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Despite a dramatic increase in the understanding of the neuropathologic and neurochemical alterations accompanying Alzheimer's disease, by far the largest cause of progressive and incapacitating cognitive dysfunction in the elderly, physicians have as yet no pharmacologic agent that can be prescribed safely either to arrest or reverse this decline. This lack of effective therapeutic agents is contributing to the use by an increasing number of health professionals, including physicians and concerned families, of unproved, costly, and potentially dangerous modalities, such as chelation therapy. The purpose of this paper is to describe some individuals with Alzheimer-type dementia who have undergone chelation therapy.

Language impairments have long been recognized as occurring in dementia of the Alzheimer type but have only recently attracted more detailed attention. Some have regarded these impairments as being a form of aphasia, as encountered in subjects with focal brain lesions. This could be misleading since there are differences between the language impairment in dementia and aphasia. With regard to specific aspects of linguistic performance, the semantic and lexical aspects appear to be rather more vulnerable to deterioration than the phonological and syntactic. In addition, the analysis of language in dementia is complicated by the fact that tests of language can also be affected by disturbances in other psychologial functions, such as memory and perception, similarly prone to disruption in dementia.

Brains came to autopsy from elderly cases that had been psychometrically tested and were shown to be either intellectually normal (n = 48) or suffering from dementia of the Alzheimer-type (n = 56), as well as elderly cases that had not been tested (n = 32). Cortical senile plaques, impregnated by von Braunmuhl's silver method, were found to range in structure from amorphous (neuritic) through to discrete (amyloid). Large numbers of the amorphous plaques were most frequently found in the outer half of the cortex of the demented cases, aged 60-75, whereas small numbers of the discrete plaques were most frequently found in the inner half of the intellectually normal cases, aged 75 onwards. The distribution of the senile plaques per se was found for four different regions of the cortex as well as the correlation of their numbers with the ages of the cases. The pathogenesis of the plaques is discussed.

Serum vitamin B12 levels (as determined by radio-immunoassay) were measured in 20 subjects aged 65 years and over with Alzheimer-type dementia, 20 age-matched subjects with non-Alzheimer type dementia and 20 age-matched subjects with no dementia. Serum vitamin B12 levels were significantly lower and serum vitamin B12 deficiency was significantly more frequent in subjects with Alzheimer-type dementia and were independent of age, sex, haematological abnormality or serum folate.

Cerebral atrophy was measured by comparing brain volume and cranial capacity at necropsy on 20 severely demented patients aged 64--92 years and 18 non-demented controls of similar age. The volumes of cerebral cortex and white matter and of the lobes of the cerebral hemispheres were found by point-counting morphometry. Patients with Alzheimer type dementia aged less than 80 years mainly showed pathological cerebral atrophy with global loss of cerebral tissue (P less than 0.001) whereas over 80 years of age they generally showed selective atrophy of temporal cortex (P less than 0.005). The findings support the view that disease processes, not exaggerated age change, underlie primary neuronal dementia of Alzheimer type.

The maximum activity of choline acetyltransferase (ChAT), the affinity for choline or acetyl-CoA and the isozyme pattern in the cerebral cortex of 5 cases of Alzheimer type dementia (ATD) and 6 age-matched control subjects were examined post-mortem. Maximum activities of ChAT were estimated in 5 cerebral cortical areas of Brodmann: 4, 7, 10, 17 and 22. A significant reduction in maximum activities of ChAT was found in all cortical areas for the cases of ATD. The affinity for choline or acetyl-CoA was measured in the frontal cortex (Brodmann's areas 4 and 6) and in the temporal cortex (Brodmann's areas 21 and 22). The affinity was significantly decreased in both cortices of demented patients. A significant correlation was observed between maximum activity of ChAT and the affinity for choline or acetyl-CoA. The isozyme pattern obtained by column chromatography on Sephadex G-200 was similar to that obtained by centrifugation on a sucrose density gradient. The isozyme pattern of ATD was different from that of the control subjects. These results suggest qualitative as well as quantitative abnormalities in the ChAT in autopsied brains of ATD.

