Premorbid brain size as a determinant of reserve capacity against intellectual decline in Alzheimer's disease.

OBJECTIVE: Both the magnitude of brain atrophy and premorbid brain size determine the volume of the brain affected by Alzheimer's disease. To examine the possibility that premorbid brain volume is a determinant of cognitive reserve in patients with Alzheimer's disease, the relation between diffuse brain atrophy and cognitive decline and the impact of premorbid brain size on cognitive decline were studied in patients with Alzheimer's disease. METHOD: By measuring whole brain volume and intracranial volume in 60 patients with probable Alzheimer's disease, mild to moderate in severity, with the use of high-resolution magnetic resonance imaging and image processing, the authors studied the impact of premorbid brain volume and magnitude of diffuse brain atrophy on cognitive functions. On the basis of the normative brain-calvarium relationship derived from data an 28 healthy adults and the total intracranial volume measure of each patient, the magnitude of brain atrophy and premorbid brain volume were estimated. RESULTS: After control for the effects of age, sex, and education as confounding factors, it was found that the Alzheimer's disease patients' intelligence was correlated both positively with premorbid brain volume and negatively with magnitude of brain atrophy, while impairments in language and memory were correlated with magnitude of brain atrophy but not with premorbid brain volume. CONCLUSIONS: These findings partially support the hypothesis that premorbid brain volume is a determinant of reserves against intellectual decline in Alzheimer's disease.

A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2.

OBJECTIVE: To disclose a novel mutation of the presenilin 1 (PS1) gene responsible for early-onset Alzheimer disease and to clarify genotype-phenotype correlation that should help to establish the function of this protein. BACKGROUND: The PS1 and presenilin 2 (PS2) genes carry missense mutations in families with Alzheimer disease. The PS1 and PS2 proteins have similar structures, and all presently known mutations are in nucleotides coding for amino acids that are conserved between the 2 presenilins. METHODS: Sequence and restriction fragment length polymorphism analyses of PS1 gene of DNA from a pedigree with early-onset Alzheimer disease. RESULTS: Sequence analysis disclosed a novel PS1 mutation in a pedigree of Japanese origin with early-onset Alzheimer disease. This mutation, which is predicted to cause a missense substitution of lysine for glutamic acid, occurred at codon 123 of PS1 that was not a conserved residue in PS2. The 2 patients of this pedigree shared an early clinical phenotype consisting of later-onset, progressive aphasia, but preserved visuospatial ability, which was indistinguishable from those of other PS1-associated Alzheimer disease cases. CONCLUSION: These results demonstrate that a missense mutation in a region not conserved between PS1 and PS2 can cause Alzheimer disease.

Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS.

We report a 36-year-old man with MELAS in whom a 5-month course of high-dose oral idebenone, a derivative of coenzyme Q10, increased markedly cerebral metabolic ratio of oxygen and oxygen extraction fraction without increased cerebral blood flow with PET. The results indicate that idebenone improves mitochondrial oxidative metabolism in the brain and suggest a therapeutic potential of idebenone for MELAS.

Frontal lobe hypometabolism and depression in Alzheimer's disease.

Depression is common in Alzheimer's disease (AD). Clinicoanatomic studies in focal brain injuries and functional imaging studies both in primary depression and in depression secondary to neurologic diseases have demonstrated involvement of the frontal lobe. Frontal involvement has not been established in the depression of AD. We studied the correlation between focal brain metabolic abnormalities and depression in AD. In 53 patients with probable AD of minimal to moderate disability, we assessed the severity of depression using the Neuropsychiatric Inventory and correlated the depression score with regional cerebral glucose metabolism determined by 18F-fluorodeoxyglucose and PET. Depression was present in 19 patients (36%). The depression score correlated significantly with normalized glucose metabolic rates in the bilateral superior frontal and left anterior cingulate cortices. These results indicated an association between depression and decreased activity in the frontal lobe in AD and support frontal involvement, especially in the left side, in depression, irrespective of disease etiology.

Age at onset and language disturbances in Alzheimer's disease.

