Novel drug delivery systems: opportunities and caveats.

Programmed infusion pumps, polymers and neural transplants provide the capability of delivering a variety of agents to specific locations in the central nervous system. If a necessary or therapeutically useful substance cannot otherwise penetrate the blood-brain barrier, or must be delivered to a precise location in the CNS, these strategies may be of value in neurologic disease. The possibility of transplanting functioning tissue into the brain raises the hope of providing "new parts for old." For drugs that can penetrate the blood-brain barrier, and do not require a single precise anatomic site of action, systemic administration remains the "gold standard." The role of these novel drug delivery systems in treatment of Alzheimer's disease is as yet unclear.

The indusium griseum: is it involved in Alzheimer's disease?

The histopathology of the indusium griseum (IG), a displaced hippocampal anlage, was studied in five patients with Alzheimer's disease (AD) and five controls. In the AD group, the IG had occasional neurons with granulovacuolar change (GVD) and rare Hirano bodies (HB), but no senile plaques (SP), neurofibrillary tangles (NFT), or neurons staining for phosphorylated neurofilament antigen. There was a slight but not statistically significant diminution of neurons within the IG. In all AD cases, the hippocampus showed abundant AD-associated histopathology. In the control cases, only rare neurons with GVD were present in the IG. These findings indicate that although single neurons within the IG may show some of the cytologic changes seen in the hippocampal neurons in normal aging and AD, IG neurons do not express the full range and severity of histopathologic abnormalities characteristic of AD. This suggests that factors other than selective vulnerability of neurons of hippocampal origin might be operating to induce the neuropathologic picture of AD.

Alzheimer's disease and aging: effects on perforant pathway perikarya and synapses.

The hippocampal perforant pathway originates in the entorhinal cortex (ERC) and terminates in the outer molecular layer of the dentate gyrus (DG). To compare the effects of normal aging and Alzheimer's disease (AD) on the elements of the perforant pathway, we compared relative perikaryal numbers (determined by counting cell bodies and estimating volumes) in layer II of the ERC with synaptic quantities (estimated from immunoreactivity for the synaptic terminal protein synapsin I and DG volume) in the molecular layer of the DG. The brains of 5 young and 9 elderly cognitively normal individuals, and of 9 AD patients were studied. In normal aging we found a significant age-related decline in perikaryal numbers in the ERC without demonstrable synaptic loss in the DG. In AD there was marked and equivalent, (or proportional) reduction in both ERC perikaryal numbers and DG synapses. These data suggest that in normal aging remaining neurons may continue to support a full array of synapses, perhaps due to mechanisms such as axonal sprouting, synaptic enlargement, or synaptic ingrowth. In AD, however, the accelerated neuronal loss may overwhelm such compensatory mechanisms or alternatively, independent synaptic and perikaryal losses may occur.

Aging, memory, and the cholinergic system: a study of dichotic listening.

Impairment of cholinergic neural function has been proposed as a cause of memory and cognitive (M/C) disorders of the aged since with cholinergic blockade young subjects show the M/C pattern of the elderly. To validate this hypothesis, we compared the performance of young normal subjects, young scopolamine-treated subjects, and aged subjects, using a different type of behavioral task, a dichotic listening test, which primarily measures neural channel capacity. With simultaneous dichotic presentation, undrugged young subjects reported both messages correctly in 35% of trials. Aged subjects scored double-correct responses in only 19% of trials, a highly significant difference (p less than 0.001). Following treatment with 1.0 mg scopolamine, young subjects also scored double correct responses in only 19% of trials, a highly significant reduction from their undrugged performance (p less than 0.01), but virtually the same as that of normal aged subjects. Similar findings were obtained with a staggered dichotic presentation. These results extend the observation that cholinergic blockade in young subjects reproduces the pattern of M/C decline of the aged; thus providing further for the hypothesis that this decline may result from impaired function in cholinergic neurons. The neurobiologic implications of cholinergic impairment are discussed.

Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know.