A gradual deterioration of mental and physical condition is one of the main clinical signs of dementia of the Alzheimer type (DA T). To describe this deterioration, we evaluated 88 institutionalized patients with DA T and plotted their current status on a number of different clinical parameters as a function of time from the estimated onset of dementia. Ratings of speech, cooperation, social contact, and communication were in the very low range in patients with duration of DA T of three years or longer, while the rating of mood was similar regardless of duration of DA T. Half of the patients were unable to dress themselvesfive years after onset of symptoms and unable to sleep regularly six years after onset. By seven years 50% had developed rigidity on passive movement, and by eight years half were unable to feed themselves and to walk without assistance. By nine to ten years, 50% had developed contractures of the limbs and were mute, and by twelve years, half of those who survived had lost eye contact with caregivers.

Choline acetyltransferase (ChAT) activities were measured in the cerebral cortex and the nucleus basalis of Meynert (nbM) of post-mortem human brains from 8 cases with Alzheimer type dementia (ATD) and 5 age-matched control subjects. The lowest ChAT activity was detected in the temporal cortex (Brodmann's area 22) and the nbM in ATD. A significant correlation was found between ChAT activities in the nbM and those in Brodmann's areas 4, 7, 10, 17 and 22. Present results provide evidence of a cholinergic projection from the nbM to the cerebral cortex observed by retrograde or anterograde degeneration studies in animals.

Concentrations of free amino acids were measured in the cerebral cortices of post-mortem brains from 5 histologically verified cases of Alzheimer-type dementia (ATD) and 8 histologically normal controls. The concentration of glutamate in the ATD brains was significantly lower in the superior frontal, orbital, cingulate and inferior temporal cortices when compared with the control brains. The concentrations of taurine and γ-aminobutyric acid in the ATD brains were significantly lower in the inferior temporal cortex. These findings suggest that amino acid neurons could be involved in ATD.

Positron emission tomography with [18F]fluorodeoxyglucose revealed greater right than left hemispheric impairment of cortical glucose metabolism in patients with probable Alzheimer's disease who were younger than 65 but not in those over 65. This asymmetry was related to poor visuospatial performance.

Items from Luria's Neuropsychological Investigation (LNI) were used to assess cognitive functioning in three groups: patients with Alzheimer-type dementia (ATD), with alcoholic Korsakoff syndrome (KS) and control subjects of comparable age. The LNI was shown to be a sensitive assessment in that it distinguished differences within the ATD group and among the three groups. The validity and usefulness of the LNI in Alzheimer-type dementia are discussed.

Five institutionalized patients with Alzheimer-type dementia were observed (video-recorded) during meals. The aim was to assess their meal behaviour and social interaction. The results showed that when the patients ate without the participation of staff, the two least demented patients became 'caregivers' in the group and helped the three most demented patients to eat. When two mental nurses joined the group, the patients dropped their roles as helpers. The conversation in the group could be characterized as incomplete, with short sentences and a lot of breaks. Sixty-three per cent of all comprehensible utterances concerned food and eating and almost all conversation concerned the present.

In reviewing the psychological research into dementia a little over a decade ago it was evident that most of the systematic work had been directed at examining the memory impairment (Miller, 1977). There was then very little work directed at any other psychological functions. Since that time the psychological literature relating to dementia, and Alzheimer type dementia in particular, has increased considerably. Not only has it grown in volume but it has also extended much more deeply into other functions aside from memory. The purpose of this review is to consider what has been achieved in exploring the nature of language impairment in Alzheimer type dementia.

Chromosome analyses were performed on lymphocytes from patients with Alzheimer type dementia, multi-infarct dementia, Down's syndrome and healthy controls. At least 100 cells were scored from each individual. A significant increase in aneuploidy was observed in the demented patients compared to controls but there was no difference between multi-infarct dementia and senile dementia of Alzheimer type. Nor was there any sex difference in the different groups. Also there was a significantly increased frequency of structurally altered chromosomes among the patients with senile dementia of Alzheimer type compared to other forms of dementia. In the control group such an anomaly was not observed.

