Conservation conflicts across Africa.

There is increasing evidence that areas of outstanding conservation importance may coincide with dense human settlement or impact. We tested the generality of these findings using 1 degree-resolution data for sub-Saharan Africa. We find that human population density is positively correlated with species richness of birds, mammals, snakes, and amphibians. This association holds for widespread, narrowly endemic, and threatened species and looks set to persist in the face of foreseeable population growth. Our results contradict earlier expectations of low conflict based on the idea that species richness decreases and human impact increases with primary productivity. We find that across Africa, both variables instead exhibit unimodal relationships with productivity. Modifying priority-setting to take account of human density shows that, at this scale, conflicts between conservation and development are not easily avoided, because many densely inhabited grid cells contain species found nowhere else.

Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.

Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

Synthetic lipid second messenger sn-1,2-didecanoylglycerol: a complete tumor promoter in mouse skin.

sn-1,2-Didecanoylglycerol, a synthetic lipid second messenger and model diacylglycerol, was evaluated as a complete skin tumor promoter in CD-1 mice. In addition, sn-1,2-dioctanoylglycerol, sn-1,2-didecanoylglycerol, the second stage tumor promoter mezerein, and the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined for their ability to stimulate epidermal protein kinase C activity in vitro. All four compounds stimulated epidermal protein kinase C activity utilizing lysine-rich histone as the phosphate acceptor substrate. sn-1,2-Dioctanoylglycerol and sn-1,2-didecanoylglycerol stimulated epidermal protein kinase C activity to a maximum velocity similar to that obtained when the enzyme was stimulated with TPA; however, about 1000 times greater concentration of the sn-1,2-diacylglycerols was required. sn-1,2-Didecanoylglycerol was evaluated as a complete skin tumor promoter in CD-1 mice utilizing a dosing regimen demonstrated to produce epidermal hyperplasia. Mice were initiated with 200 nmol 7,12-dimethylbenz[a]anthracene. One week later the mice received twice daily topical applications of 1 nmol TPA, 2 mumol sn-1,2-didecanoylglycerol or 5 mumol sn-1,2-didecanoylglycerol, 5 days/week. Additional initiated mice received twice weekly topical applications of 2 or 5 nmol TPA. Initiated mice treated with 5 nmol TPA twice weekly or with 1 nmol TPA twice daily for 5 days/week (cumulative weekly doses of 10 nmol TPA) responded similarly, based on the tumor incidence and the average number of tumors per mouse. Initiated mice treated with 2 or 5 mumol sn-1,2-didecanoylglycerol twice daily developed tumors in a dose-dependent manner. Initiated mice treated with 5 mumol sn-1,2-didecanoylglycerol twice daily developed many tumors, and at 20 weeks there was a 74% tumor incidence and an average of 6.0 tumors/mouse. At 20 weeks, 24% of the initiated mice treated with 2 mumol sn-1,2-didecanoylglycerol twice daily developed tumors, with an average of 1.1 tumors/mouse. Mice which were not initiated but treated twice daily with 5 mumol sn-1,2-didecanoylglycerol for 20 weeks did not develop any tumors. These data demonstrate that the representative synthetic lipid second messenger sn-1,2-didecanoylglycerol, like TPA, is a complete tumor promoter in DMBA-initiated mouse skin.

Differential down-regulation of epidermal protein kinase C by 12-O-tetradecanoylphorbol-13-acetate and diacylglycerol: association with epidermal hyperplasia and tumor promotion.