This study examined the effect of age at symptom onset of Alzheimer's disease (AD) on the pattern of language disturbance. We assessed 150 consecutive patients with a clinical diagnosis of mild-to-moderate AD using the Western Aphasia Battery and a 100-item picture-naming test. A multivariate linear regression analysis examined the effect of age at onset after controlling for gender, education, severity of dementia and duration of the disease. Patients with early onset performed significantly worse than did patients with late onset on the word comprehension and sequential commands subtests. On the other hand, late-onset patients performed more poorly than early-onset patients on the picture-naming test in a subgroup with mild language deficits. However, the trend disappeared in other subgroups with more degraded language function. We consider that the concomitant effects of normal aging worsened the picture-naming deficits in the late-onset patients, and the rapid decline of naming ability in the early-onset patients masked the aging effect with the progression of language deficits. The deterioration of word comprehension and the rapid decline of naming ability are the characteristics of early-onset patients. The different patterns of language deficits between early- and late-onset patients may correspond to the genetic heterogeneity of AD.

Different neural substrates for Kanji and Kana writing: a PET study.

To investigate the neural substrate underlying the mechanisms of Kanji and Kana writing, we conducted a PET activation study during mental writing task in eight right-handed normal Japanese subjects. During scans subjects were required to mentally write a Kanji or three Kana letters with their right hand, for each stimulant word presented auditorily. The direct comparisons between Kanji writing and Kana writing revealed that the left posterior inferior temporal gyrus was activated in Kanji writing while the left angular gyrus was activated in Kana writing. In addition, more extensive areas were activated in Kanji writing compared with Kana writing. These results suggest that different respective neural substrates are involved in Kanji and Kana writing respectively.

Theta rhythm increases in left superior temporal cortex during auditory hallucinations in schizophrenia: a case report.

Auditory hallucinations (AH), the perception of sounds and voices in the absence of external stimuli, remain a serious problem for a large subgroup of patients with schizophrenia. Functional imaging of brain activity associated with AH is difficult, since the target event is involuntary and its timing cannot be predicted. Prior efforts to image the patterns of cortical activity during AH have yielded conflicting results. In this study, MEG was used to directly image the brain electrophysiological events associated with AH in schizophrenia. We observed an increase in theta rhythm, as sporadic bursts, in the left superior temporal area during the AH states, whereas there was steady theta band activity in the resting state. The present finding suggests strong association of the left superior temporal cortex with the experience of AH in this patient. This is consistent with the hypothesis that AH arises from areas of auditory cortex subserving receptive language processing.

Somatosensory evoked potentials to median nerve stimulation after partial section of the corpus callosum.

Cortical somatosensory evoked potentials (SEPs) to electrical stimulation of the median nerve were studied in four patients with intractable epilepsy who had undergone callosotomy and in a patient with infarction in the corpus callosum in order to determine whether the corpus callosum was involved in the generation of ipsilateral frontal components. Both pre- and postoperative SEPs were recorded in three of four epileptic patients. There were no significant differences in the latencies and amplitudes of the bilateral frontal components (P20, N26) between pre- and postoperative recordings. Furthermore, irrespective of the extent of the section or lesion in the corpus callosum, the nature of the impairment and the existence of the disconnection syndrome, the SEP findings showed no significant differences compared with those of normal subjects. It thus appears unlikely that the ipsilateral SEP responses are transmitted from the contralateral hemisphere through at least the anterior portion of the corpus callosum.

A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy.

A number of missense mutations associated with early-onset familial Alzheimer's disease have been reported in the presenilin-1 gene. The mutations were demonstrated to cluster in specific regions of the the protein. We report here a novel missense mutation at the C-terminus of the third transmembrane domain in the presenilin-1 protein in a family of Japanese origin with early-onset Alzheimer's disease. This mutation is located at a site that is different from the sites at which mutations are known to cluster. Although the clinical phenotype is similar to those of pedigrees associated with other presenilin-1 mutations, postmortem examination of this pedigree revealed heavy amyloid deposits in the walls of small meningeal arteries as well as around small vessels within the brain parenchyma. These results indicate that a mutation at the C-terminus of the third transmembrane domain in the presenilin-1, which is a novel site for mutations, may play a key role in Alzheimer's pathogenesis.

