Hirotaka Tanabe

Epidemiology and genetics of frontotemporal dementia/Pick's disease.

Epidemiology Frontotemporal dementia (FTD) is believed to be much less common than Alzheimer’s disease (AD), but data on prevalence and incidence of FTD are very sparse. The lack of data is in large part the result of the lack of methodology for diagnosing and enumerating cases of FTD. With an incidence rate of AD of approximately 1 case per 100 patients, or a prevalence of 6% or higher among individuals over age 70, traditional methods of case ascertainment yield stable and reliable estimates for AD. Because of challenges it presents in clinical diagnosis, incidence or prevalence of FTD could not be estimated by the traditional methods of case identification. What we currently know about the descriptive epidemiology of FTD comes largely from autopsy series. Because the neuropathological diagnosis of FTD was in flux until very recently, there has been a wide divergence of estimates of the incidence of FTD. One major reason for this variation derived from confusion over the relationships between Pick body–positive dementia (ie, “true” Pick’s disease to North American neuropathologists, or Pick’s type A), dementia with swollen chromatolytic neurons (Pick cell dementia, corticobasal degeneration, or Pick’s type B), and dementia lacking distinctive histology (nonspecific degeneration, or Pick’s type C). Pathologists sometimes included only one or two of these variants in their “Pick’s disease” category. In addition, clinical-pathological series could have selection biases that might exclude individuals with the FTD phenotype. Some series report very few FTD cases. Knopman and colleagues reviewed the experience of a brain bank in Minneapolis–St. Paul, Minnesota. Although FTD was infrequent overall (approximately 6%), it represented 17% of dementia patients who were under age 70 years at death. More recently, a neuropathological review of 382 cases from the State of Florida Brain Bank showed that FTD constituted 5% of the total but 8% of those cases under the age 70 years. Two groups have attempted to determine the clinical prevalence of FTD. These studies used novel methods for case identification. In the study from the United Kingdom, record review in the specialty clinics and hospitals in several communities in Cambridge was used to identify dementia cases. Seventeen FTD patients were detected. The mean age at onset was 52.8 ( 8.7) years. Men predominated (14:3). The prevalence of FTD was estimated at 15 cases per 100,000 persons in the 45to 64-year-old age range. The prevalence of AD was identical, so the proportion of FTD to AD was 1.6/1. The other study of FTD prevalence comes from The Netherlands. A total of 245 cases of FTD was reported, with emphasis on the prevalence in the province of Zuid-Holland, where the main study center was located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund–Manchester criteria, and the diagnosis was supported by neuroimaging and neuropsychology. Tau mutation analysis and apolipoprotein E (ApoE) genotyping was performed in a large subgroup of patients, and 40 of 98 patients who died during the follow-up came to autopsy during the course of the study. The prevalence of FTD in the province ZuidHolland was 3.6 cases per 100,000 persons at ages 50 to 59 years, 9.4 per 100,000 at ages 60 to 69, and 3.8 per 100,000 at ages 70 to 79. The average age at onset of the 245 patients (51% female) was 57.6 9.0 years. Dementia in one or more first-degree family members was found in 43% of patients, and mutation analysis of the tau gene showed mutations in 34 patients (19, P301L; 5, L315R; 4, G272V; 4, R406W; 1, K280; 1, S320F), all with a positive family history (14% of the total population, and 32% of patients with a positive family history). Neither the ApoE2 nor the ApoE4 allele was overrepresented compared with previously published results from a control group in The Netherlands. Pathological findings in the 40 autopsied patients consisted of dementia lacking distinc-

MRI-based quantitative assessment of the hippocampal region in very mild to moderate Alzheimer's disease

We investigated the hippocampal region in six patients diagnosed with possible Alzheimers disease (AD), eight patients with probable AD, and eight agematched controls, using a high-resolution magnetic resonance imaging technique. Coronal T1-weighted images were used for area measurements of the hippocampal formation (HF), parahippocampal gyrus (PHG), and temporal lobe (TL), normalised to cranial area. Both the normalised HF and PHG were significantly smaller in both AD groups than in the controls, but did not differ between patients with possible and probable AD. The normalised TL was significantly smaller in patients with probable AD than in those with possible AD and controls, but did not differ in patients with possible AD and controls. We conclude that hippocampal and parahippocampal atrophy occurs in early AD, and is more useful than neocortical atrophy for early detection of the disease. At a more advanced stage, the neocortical area is involved.

Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families

Presenilin-1 (PS-1) gene of three Japanese pedigrees with early-onset familial Alzheimers disease (FAD) disclosed two novel missense mutations resulting in Val96Phe and Ile213Thr, and one mutation resulting in His163Arg. The mean age at onset in a family with His163Arg mutation was similar to those reported in other families with His163Arg. Our results suggested the existence of a variety of PS-1 mutations, and that early-onset FAD with PS-1 mutations is highly penetrant and is only rarely subject to modulation by genetic or environmental modifying factors.

Conduction aphasia and arcuate fasciculus

Abstract Three patients are presented who developed conduction aphasia after a small infarction almost exclusively confined to the arcuate fasciculus. All of them were diagnosed as conduction aphasia within a week after the stroke and showed a rapid amelioration. On the basis of the 3 patients and conduction aphasics in the literature, the relation between conduction aphasia and the arcuate fasciculus is discussed.