BACKGROUND: Published studies now show a clear association between Alzheimer's disease (AD) and the apolipoprotein E epsilon 4 allele (APOE* epsilon 4). The clinical value of this information to estimate a healthy individual's lifetime risk of AD has not been well delineated. Physicians dealing with AD may not know either the lifetime risk of developing AD or the effect of the APOE genotype on this risk. Because the lifetime risk of AD depends in part on life expectancy, and available figures on APOE are not population based, a computation is necessary to derive risk estimates useful to physicians. OBJECTIVES: To estimate the lifetime risk of AD and the effect of APOE genotype information on that risk and to assess the knowledge of these risks among physicians who manage patients with dementia. DESIGN: Estimation of risk of AD and survey of physician awareness. The lifetime risk of developing AD without APOE genotype information was first computed for 65-year-olds from existing epidemiologic studies of age-related AD incidence and an actuarial life-table analysis. Using this computed a priori risk of AD and published studies of APOE genotypes in individuals with and without AD, we used a Bayesian analysis to determine the risk of developing AD, with and without an APOE* epsilon 4 allele, for unaffected 65-year-olds. To assess physician knowledge of the lifetime risk of AD and the effect of APOE genotyping on the risk, 50 neurologists, internists, geriatricians, geriatric psychiatrists, and family physicians who manage patients with dementia were randomly selected to participate in a questionnaire-driven telephone survey. RESULTS: In a person with no family history of AD, the epidemiologic/actuarial lifetime risk of AD is approximately 15%. Based on a Bayesian calculation and published APOE data, the lifetime risk of AD is 29% for individuals with one APOE* epsilon 4 allele and it is 9% if no APOE* epsilon 4 allele is present. Physician awareness survey results were as follows: 42% of physicians correctly estimated the approximate lifetime risk of AD; of these, only one third were moderately sure of their response. Only three physicians correctly estimated the change in risk given the APOE* epsilon 4 genotype; only one of these was at least moderately sure. CONCLUSIONS: Determining the APOE* epsilon 4 status of healthy adults with no family history of AD approximately doubles (for the epsilon 4 allele) or reduces by 40% (for the non-epsilon 4 allele) the uninformed lifetime risk of developing AD. Even with an APOE* epsilon 4 allele, the lifetime risk remains below 30%. Most physicians managing patients with AD do not know the lifetime risk of AD, and very few know how APOE* epsilon 4 status modifies the risk. These clinically relevant risk figures should be more widely disseminated among physicians.

Hand muscle atrophy in multiple sclerosis.

The occurrence of muscular atrophy in multiple sclerosis (MS) has been considered unusual and classically has been ascribed to disease involving the motor unit. Nine patients with MS in a single clinic were found by strict criteria to have focal hand muscle atrophy associated with weakness. None had electrodiagnostic evidence of either anterior horn cell or axonal abnormalities. These observations indicate that focal muscular atrophy is common in MS; it may often occur as a result of relative disuse resulting from disease of central pathways involved in motor control.

Vacuolar change in Alzheimer's disease.

A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.

Histocompatibility (HL-A) factors in familial multiple sclerosis. Is multiple sclerosis susceptibility inherited via the HL-A chromosome?

In order to study a possible hereditary factor leading to multiple sclerosis (MS) susceptibility, histocompatibility (HL-A) types were studied in families where two or more first-degree relatives had MS. Neither the inheritance of a particular parental HL-A chromosome, nor the occurrence of any specific HL-A antigens, could be shown to be necessary or sufficient for the development of MS in family members. The distribution of HL-A chromosomes was essentially the same for affected and unaffected family members. An excess of 3,7 haplotype and W21 antigen was demonstrated, both in affected patients and in unaffected family members, in equal proportions. We conclude that the HL-A chromosome has no direct causal relationship to MS susceptibility, although it may be indirectly associated by population stratification, maternal factors, or some other mechanism.

Vascular amyloid deposition in Alzheimer's disease. Neither necessary nor sufficient for the local formation of plaques or tangles.

OBJECTIVE: To determine the relationship between vascular beta-amyloid (beta A4) and senile plaques (SPs) and neurofibrillary tangles (NFTs). DESIGN: We counted vascular amyloid deposition with SP and NFT density in the medial temporal lobe (CA1 plus the subiculum) and the cerebellum. PATIENTS: The brains of seven patients with Alzheimer's disease and of three age-matched nondemented control subjects were studied. RESULTS: In Alzheimer's disease, the density of beta A4-laden blood vessels was significantly higher in the cerebellum than in CA1 plus the subiculum. Conversely, the densities of SPs and NFTs were much greater in the CA1 plus the subiculum than in the cerebellum. CONCLUSIONS: This study indicates that local vascular beta A4 deposition is not directly correlated with SP and NFT densities. Deposition of beta A4 in blood vessel walls may not be instrumental in the formation of SPs and/or NFTs in the brain.

The prognosis in Alzheimer's disease. 'How far' rather than 'how fast' best predicts the course.