Alteration of white matter MR signal intensity in frontotemporal dementia.

PURPOSE: To determine the diagnostic potential of MR imaging to show white matter involvement in frontotemporal dementia. METHODS: We evaluated MR signal intensity in cerebral white matter by visually inspecting and by quantitatively measuring signal intensity on MR images in 22 patients with frontotemporal dementia. The findings were compared with those in 22 age- and sex-matched patients who had had Alzheimer disease for the same length of time and with 16 age- and sex-matched healthy control subjects. RESULTS: Patients with frontotemporal dementia had a significant increase in white matter signal intensity in the frontal and/or temporal lobes on T2- and proton density-weighted images. Visual inspection of regular proton density-weighted images and measurements made on the T2- and proton density-weighted images were sensitive to changes in white matter signal. CONCLUSION: Increased MR signal intensity in the frontotemporal white matter on T2- and proton density-weighted MR images is a useful diagnostic sign of frontotemporal dementia and distinguishes this condition from Alzheimer disease.

The neural basis of perceptual and conceptual word priming--a PET study.

Positron emission tomography scans were obtained in 13 normal subjects during perceptual and conceptual word priming tasks with the aim to investigate the neural system specific to the two priming conditions. In the prescan phase, subjects were primed perceptually or conceptually with two separate procedures, while in the scan phase, they performed the same stem completion task. Therefore we could compare the results of the two priming tasks in a direct manner. A fixation control task and a baseline task (completion of stems that did not correspond to previously seen words) were also given. A specific blood flow decrease was found in the left inferior temporal cortex in the perceptual word priming condition and in the left superior temporal / inferior parietal cortex in the conceptual word priming condition. Each blood flow change may reflect transient changes in the cortical areas subserving the processing of the perceptual and conceptual components of word priming.

Functional anatomical study of psychogenic amnesia.

Psychogenic amnesia is characterized by an inability to recall information already stored in the patient's memory. It is usually related to a stressful or traumatic event that cannot be explained by manifest brain damage. To examine the underlying functional disturbance of brain areas in this condition, we performed a positron emission tomography (PET) activation study on a psychogenic amnesic patient and on 12 normal control subjects. A task requiring explicit retrograde memory of faces was compared with a control task. To assess functional modifications associated with the processes of recovery, a second PET study was performed on the patient 12 months after onset. During the task, activation of the right anterior medial temporal region including the amygdala was increased in the psychogenic amnesic patient. Activation of the bilateral hippocampal regions increased only in the control subjects. During recovery, the right anterior medial temporal region became less active while the right hippocampal region became more active. Activation levels also differed in the anterior cingulate cortex, prefrontal cortex and some other cortical regions between control subjects and the patient. These findings suggest that the changes in these limbic and limbic-cortical functions are related to symptoms of the psychogenic amnesia.

Perception and conception: separate memory systems in the medial temporal lobe.

The purpose of the present study was to investigate, by using positron emission tomography, whether the functionally different types of information are subserved by different memory systems in human medial temporal lobe structures. Before explicit retrieval tests during scans, subjects studied words in perceptually and conceptually processed manners separately. It was found that different parts of the medial temporal lobe structures were involved in each of the different conditions. These results indicated that perceptually and conceptually processed types of information were subserved by at least two partially segregated memory systems in human medial temporal lobe structures.

The clinical utility of visual evaluation of scintigraphic perfusion patterns for Alzheimer's disease using I-123 IMP SPECT.