Memory loss due to transient hypoperfusion in the medial temporal lobes including hippocampus.

ABSTRACT A typical case of transient global amnesia (TGA) was investigated with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) with 1.5‐tesler scans. During the amnesic eposide, a marked decrease of cerebral blood flow was observed in the areas confined to the territory of the bilateral posterior cerebral arteries including the hippocampus. After the episode, cerebral blood flow returned to normal and a circumscribed lesion was detected in the middle portion of CA 1 field of the left hippocampus. The SPECT findings prove direct evidence that the medial temporal structures are involved in the establishment of new memories, as well as in process of recalling only recently acquired memories, but not in retrieval of memories acquired long ago. The MRI findings indicate that a unilateral partial damage to CA 1 sector of the hippocampus does not develop a definite memory impairment and that high‐resolution MRI study on the hippocampus is necessary in TGA patients.

Retrograde temporal order amnesia resulting from damage to the fornix

Some amnesic patients show an impairment of temporal order memory that cannot be accounted for by content memory deficits. The performance of an amnesic patient on memory tasks assessing the patient’s content and temporal memories for remotely acquired material is described, after a lesion including the bilateral anterior fornix and adjacent anterior thalamus. The patient displayed a deficit in the temporal order tasks for remotely acquired information. Neither frontal cognitive deficits nor recognition deficits can account for this patient’s poor temporal memory. This retrograde temporal order memory impairment without content memory deficits were not seen in previously reported thalamic amnesic patients. Accordingly, the present patient’s poor retrograde temporal memory could hardly be explained by only a thalamic lesion. It is concluded that the patient’s impairment of temporal order memory for the retrograde material is probably due to the direct disconnection between the frontal lobe and the hippocampus by disruption of the fornix.

Lateralization phenomenon of complex auditory hallucinations

Abstract— A case is described of a patient who developed a transient verbal hallucination, lateralized to the right ear, and fluent aphasia after a hemorrhagic infarction in the left superior temporal gyrus. On the basis of this patient and the cases in the literature showing unilateral complex auditory hallucinations, the clinical significance of the lateralization phenomenon of complex auditory hallucinations was investigated. As a result, the lateralization phenomenon of complex auditory hallucinations could be considered a significant clinical sign indicating the existence of a lesion in the superior temporal gyrus opposite the hallucination side.

Completion phenomenon in transcortical sensory aphasia

We investigated completion phenomenon for proverbs in cases demonstrating transcortical sensory aphasia due to a variety of diseases. Lack of this completion was exclusively observed in patients with focal atrophy. These patients showed a selective and consistent impairment in word comprehension without phonemic cue effects in naming. The completion phenomenon was present in patients demonstrating transcortical sensory aphasia due to other cerebral diseases. In these patients, comprehension deficits were not selective for words, or words not comprehended were inconsistent and some phonemic cue effects were observed. In a previous study, we reported that completion phenomena for multiplication tables, serial numbers and names of days were frequently noted in patients with focal atrophy. Together with the present findings, these results suggest that lack of proverb completion may be attributed to a selective, systematic and complete loss of the meaning representations for language units such as words and proverbs. In addition, pathological processes of focal atrophy with temporal predominance might selectively affect the semantic memory for language as a unit.

A case of acquired conduction aphasia in a child

ABSTRACT— A 10‐year‐old right‐handed boy showed conduction aphasia with left‐ear verbal extinction (paradoxical ipsilateral ear extinction) after removal of a arteriovenous malformation in the left parietal lobe. Buccofacial and ideomotor apraxia were not observed. Recovery from aphasia was dramatic. Postoperative computed tomography (CT) and magnetic resonance imaging scans demonstrated damage confined to the left supramarginal gyrus invading the arcuate fasciculus. Together with recently reported cases of acquired fluent aphasia in children with CT‐verified left posterior lesions, this case seems to support the current view that both fluent and nonfluent aphasia that share many similarities with the symptoms and lesion localization associated with adult cases may exist in children.

APOE Genotype and Alzheimer´s Disease

Rubinsztein and Easton [1] have recently reported a meta-analysis of the variation in the apolipoprotein E (APOE) genotype with Alzheimer’s disease (AD). Unfortunately, in their study, they have misrepresented our data [2] in figures 1 and 3. In figure 1, the risk for those patients possessing an Â4 allele is shown for 27 separate studies of late-onset cases. In all but our study, the odds ratio exceeds a value of 1.0. In other words, there is an increased risk for AD in those with an Â4 allele. In reporting the data from our study, however, both the odds ratio and the confidence intervals have been recorded as being significantly below the value of 1.0. This infers that our study demonstrated a decreased risk for AD for patients possessing an Â4 allele. These values, and those for the Â2 allele in figure 3, are simply incorrect. Furthermore, the inclusion of such data would underestimate the risk for AD associated with the Â4 allele in the meta-analysis (table 3 and 4). The Â4 allele frequency for controls in our study was 0.147 as compared with 0.134 in other studies (n = 5,008), and the Â4 allele frequency in AD was 0.328 in our study and 0.38 (range 0.236–0.52) in the other studies (n = 2,896) [2]. Unfortunately, our data in the recent analysis [1] have been made conspicuous by the erroneous values shown in figures 1 and 3.