Our findings dispel the commonly held belief that the EEG always worsens progressively in dementia of the Alzheimer's type. In a continuing cohort analytical study of dementia, 139 patients with Alzheimer's disease and 148 controls were studied for EEG abnormalities and progression. EEGs were read without knowledge of the previous EEGs or clinical condition, and classified according to the presence of diffuse delta or theta, bisynchronousspikes, projected activity, and focal activity. EEGs were significantly different in the two groups. EEG scores generally worsened over 1-4 years, but most of the subjects showed no alteration in their EEG scores. A few patients with Alzheimer's disease showed improvement of EEG findings.

Eleven patients with presenile Alzheimer type dementia (ATD) were treated with N-terminal ACTH fragments for 14 days. No change in cognitive functions was observed during the treatment. A significant increase in CSF beta-endorphin (beta-EP) levels was found, while ACTH and beta-lipoprotein remain unaffected. The possibility that ACTH and its moieties could interfere with beta-EP activities in CNS is discussed.

正常者 (54±3歳) 154例及び臨床症状, CTより診断した脳動脈硬化症 (68±9歳) 12例, 慢性期脳梗塞 (69±9歳) 20例これら脳血管障害が痴呆の原因と考えられる脳血管性痴呆 (71±8歳) 12例, アルツハイマー型痴呆 (74±7歳) 9例について, 平均血小板容積, 血小板数, 血小板停滞率を測定し正常者及び脳循環障害者のこれら血小板パラメーターの診断的意義を検討し, つぎの結果を得た.1) 平均血小板容積は脳動脈硬化症では正常者に比し有意差を認めないが脳硬塞では有意に増加した.2) 血小板数は正常者に比し脳動脈硬化症, 脳梗塞で有意に減少した.3) 脳血管障害患者において平均血小板容積, 血小板数は有意の逆相関を示した.4) 脳血管性痴呆ではアルツハイマー型痴呆に比し有意の平均血小板容積の増加と血小板数の減少を認めた.5) 血小板停滞率は脳梗塞, 脳動脈硬化症, アルツハイマー型痴呆において有意差を認めなかった.以上より平均血小板容積, 血小板数の変動は脳血管障害を反映している可能性が考えられ, これら血小板パラメーターの測定が脳血管障害患者においては梗塞発作を予知するうえで, 痴呆患者においては病因を鑑別するうえで有用な情報のひとつになり得ることを示唆しているものと思われた.

A characteristic profile of subtest scores from the Wechsler Adult Intelligence Scale (WAIS) similar to that seen in clinically tested dementia patients was found in 10 of 19 normal young adult subjects with a drug-induced cholinergic deficiency of mental functioning but in only 4 of 22 control subjects. The same subtest profile was then found in test data from two groups of consecutive dementia patients (61 and 77 patients, respectively) with research diagnoses of Alzheimer-type dementia (DAT, senile and presenile), multi-infarct, and other dementias. The profile identified 44% of testable patients with AD and was 96% specific to DAT (only two false positives). A Verbal-Performance IQ discrepancy of 15 or more points was associated with cholinergic dysfunction in the normal drug subjects, but this IQ-score discrepancy did not differentiate AD from multi-infarct dementia patients. It was concluded that the subtest profile could contribute to the differentiation of DAT from other dementias. The association of this profile with drug-induced cholinergic deficiency suggested that the cholinergic deficiency of DAT might be responsible for the intellectual changes seen in this disease.

The cerebrospinal fluid level of homovanilic acid (HVA), 5 hydroxyindolacetic acid (5HIAA) and 3 methoxy-4-hydroxy phenylglycol (MHPG) was determined twice at 12 to 15-day intervals in 23 patients with Alzheimer-type dementia (ATD). No correlation was found with the degree of dementia as assessed by psychometric testing. In most of the patients, the CSF levels of 5HIAA, MHPG and to a lesser extent HVA were found to be rather stable within a period of 2 weeks. The observation of a decrease in the concentration of HVA but not of 5HIAA or MHPG in 10 out of 12 patients treated with ergoloid mesylate may therefore be of interest in elucidating the mechanism of action of this drug in ATD.

