beta-Amyloid protein (A beta) containing plaques are a fundamental neuropathological feature of Alzheimer's disease (AD). Using computer enhanced image analysis the relationship between apolipoprotein E (apoE) epsilon 4 allele and the presence of amyloid plaques, both classic and diffuse, was examined in 29 histopathologically confirmed cases of AD. In keeping with previous studies the density of both plaque types and amyloid load correlated with each other and increasing age. The results showed that the presence of the apoE epsilon 4 allele had the strongest effect on amyloid load and density of classic plaques and a much smaller effect on the diffuse plaque density which did not reach significance. It is suggested that the presence of the apoE epsilon 4 allele may drive the formation of classic plaques in preference to diffuse plaques in AD.

1. Alzheimer's disease is a heterogeneous disorder that may be caused by genetic or environmental factors or by a combination of both. Abnormalities in chromosomes 1, 14, and 21 have all been implicated in the pathogenesis of the early-onset form of the disease, while the ε4 allele of the apolipoprotein E gene (on chromosome 19) is now recognized as a risk factor for early- and late-onset sporadic and familial Alzheimer's disease.

Diffuse axonal injury (DAI) in the central nervous system is a common cause of post‐traumatic coma and may result in varying degrees of disability up to and including the vegetative state. Experimental studies in man and animals have previously relied upon semiquantitative grading systems for determining the relationship between the extent of DAI and the clinical features of patients. Using β‐amyloid precursor protein immunocytochemistry for the detection of DAI in sections of corpus callosum from 15 cases of fatal head injury, we have developed a quantitative image analysis technique for the assessment of axonal injury. This new method is objective and reproducible and should allow better correlation with biomechanical, radiological, and clinical parameters to increase our understanding of DAI.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti‐inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia‐derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin‐1 is a key initiating and coordinating agent. Interleukin‐1 promotes neuronal synthesis and processing of the β‐amyloid precursor protein, thus favoring continuing deposition of β‐amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100β, is a neurite growth‐promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine‐induced neuronal insults can activate microglia with further overexpression of interleukin‐1, thus producing feedback amplification and self‐propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Chronic overexpression of the neurite growth-promoting factor S100β has been implicated in the pathogenesis of neuritic plaques in Alzheimer’s disease. Such plaques are virtually universal in middle-aged Down’s syndrome, making Down’s a natural model of Alzheimer’s disease. We determined numbers of astrocytes overexpressing S100β, and of neurons overexpressing β-amyloid precursor protein (β-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down’s syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100β-immunoreactive (S100β+) astrocytes in Down’s patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down’s patients. The numbers of S100β+ astrocytes in young and adult Down’s patients correlated with the numbers of neurons overexpressing β-APP (p < 0.05). Our findings are consistent with the idea that conditions—including Down’s syndrome—that promote chronic overexpression of S100β may confer increased risk for later development of Alzheimer’s disease.

Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer's disease. We used computerized image analysis to determine the number of IL-1 alpha-immunoreactive (IL-1 alpha +) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann's area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1 alpha + microglia were similar in Alzheimer and control patients. For layers III-VI, the numbers of IL-1 alpha + microglia were higher than that seen in layers I-II for both Alzheimer and control patients. Moreover, for layers III-VI, the number of IL-1 alpha + microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III-V and twofold for layer VI; P < 0.05 in each case). The cortical laminar distribution of IL-1 alpha + microglia in Alzheimer patients correlated with the cortical laminar distribution of beta-amyloid precursor protein-immunoreactive (beta-APP+) neuritic plaques found in Alzheimer patients (r = 0.99, P < 0.005). Moreover, the cortical laminar distribution of IL-1 alpha + microglia in control patients also correlated with the cortical laminar distribution of beta-APP+ neuritic plaques found in Alzheimer patients (r = 0.91, P < 0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1 alpha + microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of beta-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer's disease.

The licensing of donezepil, an acetylcholinesterase inhibitor, for the symptomatic treatment of mild or moderate dementia in Alzheimer's disease has been strongly welcomed by patients, relatives and professionals, bringing optimism on a previously desolate scene. However, the introduction of this completely novel treatment1'2 has generated clinical, moral, ethical and economic dilemmas3. Here we highlight some issues that require further attention.