A single topical application of 2 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) to CD-1 mouse skin resulted in a rapid decrease in cytosolic, particulate, and total epidermal protein kinase C (PKC) activity at 6 h, which remained decreased by 70% at 96 h. This dose of TPA produced epidermal hyperplasia as determined by an increase in the number of nucleated epidermal cell layers. A single application of 10 mumol sn-1,2-didecanoylglycerol, a model sn-1,2-diacylglycerol and complete tumor promoter, induced ornithine decarboxylase to an extent similar to that of 2 nmol TPA. However, sn-1,2-didecanoylglycerol produced an 80% increase in particulate PKC activity that was accompanied by a 45% decrease in cytosolic PKC activity, resulting in no net change in total PKC activity. Unlike TPA, this dose of sn-1,2-didecanoylglycerol did not produce a hyperplastic response. Additional dosing regimens were examined to determine whether the down-regulation of particulate PKC activity was associated with hyperplasia and tumor promotion. A tumor-promoting dosing regimen consisting of multiple applications of 5 or 10 mumol sn-1,2-didecanoylglycerol twice daily for 1 week resulted in more than a 60% decrease in cytosolic and particulate PKC activity and a marked epidermal hyperplasia. Twice-weekly application of 10 mumol sn-1,2-didecanoylglycerol, a nonpromoting dosing rate, for 1 week decreased cytosolic PKC activity but increased particulate PKC activity and did not produce hyperplasia. Dosing regimens utilizing multiple applications of TPA decreased both particulate and cytosolic PKC activity and were also hyperplastic. PKC activity was also measured in epidermal papillomas from mice initiated with 7,12-dimethylbenz[a]- anthracene and promoted with either sn-1,2-didecanoylglycerol or TPA. Cytosolic- and particulate-associated PKC activity in these papillomas was decreased by at least 70% and 40%, respectively, when compared with epidermis and whole skin. After 2 months without promoter treatment, both cytosolic and particulate PKC activity remained decreased in the papillomas, whereas epidermal PKC activity returned to control values by 2 to 3 weeks following cessation of several weeks of TPA treatment. Collectively, these data demonstrate that the down-regulation of epidermal PKC is associated with and may be a permissive event for epidermal hyperplasia and tumor promotion.

The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors.

Previous studies using keratinocytes from epidermal growth factor receptor (EGFR)-deficient mice revealed that the EGFR is not required for papilloma formation initiated by a mutant rasHa gene, although the tumors that develop are very small (A. A. Dlugosz et aL, Cancer Res., 57: 3180-3188, 1997). The current study used a combination of bromodeoxyuridine pulse-chase, proliferating cell nuclear antigen distribution, and differentiation marker analysis to reveal the following: (a) the EGFR was required to maintain the proliferative population in the basal cell compartment of papillomas; (b) in the absence of EGFR, cycling tumor cells migrated into the suprabasal compartment and initiated the differentiation program prematurely; and (c) these changes were associated with cell cycle arrest. Further analysis of v-rasHa-transformed EGFR-deficient keratinocytes in vitro indicated that such cells migrated more on and attached less to extracellular matrix components. Together, these studies reveal that an essential function for the EGFR pathway in squamous tumors is to maintain a proliferative pool of basal cells and prevent premature terminal differentiation.

The shifting patterns of HIV encephalitis neuropathology.

HIV infected macrophages infiltrate the nervous system early in the progression of HIV infection, leading to a complex set of neuropathological alterations including HIV encephalitis (HIVE), leukoencephalopathy and vacuolar myelopathy that in turn result in neurodegeneration of selective cellular populations and pathways involved in regulating cognitive and motor functioning. Rapid progress in the development of highly active antiretroviral therapy (HAART) has changed the patterns of HIV related neuropathology and neurological manifestations in the past 10 years. The prevalence of opportunistic infections and central nervous system (CNS) neoplasms has decreased, and some groups have proposed that the frequency of chronic forms of HIVE have been rising as the HAART-treated HIV population ages. Accordingly, clinical manifestations have shifted from severe dementia forms to more subtle minor cognitive impairment, leading to the suggestion of a classification of HIV associated neurological conditions into an inactive form, a chronic variety, and a 'transformed' variant. From a neuropathological point of view these variants might correspond to: a) aggressive forms with severe HIVE and white matter injury, b) extensive perivascular lymphocytic infiltration, c) 'burnt-out' forms of HIVE and d) aging-associated amyloid accumulation with Alzheimer's-like neuropathology. Factors contributing to the emergence of these variants of HIVE include the development of viral resistance, immune reconstitution, anti-retroviral drug toxicity and co-morbid factors (e.g., methamphetamine, HCV). More detailed characterization of these proposed variants of HIVE is important in order to better understand the pathogenesis of HIV-associated neurological damage and to design more effective treatments to protect the nervous system.

Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department.