Analyse des effets de l'administration aigue de physostigmine sur les performances mnesiques et les caracteristiques de l'onde P300 chez des malades d'Alzheimer

The occurrence of geriatric depression and dementia of the Alzheimer type, two of the most common diseases of late life, is certain to increase as the proportion and absolute number of Americans over the age of 65 grow larger. Overlapping symptomatology can sometimes make it difficult to determine whether a patient suffers from geriatric depression with cognitive abnormalities, Alzheimer-type dementia with depressive symptoms, or coexisting depression and dementia. In this review of the course, symptomatology, and pathophysiology of Alzheimer-type dementia and geriatric depression, the authors describe the symptoms often shared by these diseases as well as the characteristics usually associated with one or the other. Factors that complicate diagnosis, such as the presence of other medical illnesses and pharmacokinetic and pharmacodynamic changes associated with aging, are also discussed.

This study investigated the relationship between articulation rate and memory span in a sample of 21 patients with early Alzheimer type dementia (AD), comparing their performance with 21 matched controls. Memory span was measured using auditorily and visually presented digits. The AD patients were moderately impaired in both conditions. Articulation rate was measured either by requiring subjects to read lists of random digits or repeatedly count from 1 to 10. The AD patients were able to read the digits as fast as the controls but were slower in the counting task. The measures of memory span and articulation rate correlated significantly for the controls but not for the AD patients, indicating that the normal association between articulation and memory span is disrupted. These results are discussed in relation to previous results and suggest that articulatory rehearsal processes in primary memory are unimpaired at the early stages of AD.

Multiple aspects of verbal learning and memory performance in mild as compared to moderate Alzheimer-type dementia (ATD) were studied with the Buschke selective reminding paradigm. Results show that (1) both groups of ATD subjects depend less on long-term memory (LTM) and more on short-term memory (STM) relative to elderly control subjects, (2) mild ATD subjects show less LTM encoding than moderate ATD subjects, (3) moderate ATD subjects retrieve a smaller portion of the items presumed to be encoded into LTM than do mild ATD subjects, and (4) high-imagery words increase LTM encoding and retrieval as compared to low-imagery words for moderate ATD subjects only. These results are explained by the inability of ATD subjects to attend to more than one component of the list-learning task, in conjunction with differences in the deployment of attention between mild and moderate ATD subjects.

Nerve cell nucleolar volume in reduced, in senile dementia of Alzheimer type, by 15 - 25% in nerve cells not containing neurofibrillary tangles and by over 35% in those which do contain such changes, in a wide variety of brain regions, when compared to similar cells from non-demented control cases, suggesting that interference with production of proteins may be an early consequence of the pathogenic process. The extent to which nucleolar volume is decreased in the non-tangle-bearing cells is related to frequencies of both neurofibrillary tangle and senile-plaque formation within that region, but the reduction in volume in the tangle-bearing cells correlated with neurofibrillary changes only. It seems, therefore, that the severity with which the dementing process affects an area of brain is initially shown by alterations in cell metabolism, which may invoke reductions in protein synthesis in non-tangle-bearing cells, and is later marked by the proportion of these affected cells which go to form neurofibrillary tangles. Changes in nerve cell function do not seem to be as well indicated by the density of senile plaques within that area.

Retrieval from semantic memory, measured by tasks requiring subjects to name items from a given category, was studied in mild Alzheimer-type dementia (Mild-ATD) subjects, moderate-to-severe Alzheimer-type dementia (MS-ATD) subjects, and normal controls. Semantic retrieval performance was shown to be highly sensitive to both the presence and the severity of ATD. Retrieval from both semantic categories and letter categories showed differences in the rate of production of correct responses between subject groups. These rate differences were not due to differences in accessibility of low-dominance semantic category members or low-frequency letter category members. An increase in errors as well as a decrease in correct responses contributed to the performance deficits of the ATD subjects. Furthermore, the pattern of errors changed from Mild- to MS-ATD. Qualitative as well as quantitative differences were also observed in the performance of Mild- versus MS-ATD groups on a third type of semantic retrieval task--the supermarket task. As performance of the ATD subjects declined on these semantic retrieval tasks, so did their performance on other tasks assessing primarily attention, language, and memory. The findings are discussed in terms of the progressive breakdown in both attentional and semantic memory functions which are associated with ATD.

Meta-analytic techniques were used to integrate the Wechsler Adult Intelligence (WAIS) scores of healthy elderly subjects and Alzheimer type dementia patients from 21 studies. Although age-scaled scores for demented subjects were lower than those of healthy elderly subjects for all subtests, the profiles for both groups were essentially parallel, with no subtest having significantly poorer scores than the others for the dementia patients. The pattern confirms other findings that verbal tests do not ‘hold’ to a greater degree than performance tests in dementia.