The authors examined the role of SPECT perfusion pattern in the diagnosis of Alzheimer's disease (AD) using I-123 IMP. They studied 93 patients who had memory and cognitive disorders, including 42 patients with a diagnosis of probable AD, classifying SPECT images into determined perfusion patterns. The probability of AD was 54% with bilateral temporal and/or parietal defects, 69% with bilateral temporoparietal defects with additional defects, 17% with no defects, and 11% with frontal defects only. The sensitivity of bilateral temporoparietal perfusion defects for AD was 95.2%, whereas the specificity was 56.9%. In the absence of bilateral temporal and/or parietal defects on visual evaluation of SPECT, the diagnosis of AD was unlikely, although it is not pathognomonic for AD, because this sign would be seen in various neuropsychiatric diseases causing memory and cognitive impairments. Visual evaluation of SPECT is of value in the diagnosis of AD among patients with dementia.

Partial callosotomy for Lennox-Gastaut syndrome--first cases in Japan.

Corpus callosotomy is a well established procedure for the treatment of intractable epilepsy. However, this is the first clinical report of surgical division of the corpus callosum in Japan. Four patients with refractory seizures suffering from Lennox-Gastaut syndrome underwent anterior partial corpus callosotomy. Their seizures consisted of absences, tonic, atonic, tonic-clonic attacks and were characterized by frequent falls. Electroencephalograms showed paroxysms of bilateral synchrony of slow spike and wave complexes. Postoperative follow-up during 12-27 months showed that partial callosotomy reduced the frequency and severity of seizures in all the patients, although they still require antiepileptic medication. This procedure was effective even in patients with mixed cerebral dominance and also in a patient with low intelligence quotient. Postoperatively, disconnection syndrome developed in three patients, which was transient in one and lasting in two.

[A case of pure agraphia with a deficit of drawing].

We examined a drawing ability in a case with pure agraphia. The patient, having lesions in the left middle frontal gyrus and inferior parietal lobule, could not write in both dictation and spontaneous writing tasks, with the ability to copy letters being well spared. Correspondingly, he showed a deficit of spontaneous drawing, with the ability to copy complex figures being well spared. These findings suggest that he could have an impairment of retrieving visual image, not restricted to letter image. Although some previous cases with pure agraphia were attributed to an impairment of retrieving visual letter image, drawing ability which seemed to be related to retrieving visual image had not been investigated. In the present case, disability of both writing and drawing could be attributed to a common mechanism, that was an impairment of retrieving visual image. In addition, the patient did not show a significant difference between the performance on Kana writing and on Kanji writing. But it has been said that an impairment of retrieving visual letter image could be related to a deficit of Kanji writing more than of Kana writing. Then, it could be assumed that the mechanism of Kana writing involved not only the pathway depending on graphical motor pattern but one depending on visual image.

[Two cases of primary progressive non-fluent aphasia].

Two patients were described with a five to seven-year history of primary progressive non-fluent aphasia. One patient developed atypical trascortical motor aphasia with marked anarthria, which has led to mutism. Magnetic resonance (MR) imaging showed lobar atrophy of the frontal lobe accentuated in the bilateral superior frontal gyri, the left middle frontal gyrus, the left anterior cingulate gyrus and the left operculum with some extension into the left temporal lobe. Single photon emission computed tomography (SPECT) scans demonstrated a decrease of regional cerebral blood flow (rCBF) in the atrophic site. The patient was clinically and neuroradiologically diagnosed as having Pick's disease. Another patient presented with atypical Broca's aphasia, which has worsened with slowly progressive right hemiparesis. Mitigated, sometimes complete, echolalia was also observed. MR imaging and SPECT scans showed mild atrophy and a decrease of rCBF in the left perisylvian region involving the frontal operculum, while a positron emission tomographic study disclosed diffuse hypometabolism in the left hemisphere. We pointed out that the features of primary progressive aphasia were frequently atypical in the light of classical classification of aphasia and that non-fluent aphasia might be observed even in the early stage of cortical degenerative processes.

[Japanese version of the Neuropsychiatric Inventory--a scoring system for neuropsychiatric disturbance in dementia patients].