BACKGROUND: --The purpose of this study is a prospective assessment of morphine sulfate administration by intermittent intravenous (IV) injections (Int-IV) vs patient-controlled analgesia (PCA) in patients in the emergency department (ED) with sickle cell crisis pain. METHODS: --Patients were at bed rest and received intravenous hydration. Linear analog scale for pain intensity and verbal pain scale, level of alertness, and vital signs were assessed prior to therapy, every 60 minutes thereafter, and at the time of discharge from the ED. Patients were randomized to Int-IV or PCA. During phase 1, patients in the Int-IV group received morphine sulfate 4 mg IV every 30 to 60 minutes as necessary for a linear analog scale for pain intensity greater than 50 mm. The patients in the PCA group received morphine sulfate 2 mg bolus then 1.0 mg with a 6-minute lockout. During phase 2, patients in the Int-IV group received morphine sulfate 8 mg IV every 30 to 60 minutes as necessary for a linear analog scale for pain intensity greater than 50 mm. The patients in the PCA group received morphine sulfate 5 mg bolus then 2.7 mg with a 10-minute lockout. Data were analyzed by unpaired t test, general linear modeling, Mann-Whitney U test, and chi 2 test. RESULTS: --During phase 1, 10 patients (28.3 +/- 7.3 years) received Int-IV and 10 patients (33.9 +/- 12.5 years) received PCA. Treatment groups did not differ significantly regarding duration of pain, amount of morphine administered, linear analog scale for pain intensity, verbal pain scale, level of alertness, or vital signs except for a significantly lower final respiratory rate with Int-IV. In phase 2, 12 patients (28.4 +/- 5.6 years) received Int-IV and 13 patients (26.8 +/- 8.1 years) received PCA. The PCA groups had a significantly shorter elapsed time between onset of pain and treatment (7.3 +/- 6.5 hours) when compared with the Int-IV group (18 +/- 16.9 hours). Treatment groups did not differ significantly with respect to total amount of morphine administered, linear analog scale for pain intensity, verbal pain scale, vital signs, or level of alertness. The PCA group had a significant reduction in length of stay in the ED during phase 2 when compared with phase 1. The ED discharge rate and the incidence of side effects did not differ significantly between groups. CONCLUSION: --At both the low- and high-dose regimens, PCA is equally safe and effective and may be used in place of Int-IV administration of morphine in the ED treatment of sickle cell crisis pain.

Changes in pathological findings at autopsy in AIDS cases for the last 15 years.

OBJECTIVE: To analyze changes in frequency of systemic AIDS pathology over time and its relationship to central nervous system pathology. DESIGN AND METHODS: A total of 390 AIDS autopsy cases obtained at University of California at San Diego Medical Center from 1982 to 1998 were reviewed retrospectively and linear regression analysis was used to evaluate significance of changes over time. RESULTS: Overall, the frequency of cytomegalovirus, Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. The frequency of non-Hodgkin's lymphoma showed an upward trend over time, while the frequency of Kaposi's sarcoma remained unchanged. Following involvement of the lung (84%), the brain continued to be the second most frequently affected organ (63%). Whereas alterations of the brain by opportunistic infections or non-Hodgkin's lymphoma showed a downward trend, HIV encephalitis continued to be detected in at least 25% of the cases. Cases with advanced HIV-related neuropathology and cases with no HIV involvement of the brain showed significant systemic pathology with opportunistic infections and neoplasms. In contrast, cases with early brain pathology (e.g., lymphocytic meningitis) showed minimal systemic pathology. Overall these trends remained unchanged throughout the total period covered by this study. CONCLUSIONS: This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding.

Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease.