EEG topography correlates of severity and type of Alzheimer type dementia (DAT) have been studied in 21 senile dementia (SD), and in 18 Alzheimer disease (AD) patients, as well as in 15 mentally normal elderly persons. EEG maps in SD and AD patients differed from that in normals by increase of theta-delta EEG spectral power, and by suppression of alpha band power, more pronounced in AD than in SD patients, especially, in the left hemisphere. AD and SD patients also showed different EEG topography dynamics with increase in degree of cognitive functions impairment assessed by MMSE. Results obtained are in good concordance with data on metabolism and local cerebral blood flow decrease, and on cognitive deficiencies in different clinical forms of DAT.

• As part of a longitudinal cohort study of dementia, 139 patients with Alzheimer's disease (dementia of the Alzheimer type, senile dementia of the Alzheimer type, and mixed type [ischemic score, 4 to 7]) and 148 age-matched control subjects were evaluated for electroencephalographic (EEG) abnormalities and their evolution. Electroencephalograms were significantly different in the two groups; EEGs worsened overall in the two groups during a period of one to four years, but most subjects showed no alteration in their EEGs. Some patients showed improvement in their EEG findings during the follow-up period. A strong correlation between EEG grade and psychometric scores was consistently found over sequential studies. In a subgroup of patients on whom autopsies were performed, morphometric neuron loss correlated significantly with EEG severity.

Post-mortem brain samples from patients with either Huntington's disease, Alzheimer-type dementia or appropriate controls were assayed for endoplasmic reticulum enzymes, NADPH-cytochrome c reductase, neutral alpha-glucosidase, inosine diphosphatase, alpha-mannosidase and glucose-6-phosphatase and for Golgi enzymes, fucosyl- and galactosyl-transferases. In Alzheimer-type dementia there was a selective decrease in alpha-glucosidase activity in the temporal cortex. In Huntington's disease there was a selective decrease of putamen alpha-glucosidase and fucosyl-transferase activities. It is suggested that these changes reflect highly specific alterations in glycoprotein synthesis and processing and may contribute to the underlying pathology of these disorders.

To the Editor. —A number of studies have identified structural and biochemical similarities between dementia of the Alzheimer type (DAT) and Down's syndrome. Heston 1 has reported interesting data that support a common genetic origin for DAT and Down's syndrome. Cohen et al 2 first described the fact that offspring born to comparatively old mothers may be at high risk for developing DAT. However, the association between DAT Age of Parents at Time of Subject's Birth for Patients With DAT and MID* Mother's Father's Group No. Age, y† Age, y† DAT 77 26.58 ± 6.63‡ 31.44 ± 8.65§ MID 52 24.12 ± 5.73 27.21 ± 6.99 *DAT indicates dementia of the Alzheimer type; MID, multi-infarct dementia. †Values are means ± SDs. ‡P 3-7 No information on association between DAT and parental

The prevention of fall-related injuries in patients with Alzheimer-type dementia (ATD) is hampered by an incomplete understanding of their causes. We studied falls and fractures in 157 ATD patients, including 117 with three-year follow-up. Initially all but one patient could walk; 31% reported falls. During follow-up, 50% either fell or became unable to walk. The fracture rate during follow-up (69/1000/y) was more than three times the age- and sex-adjusted fracture rate in the general population. Features of both ATD and comorbid conditions contributed to the risk of falls and fractures. In particular, patients who experienced toxic reactions to drugs on entry into the study were more likely to report they had fallen prior to entry (odds ratio, 4.9; 95% confidence interval, 1.78 to 13.3), and patients who wandered were more likely to sustain fractures (odds ratio, 3.6; 95% confidence interval, 1.25 to 10.4) during the follow-up period, including hip fractures for which the odds ratio of 6.9 (95% confidence interval, 1.66 to 28.6) was unexpectedly high. Preventive measures may be possible, including controlling wandering, avoiding toxic reactions to drugs, and treating comorbid illnesses. (JAMA1987;257:1492-1495)