. [12] Langlois NE, Grieve JH, Best PV. Changes of diffuse neurofibrillary tangles with calcification (DNTC) in a woman without evidence of dementia. J Neurol Neurosurg Psychiatry 1995;59:103.