Clinical features at the initial examination of 42 patients with probable Alzheimer's disease were tested for prognostic value at subsequent follow-up of 54 +/- 25 months. These potential prognostic features were of three types: degree of severity features (eg, IQ scores); variable clinical features (eg, extrapyramidal signs); and individual distinguishing features (eg, gender, education, and age). The power of these potential prognostic features to predict prognosis was assessed using the Kaplan-Meier life-tables method and the Cox proportional hazards model. Three clinical end points were considered: total dependence in activities of daily living; incontinence; and institutionalization at follow-up. Degree of severity features (subtests of the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale, and the Clinical Severity Score) predicted subsequent dependence in activities of daily living, incontinence, and institutionalization. Historical disease duration, age, gender, family history of dementia, retrospective rate of progression, anxiety, psychosis, depression, and extrapyramidal signs did not influence prognosis. These results suggest that initial degree of severity ("how far") rather than variation in the rate of progression ("how fast") best predicts prognosis in the early to intermediate stages of Alzheimer's disease. The relationship of disease severity to prognosis should be taken into account before concluding that there are subtypes of Alzheimer's disease that have different rates of progression.

Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease.

BACKGROUND: Previous studies have examined the relation between postmenopausal estrogen replacement therapy (ERT) and the risk of Alzheimer disease (AD). The findings have been inconsistent, since some studies have been interpreted as showing a protective effect while others have reported no effect. OBJECTIVE: To determine whether exposure to ERT is associated with a reduced risk of AD. DESIGN: Population-based nested case-control study. SETTING: The United Kingdom-based General Practice Research Database. PATIENTS: The base cohort consisted of women who were recipients of ERT (n = 112 481) and a similar cohort of women who did not use estrogens (n = 108 925). The 2 cohorts were restricted to women born on or before January 1, 1950. From the 2 cohorts, we identified and verified 59 newly diagnosed cases of AD and 221 matched control subjects. MAIN OUTCOME MEASURE: Prior and current use of ERT in cases compared with controls. RESULTS: Among the 59 newly diagnosed cases of AD, 15 (25%) were current estrogen users, while among the controls, 53 (24%) were current users. The adjusted odds ratio comparing all current estrogen recipients with nonrecipients was 1.18 (95% confidence interval, 0.59-2.37). In estrogen users who took the drug for 5 years or longer compared with nonusers, the odds ratio was 1.05 (95% confidence interval, 0.32-3.44). Odds ratios were similar for estrogen recipients who received estrogens alone and recipients who received combined estrogen-progestin treatment. CONCLUSION: The use of ERT in women after the onset of menopause was not associated with a reduced risk of developing AD.

Status epilepticus and Epstein-Barr virus encephalopathy. Diagnosis by modern serologic techniques.

Three patients had status epilepticus appearing de novo as the presenting manifestation of Epstein-Barr virus (EBV) encephalopathy. Clinical findings of infectious mononucleosis were absent and EBV-specific serologic tests made or confirmed the diagnosis in each case. Epstein-Barr virus should be considered as a potential cause when status epilepticus occurs in the absence of previous seizures or an identified cause of seizures. The diagnosis may be made in some cases only with the use of EBV-specific serologic testing.

Marker proteins of platelet activation in patients with cerebrovascular disease.

Platelet activation is assumed to occur in many patients with strokes of transient ischemic attacks (TIAs). Determination of this activity can now be measured by assaying the platelet-specific proteins, platelet factor 4 and beta-thromboglobulin. These proteins are platelet specific and are released during irreversible aggregation. The plasma level of these proteins was measured in patients with strokes and TIAs and both groups had significantly greater values than healthy control subjects. These markers of platelet activation may provide further understanding of the role of platelets in the etiology, diagnosis, and treatment of cerebrovascular disease.

Memory and cognitive function in man: does the cholinergic system have a specific role?

Interference with cholinergic function produces disruption of memory/cognitive (M/C) performance in both animals and man. It is uncertain whether this disruption is due to a specific relation of cholinergic neurons to M/C functions, or whether the effect is nonspecific, resulting either from alteration of alertness and attention, or from a "mass action" effect, with loss of functioning neurons. Scopolamine was given to normal subjects to produce an M/C impairment. Half the test subjects then received physostigmine and half d-amphetamine. Physostigmine, a pharmacologic antagonist of scopolamine, markedly improved M/C functions; amphetamine failed to produce M/C improvement, although alertness was improved, and activity in catecholaminergic neurons presumably increased. This comparison supports a specific role for cholinergic neurons in M/C processes. Possible mechanisms of cholinergic neural functioning in memory include plasticity of cholinergic synapses, as well as other acetylcholine-depended operations of the limbic system crucial to memory.