BACKGROUND AND PURPOSE: Neuropsychiatric disturbances are common and burdensome symptoms of dementias. Assessment and measurement of neuropsychiatric disturbances are indispensable to the management of patients with dementia and for clinical research. No standardized instruments have been developed for these purposes in Japan. The Neuropsychiatric Inventory (NPI), developed by Cummings et al., is a standardized, validated, and reliable tool to assess a wide range of neuropsychiatric derangements in patients with dementia, and has been used in clinical studies in North America. In this study, we prepared a Japanese version of the NPI and tested its reliability and usefulness in dementia patients. SUBJECTS AND METHODS: The subjects were 174 patients with dementia, including Alzheimer's disease (140), frontotemporal dementia (12), vascular dementia (19), and normal pressure hydrocephalus (3), whose diagnosis was made on the basis of the results of extensive examinations including MRI and PET/SPECT of the brain and appropriate clinical diagnostic criteria for each disorder. The subjects consisted of 133 women and 41 men; their mean age was 72.6 +/- 7.7 years (S.D.; range: 49 to 88) years. An examiner (neurologist) used the NPI to interview a caregiver familiar with the patient's everyday behavior. In 24 randomly selected patients interview was repeated by another examiner (psychiatrist) one month later, and test-retest reliability was evaluated. The Clinical Dementia Rating (CDR), the Mini-Mental State Examination (MMSE), and the Alzheimer's Disease Assessment Scale (ADAS) were used to assess the severity of the dementia and cognitive impairment. RESULTS: The MMSE scores ranged from 5 to 29 (mean +/- SD = 19.0 +/- 4.8) and the ADAS scores ranged from 7 to 63 (24.3 +/- 10.9). The CDR score was 0.5 in 17 patients, 1 in 95 patients, 2 in 52 patients, and 3 in 10 patient. Test-retest reliability of each score was acceptably high, and the correlation coefficient for each score obtained by repeated assessments in this study was similar to the coefficient in the original report. Apathy was the most common behavior in the ten abnormal behavioral domains, and euphoria was the least common. The prevalence of abnormal findings was also comparable to the results in the original report. The total NPI scores and many of the NPI subscale scores were significantly correlated with both the severity of dementia and cognitive impairment. CONCLUSIONS: This Japanese version of NPI, whose reliability and competency are comparable to those of the original version, is a reliable and useful tool for measuring neuropsychiatric disturbances in dementia patients.

[Neuropsychological findings of functional cortical mapping in patients with brain tumors].

In 3 patients with brain tumors involving language areas, we investigated functional cortical regions and epileptogenic foci using subdural electrode stimulation before operation. These stimulation studies were useful in preserving postoperatively their language function. The following neuropsychological findings were obtained; (1) Stimulation of Broca area (Brodmann 44 and 45) did not produce anarthria (phonetic disintegration), but semantic and phonemic parahasias and word finding difficulties. (2) Stimulation of lower motor cortex elicited anarthria. (3) Buccofacial apraxia was not produced only by stimulation of frontal operculum. (4) When anarthria was elicited by stimulation, difficulty in retrieving both Kana and Kanji letter-forms and paragraphia in Kana letters were sometimes observed. (5) Stimulation at Exner's writing centre did not produce writing deficits, but elicited word finding difficulties and paraphasias.

[The efficacy of short-term hospitalizations in family care for patients with Pick's disease].

The purpose of this study is to investigate the efficacy of short-term hospitalization on family care for patients with Pick's disease (PD). Subjects were 12 patients with clinical diagnosis of PD based on clinical and neuroimaging criteria. They were selected from 483 patients with cognitive disorders who had been admitted to our hospital from January, 1994 to September, 1995. During 1.5-month hospital stay, we gave therapeutic intervention to the patients and their care-givers. Ten patients completed the planned term (1.5 months) of hospitalization. After the discharge, 9 patients continued to visit regularly the outpatient clinic. One patient discontinued to visit us and 2 patients were admitted to psychiatric hospitals because of stereotypic thefts or disinhibitional behavior. The benefits of short-term hospitalization in family care for PD patients were; i) close observation and analysis of patients' behavior under hospitalization offering strategies of behavioral therapy; ii) adequate instruction to the care-givers for their preparation for patients' malbehavior decreasing their burden; and iii) patients' familiarization to the hospital helping for patients to maintain regular visit to the hospital and to utilize other medical and social resources.