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Medial temporal lobe atrophy (MTLA) on brain magnetic resonance imaging (MRI) may help differentiate Alzheimer's disease (AD) from multiinfarct dementia (MID) and other dementias. MTLA was seen in 6 of 11 patients with clinically diagnosed AD, 16 of 20 with mixed dementia (with both AD and MID), 1 of 5 with psychiatric disease, and in none of 32 with MID or 8 with other dementias (p less than 0.0001). Increased patchy periventricular signal, or "unidentified bright objects" were seen in 2 of 11 patients with AD, 10 of 20 patients with AD and MID, and 26 of 32 patients with MID. A larger series with autopsy correlation may verify that MTLA is a reasonably specific marker for AD, and unidentified bright objects are a sensitive, but not specific, marker for vascular dementias.

Objective: To test the effect of pentoxifylline, a hemorheologic agent used to treat intermittent claudication, on the course of vascular dementia., Design: Randomized, double-blind, placebo-controlled, parallel group trial., Setting: Outpatient tertiary care center., Patients: 64 patients meeting DSM-III criteria for multi-infarct dementia with modified Hachinski ischemic scores greater than or equal to 6, 38 of whom completed the trial., Intervention: Pentoxifylline (Trental) 400 milligram tablets three times daily vs placebo for 36 weeks., Main Outcome Measure: Alzheimer's Disease Assessment Scale (ADAS)., Results: Baseline demographic values and psychometric variables were similar in the placebo and control groups; endpoint statistical analysis was used to allow the use of data from all patients in this clinically high-risk group. For the total group, the slowing of deterioration did not reach statistical significance (by 2-tailed t test), as measured by scores on the total ADAS (P = 0.058) or on the cognitive (ADAS items 1-11; P = 0.064) or non-cognitive subscales (ADAS items 12-21; P = 0.234), although it was significant on the cognitive subscales excluding memory (ADAS items 2-6, 8-10; P = 0.036). For the subgroup of 40 patients who had CT and/or MRI evidence of stroke as well as meeting the other inclusion criteria, treatment with pentoxifylline was associated with significantly slower deterioration, as measured by the total ADAS (P = 0.023) and cognitive subscores (P = 0.020) but not non-cognitive subscores (P = 0.118). For the subgroup of 37 patients who had at least one discrete clinical stroke, treatment with pentoxifylline was associated with significantly less deterioration on the total ADAS (P = 0.002) and both the cognitive (P = 0.001) and non-cognitive (P = 0.017) subscores., Conclusion: Treatment with pentoxifylline may slow the progression of dementia in patients who meet DSM-III criteria for "multi-infarct dementia" and who also have clinical and neuroradiological evidence of cerebrovascular disease.

Thiamine deficiency is a useful animal model of the interaction between biochemistry and behavior. Although numerous biochemical changes have been detected in thiamine deficiency, studies of behavioral changes are relatively scarce. We have modified and quantitated the string test, originally described by Miquel and Blasco, for application to thiamine-deficient rats. The string test is reproducible with time, and control rats have a narrow range of scores. 50% of rats treated with thiamine-deficient diet and pyrithiamine, a centrally-acting thiamine antagonist, have persistently decreased string test scores. This decrease is already present on day 5 of treatment, long before the onset of weight loss or neurological symptoms. Rats treated with oxythiamine, a peripherally acting thiamine antagonist, do not have decreased string test scores, even when anorectic and moribund. These findings suggest that impaired string test performance is a central system effect of thiamine deficiency, and that it may also be a useful behavioral parameter to follow in other animal models of metabolic encephalopathies.

Although thiamin deficiency is associated with impaired acetylcholine metabolism, the functional significance of the cholinergic lesion is controversial. Therefore, we tested the effect of cholinergic drugs on abnormal open-field behaviors in rats that were treated with a thiamin-deficient diet and thiamin antagonist. After only 1 day of treatment, staring increased significantly in rats given pyrithiamin, a centrally acting thiamine antagonist, but not in rats given oxythiamin, which acts only peripherally. Sniffing, resting and grooming were not altered by either treatment. The acetylcholinesterase inhibitor physostigmine was as effective as thiamin in decreasing staring in pyrithiamin-treated rats, but its peripherally acting analogue neostigmine had no effect. The central muscarinic blocker, atropine, blocked the effect of physostigmine. Methatropine, which acts only peripherally, did not. Arecoline, a direct muscarinic agonist, was as effective as physostigmine in decreasing staring. Nicotine had no effect, and the nicotinic ganglionic blocker mecamylamine did not block the effect of physostigmine. Increased staring behavior in pyrithiamin-treated rats appears to reflect an early central cholinergic muscarinic deficit.