Driving and Alzheimer's disease: the risk of crashes.

We designed this questionnaire-based study to determine the risk of auto crashes among Alzheimer's disease (AD) patients who continued to drive after the onset of AD, compared with normal age-matched control subjects and other drivers' statistical records. While ultimately all AD patients will become incapable of driving, it is not known whether, under current licensing regulations and self-imposed limitations, patients with AD present a definably increased risk of being involved in crashes, and if so, the relative magnitude of the risk and at what point in the course of the disease the risk may become significantly increased. We administered a brief questionnaire to the caregivers of 130 AD patients and to 112 age-matched, nondemented control subjects and their spouses. Annual rates of occurrence and severity of all crashes, and of crashes reported to the authorities, were determined from spousal or other caregiver responses. For all years of driving following the onset of dementia, AD patients had a mean of 0.091 reported crashes per year compared with matched controls, who had an average of 0.040 reported crashes per year in the same period of time. The average number of crashes per year changed with each year of driving following the onset of AD, with considerably lower reported crash rates during the initial years of dementia: in year 1, the crash rate was 0.068; in year 2, 0.097; in year 3, 0.093; in year 4, 0.159; in year 5 and beyond, 0.129.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinergic enhancement and REM sleep latency in the aged: lecithin does not reproduce physostigmine effect.

The administration of lecithin has failed to improve memory in aged or demented individuals. We studied the effect of lecithin on another cholinergic function, REM sleep latency. Intravenous doses of physostigmine shortened the latency to the first REM sleep period, but oral lecithin did not. In contrast to physostigmine, brain cholinergic function may not be enhanced by lecithin, which may explain why lecithin does not improve cognitive function.

Primary progressive aphasia with focal neuronal achromasia.

We describe the clinical, radiologic, neuropsychological, and neuropathologic features of a 69-year-old man with a 3-year history of progressive transcortical expressive aphasia. Neuropsychological testing showed progressive dysfunction of expressive language. Neuropathologic examination demonstrated focal cortical degeneration involving the left superior frontal gyrus, with swollen achromasic neurons and no evidence of Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Lewybody disease, or other dementing disorders. This case adds to the known heterogeneity of the underlying pathology of patients with primary progressive aphasia.

Memory decline in the aged: treatment with lecithin and physostigmine.

Normal aged subjects were given lecithin and placebo for 5 weeks each in a double-blind crossover study. Supraspan tests of memory and learning failed to show any significant changes as a result of these treatments. Addition of a single IV infusion of physostigmine did not improve performance. These findings neither support nor weaken the "cholinergic hypothesis" of cognitive impairment in aging and dementia, but they imply that simple cholinergic hypofunction is unlikely.

Thalamic dementia and motor neuron disease.

A 46-year-old woman developed a progressive neurologic disorder over the course of 30 months which was characterized by profound dementia complicated by a motor neuron disorder that became evident 10 months prior to death. Postmortem examination of the nervous system disclosed extensive neuronal loss and gliosis of the thalamus, predominantly involving the dorsomedial nuclei, as well as severe degeneration of the corticospinal tracts, spinal anterior horns, and hypoglossal nuclei. The disease could not be transmitted to experimental animals by intracerebral inoculation of the patient's brain tissue. This case represents a unique dementing disorder, possibly familial, with associated motor neuron disease.

Synaptic loss in Alzheimer's disease and other dementias.

The extent and location of neuronal losses necessary or sufficient to produce dementia in patients with Alzheimer's Disease (AD) is unknown. To approach this question, we studied synaptic terminals in postmortem brain tissue utilizing immunohistochemical techniques. We used antibodies against two proteins found in synaptic terminals--synapsin I and synaptophysin--as synaptic markers in the hippocampal complexes of eight patients with autopsy-proven AD and eight nondemented control subjects. Quantitative microscopy measured the regional density of synaptic staining. All AD patients showed a striking decrease in synaptic staining in the outer half of the molecular layer of the dentate gyrus compared with control brains, where the density of synaptic terminals was uniform throughout. In an additional patient with progressive degenerative dementia but without plaques or tangles on neuropathologic examination, similar depletion of synaptic staining was seen in the dentate gyrus. Quantitative densitometric analyses confirmed the focal decrease in synaptic staining in the outer half of the molecular layer in demented patients. We also found a slight increase in synaptic staining in the inner half of this layer.