Patients with the Lewy body variant (LBV) of Alzheimer's disease (AD) meet diagnostic criteria for AD but have a lighter burden of plaque and tangle AD pathology despite comparable dementia. We quantified neocortical Lewy bodies (LB) in LBV patients (n = 14) using anti-ubiquitin polyclonal antibody, selecting for quantification those neocortical regions with the highest densities of LB. Neocortical neurofibrillary tangles (NFT) and neuritic plaques were evaluated with thioflavin- S. A group of classical AD patients (n = 12), matched for disease duration, was also studied. For most of these cases, entorhinal neurofibrillary pathology had previously been assessed by applying a modification of the Braak and Braak AD staging protocol. Although LBV and AD groups had similar mental test scores when last evaluated prior to death, lower neocortical NFT and plaque counts and lower modified Braak stages were observed in LBV. Neocortical NFT counts correlated with impaired neuropsychological test performance in AD but not in LBV. Plaque counts did not correlate with mental status in either group. Lewy body concentrations in four neocortical areas correlated significantly with dementia severity in LBV. The association of AD lesions in the neocortex with dementia in LBV was comparatively weaker than that observed for LB concentrations. These findings suggest that neocortical LB combined with entorhinal NFT or subcortical Parkinson's disease-type pathology may equalize the degree of dementia seen in LBV with that encountered in classical AD.

Increased Mr 60,000 protein phosphorylation is correlated with neocortical neurofibrillary tangles in Alzheimer's disease.

Increased Mr 60,000 protein phosphorylation has been found in the cytosol fraction of brain tissue from Alzheimer's disease patients. A correlation between this biochemical change and the morphologic abnormalities found in Alzheimer's disease was sought. Three neuropathologic features were studied: neurofibrillary tangles and neuritic plaques, findings characteristic of Alzheimer's disease, and gliosis, a non-specific change. The number of tangles correlated well with the extent of Mr 60,000 protein phosphorylation (p less than 0.001); but the number of plaques did not. To investigate the possibility that gliosis causes the increased Mr 60,000 protein phosphorylation, cases of Pick's disease and multi-infarct dementia were also studied. The levels of Mr 60,000 protein phosphorylation in these cases were comparable to those seen in normal controls. These findings suggest that the increased Mr 60,000 protein phosphorylation is closely related to diseased, tangle-bearing neurons and is not directly related to neuritic plaque formation or secondary gliosis.

Plaque-only Alzheimer disease is usually the lewy body variant, and vice versa.

A minority of neuropathologically confirmed Alzheimer disease (AD) brains lack neocortical neurofibrillary tangles or have very few, constituting a form of "plaque-only AD." A significant percentage of clinically diagnosed AD patients are found at autopsy to have both AD and brainstem and neocortical Lewy bodies. Many of these Lewy body variants of AD (LBV) have numerous senile plaques but no neocortical neurofibrillary tangles, and so resemble plaque-only AD. In this study, we sought to determine if plaque-only AD was usually LBV, and, conversely, if LBV was usually plaque-only AD. We analyzed 147 consecutively accessioned cases of neuropathologically confirmed AD, diagnosed according to criteria from the National Institute on Aging and the Consortium to Establish a Registry for Alzheimer's Disease. Twenty-five percent of all AD cases in this series were plaque-only AD, and 75% were plaque and tangle AD. Twenty-eight percent of AD cases in this series were LBV, and 72% were pure AD. Of the plaque-only AD cases, 75% were LBV and only 25% were pure AD. Of the LBV, 66% were plaque-only AD and only 33% were plaque and tangle AD. These results indicate that most plaque-only AD is LBV, and, conversely, that most LBV is plaque-only AD.

Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease.

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration via excitotoxicity; however, the characteristics of cell death and pathways involved are not yet clear. The main objective of the present study was to determine if deficient GT functioning in AD could be associated with cell damage and caspase activation. For this purpose, we analyzed the levels of caspase-1 and 3 immunoreactivity in AD and control brains and correlated this data with the numbers of cells displaying DNA fragmentation, GT activity, and amyloid precursor protein (APP) mRNA expression. Compared to controls, AD cases showed extensive positive labeling of neurons and glial cells with an assay for DNA fragmentation suggestive of cell damage, as well as increased neuronal caspase-3 and Bcl-2 immunoreactivity. Linear regression analysis showed a strong negative correlation between GT activity and apoptosis, and between deficient GT functioning and caspase-3 immunoreactivity. Neurons displaying DNA fragmentation presented more intense caspase-3 immunoreactivity than intact neurons. In addition, the altered ratio between the spliced forms of APP correlated with DNA fragmentation and caspase-3 immunolabeling. Taken together, these results support the possibility that excitotoxic injury associated with deficient GT functioning and an imbalance in ratio of spliced APP forms might lead to cell death via caspase-3 activation.

Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles.

Senile dementia of the Alzheimer type (SDAT) is typified pathologically by neuritic plaques (NP) and neurofibrillary tangles (NFT) in the neocortex and hippocampus. However, in a large series of cases (60) over age 74 a significant minority (30%) lacked neocortical tangles. In order to determine if these latter cases (Group B) otherwise differ from the majority which have both neocortical plaques and tangles (Group A), various clinical and neuropathological parameters were measured for both groups and the results compared. The following indices were examined: degree of dementia, rate of progression of dementia, age at death, brain weight, cerebral hemispheric weight, cortical cell counts from the frontal, temporal, and parietal lobes, the number of neocortical NP, the number of hippocampal NP and NFT, and the levels of neocortical choline acetyltransferase and somatostatin. The two groups showed no statistically significant differences in any of these categories except for increased numbers of neocortical NP in Group A in midfrontal and superior temporal regions. However, cases in Group A showed greater pathologic abnormality in nearly every parameter, albeit without attaining statistical significance. We conclude that SDAT with neocortical NFT is the same disease as SDAT without them, although the presence of such tangles is associated with a tendency towards greater severity.

Selective neuronal vulnerability in HIV encephalitis.

Recent studies of human immunodeficiency virus type 1 (HIV-1) encephalitis have shown that in addition to well established white matter damage, the neocortex shows thinning, loss of large neurons and dendritic damage. In order to identify neuronal populations affected in HIV encephalitis and to determine how neuronal damage relates to the severity of HIV infection within the nervous system, we quantified parvalbumin (PV+) and neurofilament (NF+) immunoreactive neurons in the frontal cortex and hippocampus. We found that in the neocortex, the density of NF+ and PV+ neurons was independent of severity of HIV encephalitis, and therefore changes in these neuronal subsets did not account for previously reported neuronal loss. However, neuritic processes of PV+ neurons were fragmented, atrophic and in some cases distended. In contrast to the frontal cortex, there was a trend toward decreased density of PV+ neurons in the hippocampus which only reached significance in the CA3 layer where there was a 50-90% decrease in PV+ neurons. This decrease was closely correlated with the severity of HIV encephalitis. Double-label immunocytochemical analysis confirmed neuritic damage to interneurons. These results suggest that HIV encephalitis differentially involves specific subpopulations of neurons. Since direct HIV infection of neuronal cells was not detected, damage to PV+ cells and fibers may be indirectly mediated by cytokines released by HIV-infected microglia.

Case of the month: March 1999--A 26 year old HIV positive male with dura based masses.

A 26-year-old male with AIDS presented with a chief complaint of headaches and neck pain. An MRI revealed two enhancing extra-axial dura based masses, one in the area of the left sphenoid wing and one at the level of C2-3. In both cases, microscopic sections showed actin positive spindle cell neoplasms with long slender nuclei, consistent with leiomyomas. Both tumors were positive for Epstein Barr virus by in situ hybridization. This case report serves to emphasize the importance of considering soft tissue tumors such as leiomyoma in the differential diagnosis of mass lesions that occur in the central nervous system in AIDS and discusses the role of EBV in tumorigenesis.

Case of the month: January 1998--43 year old male with radicular pain.

A 43-year-old male presented with progressively worsening right lower extremity pain. MRI of the spine showed a discrete intradural, extramedullary, homogeneously enhancing, sausage-shaped mass at L1-L2, noted intraoperatively to expand the filum terminale. Gross, histological, and electron microscopic findings were those of a paraganglioma. The case is used to discuss the differential diagnosis for sausage-shaped tumors of the filum terminale.

Position paper on diagnostic criteria for Alzheimer disease.