After only 1 day of treatment with a thiamine-deficient diet and pyrithiamine, a centrally and peripherally acting thiamine antagonist, 37.5% of rats performed poorly on a standardized string test. By day 12, 89.6% of the pyrithiamine-treated rats, but only 8.1% of the pair-fed controls, had decreased string test scores. Scores for rats treated with a thiamine-deficient diet and oxythiamine, a peripherally acting thiamine antagonist, did not decrease even on the day before death. The acetylcholinesterase inhibitor physostigmine improved the low string test scores in 69.2% of trials with the pyrithiamine-treated rats, whereas neostigmine, which acts peripherally, had no effect. The effect of physostigmine was inhibited by the muscarinic blocker atropine, but not by methatropine, its peripherally acting analog. Arecoline, a direct muscarinic agonist, was as effective as physostigmine or thiamine in restoring string test performance. Nicotine had no effect and the nicotinic blocker mecamylamine did not alter the effect of physostigmine. Incorporation of [2H4]choline and [U-14C]glucose into acetylcholine was decreased by 32 and 48%, respectively, relative to pair-fed controls after 12 days of pyrithiamine treatment. Acetylcholine levels were unchanged. Thiamine deficiency induces an early functionally significant central muscarinic cholinergic lesion.

In a retrospective study of 84 outpatients with multiinfarct dementia, urinary and gait disturbances were found in 50% and 27%, respectively, and often preceded dementia and discrete stroke-like episodes by more than 5 years. Compared to patients without urinary disturbance, those with urinary dysfunction were predominantly male and more behaviorally impaired, but were similar in age, cognitive score, depression score, computerized tomography findings, and relative survival. Compared to patients without gait disturbance, those with gait abnormality had a higher Hachinski ischemic score and depression score and were more behaviorally impaired. Urinary and gait abnormalities may be markers for cerebrovascular disease and vascular dementia even in the absence of frank stroke. Damage to bifrontal outflow tracts may be the common pathophysiological mechanism underlying the behavioral and motor symptoms characteristic of vascular dementias.

Over 5 years, we followed 199 patients with dementia of the Alzheimer type (DAT), 69 with multi-infarct dementia (MID), and 43 with mixed dementia (MIX). All three diagnostic categories had comparable progression of behavioral and cognitive impairment and need for home care or institutionalization at follow-up. However, 50% survival from diagnosis was 2.6 years for MID and 2.5 years for MIX, compared with 3.4 years for DAT. The 50% survivals from onset were longer than previous reports would suggest (8.1 years for DAT, 6.7 for MID, and 6.2 for MIX). Vascular dementias have higher mortality than DAT, even when associated with comparable cognitive and behavioral impairment.

In the course of evaluating and following more than 600 geriatric outpatients referred to a subspecialty clinic because of cognitive impairment, standardized computer-compatible evaluation and follow-up forms were developed, as well as a computerized data base. The forms cover medical, neurologic, psychiatric, psychometric, and clinical laboratory examinations; they help health professionals to perform thorough, standardized, and efficient examinations focused on those characteristics relevant to dementias. The computerized data base facilitates follow-up and other clinical studies. This article presents both the forms and their translation into query-language terminology.

An algorithm is proposed to classify the regional cerebral blood flow (RCBF) of two groups of subjects. A 32-tuple training vector is defined corresponding to 32 detectors used to measure 133Xe washout following inhalation. For any index of 133Xe washout, each detector is associated with two cumulative distributions (cds) each corresponding to a population. The 32 index values at which the differences between cds are maximum are defined as partition values. All index values are then compared to their partitions and are designated binary values of 1 or 0 for being above or below the partitions. A representative sum of the binary numbers (0 to 16) indicates the number of detectors in each hemisphere which exceed their respective threshold. In the example, a normal group of subjects (n = 40) is compared to an abnormal group (n = 82). The abnormal group was identified independently of RCBF by clinical testing as having Alzheimer's disease, a subcategory of dementing diseases. The classification algorithm defined a training vector to which the two populations were compared. The normal subjects had higher representative scores than the abnormals with a tight clustering of these scores. Although some abnormals scored well, the great majority had representative scores well below 12 for each cerebral hemisphere. The training vector can be used to classify new studies or can be updated by new studies until no significant changes result. At this point, the new tracing vector is used as a reference set of partition values.