The literature relating to the relationship between personality factors and course and outcome for the schizophrenic disorders is reviewed utilizing the approach proposed by Klein, Wonderlich, and Shea (1993). Developed to explicate the relationship between personality and depression, this approach allows for consideration of the contribution of premorbid personality and also of changes in personality occurring secondary to the onset of the psychotic disorder. A model incorporating a developmental understanding of the impact on personality of the potentially traumatic experience of the onset of a schizophrenic disorder in late adolescence is presented. Directions for future research are outlined.

All individuals with Down's syndrome (trisomy 21‐DS) develop the pathogenic hallmarks of Alzheimer's disease in old age (+40 years).1‐4 The extent of pathology is variable, but it has been shown that the amount of β‐amyloid pathology is variable and related to age and the degree of dementia.3 Thus, in DS, growing old is associated with a progressive pathological process which results in cognitive decline. However, neuropsychological studies of older DS subjects have identified a clinical dementia in only a proportion of cases.1‐4These contradictory observations could be reconciled if some factor existed which modulated the rate and amount of β‐amyloid pathology. Recent studies demonstrate an association between the apolipoprotein E4 (ApoE4) allele and the earlier age of onset in both sporadic8‐9 and familial10 AD. Increased amounts of βamyloid pathology can also be related to the E4 allele. However, at present there are no data documenting the effects of ApoE genotype on the expression or degree of clinical symptoms of the disease. We have examined the ApoE genotype in a cohort of clinically evaluated elderly patients with DS in order to examine the effects of ApoE genotype on the clinical symptoms of dementia. We report here that, despite the presence of an active disease process, the ApoE E2 allele is associated with longevity and preservation of cognitive functioning.

There is increasing evidence of a link between head injury and the subsequent onset of Alzheimer’s disease. Deposits of amyloid β-protein (Aβ) are found not only in cases of dementia pugilistica but in some 30% of patients dying after a single episode of severe head injury. Detailed clinicopathological studies have shown that Aβ deposition is most likely, but not exclusively, to occur, the older the patient at the time of injury, and if the injury is the result of a fall. Distribution studies have shown that the Aβ is widely deposited in the neocortex and there is no apparent association with any of the multiple primary or secondary pathologies of traumatic brain injury. There is an increased expression of β-APP particularly in the pre-α cells of the entorhinal cortex and in areas of axonal damage. Recent molecular genetic studies have shown that there is a strong association between deposits of Aß and the apolipoprotein E genotype of the individual.

Neurofibrillary lesions such as neurofibrillary tangles, neurites and neuropil threads are used as neuropathological markers of Alzheimer's disease (AD). However these lesions are also seen in non-demented elderly cases as well as in several other disorders such as Down's syndrome (DS), dementia pugilistica (DP) and Parkinson's disease. Quantitative studies may therefore help in understanding the pathophysiological role of these lesions. Using a novel image analysis technique we have quantified the extent of neurofibrillary damage in AD, DS and DP. We have found that the extent of neurofibrillary change did not significantly differ beween AD and DS, though there were also strong parallels between AD and DP. We conclude that both genetic (as in DS) and environmental (as in DP) risk factors for AD-type pathology provide a similar pattern of neurofibrillary degeneration to that in AD itself suggesting that similar degenerative mechanisms might be triggered in all three conditions.

The neuropathological diagnosis of Alzheimer's disease requires an assessment of the quantity of pathology present. Advances in molecular biology have highlighted the role of β-amyloid precursor protein (βAPP) in the pathogenesis of the disease. This protein is found in neurons and other cells and many neuropathological studies would benefit from a method which generates reliable data on the numbers of cells containing significant amounts of the protein. Classically, generation of such data would have involved laborious manual counting. This particular approach carries low levels of inter- and intra-rater reliability and is much dependent on the skill and experience of the operator. We have used immunocytochemistry to specifically define a single cell population, pre-α cells, containing βAPP, and have developed a computerized cell counting programme that can reliably quantify these cells in human post-mortem brain samples. We have obtained a high level of accuracy (>95%) and efficiency in identifying and quantifying target cells and have demonstrated that our protocol can be used effectively by both novice and expert. This method could be easily configured to provide quantitative data for a wide range of immunocytochemically defined cell populations.