Receiver operating characteristic (ROC) curves were used to quantitatively assess the ability of individual detectors in a 32-detector 133Xe inhalation system to discriminate between two populations over the range of regional cerebral blood flow (rCBF) values. These populations were clinically evaluated as normal (age 63.1 +/- 13.1, n = 23) and presumed Alzheimer's disease (age 72.7 +/- 7.0, n = 82). Summary statistics showed that for homologous detectors the average value of blood flow in the normal group was greater than the flow value in the group of subjects with Alzheimer's disease. Conclusions drawn from single values of flow or mean hemispheric flow can lead to erroneous conclusions about hemisphere asymmetries. However, the dynamic relationship between the correct identifications (true positives) compared with incorrect identifications (false positives) of Alzheimer's disease at each detector varies over the range of blood flow values, and quantitative characterization of this relationship in terms of an ROC curve provides more insight into the structure of the data. Detectors approximating the speech, auditory and association cortex were most effective in discriminating between groups. Frontal detectors were marginally useful diagnostically.

Open-field testing has proven useful for evaluation of the effects of drugs on behavior. We now present detailed methods for subdividing open-field behaviors into four categories: sniffing, grooming, resting, and staring. Upon initial exposure to the open field, sniffing is the predominant behavior. With habituation, sniffing and grooming decrease, and resting and staring increase. Treatment with a thiamin-deficient diet and pyrithiamin, a centrally acting thiamin antagonist, markedly increases staring behavior by day 3 of treatment. Animals that are treated with a thiamin-deficient diet and oxythiamin, a peripherally acting thiamine antagonist, do not have increased staring behavior. Therefore, increased staring behavior is an early behavioral change in central nervous system thiamin deficiency. Staring and other spontaneous open-field behaviors may be useful variables to monitor in thiamin deficiency and in other metabolic encephalopathies.

To determine the prevalence of unrecognized brain dysfunction accompanying chronic severe cardiac disease, we examined 20 clinically stable consecutive admissions to a cardiac rehabilitation service who were free of known stroke or dementia. Age range was 47 to 85 years (mean +/- SEM, 72.5 +/- 2.1 years), the male: female ratio was 10:10. Multiple cognitive deficits including significant memory impairment and disorientation were present in eight patients (40%), and seven of these eight patients were unable to administer their own medications reliably. An additional six patients (30%) showed milder impairments. One patient was found to be normal after neurological examination, four showed evidence of a single brain lesion, and 15 of 20 (75%) had multiple neurological abnormalities suggesting multifocal brain disease. The mechanism of cognitive deficits in cardiac patients is unclear, and it may be related to multiple infarcts, or acute or chronic hypoxic damage secondary to arrhythmias, cardiac failure, or small vessel disease of the brain. The term "circulatory dementia" is proposed to describe patients with vascular disease and non-Alzheimer type dementia. Patients with cardiac disease should undergo cognitive screening, as early identification of patients at risk of progressive intellectual loss may allow early use of preventive therapy.

With a computerized data base, a data retrieval system, and a computer program using the actuarial method of life-table analysis, we compared survival rates in different subgroups of patients with dementia of the Alzheimer type (DAT; n = 199). Men (n = 71) had a shorter duration of survival than women (n = 128), with 500-day survival (mean +/- SEM) 84 +/- 5% vs. 99 +/- 3%, p less than 0.01; 1000-day survival 49 +/- 10% vs. 96 +/- 8%, p less than 0.001; 50% survival 1000 days vs. 1550 days. Patients younger than 65 years at onset had a decreased relative duration of survival compared with patients over 65 at onset, suggesting a more malignant course. Patients with a longer duration of illness tended to die sooner, but this effect was not statistically significant. The Kahn-Goldfarb mental-status quotient was not a predictor of survival. Patients with high Haycox behavioral score (greater than 20; n = 50), indicating more severe behavioral impairment, had lower survival rates at 500 days than patients with low scores (less than 12; n = 65) (80 +/- 6% vs. 95 +/- 3%, p less than 0.05). Hachinski ischemic score, measuring signs and symptoms of vascular disease, had no correlation with survival. Factors associated with decreased duration of survival in DAT include male sex, presenile onset, and increased severity of behavioral impairment.