The lesions of Alzheimer disease (AD) consist of synapse and neuron loss associated with progressive deposition of amyloid as diffuse and neuritic plaques and accumulating tau abnormalities in the form of neurofibrillary tangles and neuropil threads. Diagnostic criteria for Alzheimer disease constitute arbitrary cut-off levels above which AD is deemed to exist, and below which lesser amounts of the same abnormalities are relegated to the nebulous category of aging changes. Demanding neocortical tangles for a diagnosis of AD sacrifices sensitivity on the altar of specificity, since, while such lesions usually represent an advanced stage in the orderly evolution of AD, lighter burdens of plaque-predominant AD pathology with tangles confined to the medial temporal lobe can cause dementia when associated with concomitant synapse loss. Such muted AD pathology typifies the Lewy body variant of AD, and it serves to segregate it from pure Lewy body disease. We endorse the semiquantitative neuritic-plaque based criteria from CERAD for routine diagnosis, and Braak staging with descriptive profiling of AD lesions in a research context.

An immunohistochemical quantification of fibrous astrocytes in the aging human cerebral cortex.

In order to determine whether cortical fibrous astrocytes increase with age, we studied 25 patients ranging in age from 24 to 100 years with no clinical or pathological evidence of dementia or other cerebral disorder. Paraffin sections of mid-frontal cortex were obtained and stained with the avidin-biotin immunolabeling procedure for glial intermediate filament protein. The resulting immunolabeled fibrous astrocytes were then counted in the molecular and cellular (cortical laminae 2-6) layers. Populations of fibrous astrocytes in both layers varied widely among individuals, and in the molecular layer their numbers were not significantly correlated with advancing age. In the cellular layer, however, despite widely ranging cell counts among individuals within the same decades of life, there was a significant linear increase with age. Our data suggest that the increase occurs or accelerates significantly after age 70, but the case numbers preclude reaching such a conclusion with statistical confidence. However, when the patients are divided into those less than 70 and those older, fibrous astrocytes in the cellular layer are shown to be significantly increased in the latter group compared to the former.

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients.

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Item scores from the Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination (MMSE) from 389 patients with probable Alzheimer's disease were submitted to principal component analysis with orthogonal rotation. The optimal solution identified four factors that reflected the cognitive domains of attention/registration, verbal fluency/reasoning, graphomotor/praxis and recent memory. A subgroup of patients was identified for whom both the MDRS and the MMSE had been administered within the 12 months before death. Scores were assigned to these patients for the four factors. These cognitive-domain scores were then correlated with postmortem choline acetyltransferase (ChAT) activity in the medial frontal cortex, inferior parietal cortex, and hippocampus. ChAT activity in both the medial frontal and the inferior parietal cortex significantly correlated with scores on the graphomotor/praxis factor. Medial frontal ChAT also correlated significantly with the attention/registration scores. Hippocampal ChAT correlated significantly only with recent memory scores. These results are consistent with current animal research regarding the effect of selective cholinergic lesions on behavior.

Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension.

OBJECTIVE: To determine if severe cerebral amyloid angiopathy (AA) in patients with Alzheimer's disease (AD) is associated with an increased prevalence of cerebral infarction diagnosed at autopsy. Amyloid angiopathy is increasingly recognized as a cause of ischemic infarcts, as well as cerebral hemorrhages. However, the relationship of AA to cerebral infarction in patients with AD is uncertain. DESIGN: Retrospective clinicopathological study of autopsy-confirmed cases of AD. PATIENTS: One hundred forty-five deceased patients with AD confirmed at autopsy. MAIN OUTCOME MEASURES: Semiquantitative scores of AA severity were done in four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. The finding of cerebral infarction at autopsy was modeled as a function of AA severity, hypertension, age at death, AD severity, and sex in chi 2 and multiple logistic regression analyses. RESULTS: Severe AA was significantly associated with cerebral infarction at autopsy in patients with AD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.4 to 8.9). None of the other independent variables in the multiple logistic regression analysis were significant predictors. While hypertension was equally common in the severe and mild AA subgroups, the combination of both severe AA and hypertension interacted to increase the risk of infarction (OR, 14.2; 95% CI, 3.2 to 63.4) beyond that observed with hypertension (OR, 1.1; 95% CI, 0.4 to 3.2) or severe AA (OR, 1.3; 95% CI, 0.3 to 5.3) alone. CONCLUSIONS: Severe AA is associated with an increased frequency of cerebral infarction in patients with AD. This appears to be largely due to an interaction between severe AA and hypertension that may produce multiplicative injuries on the vasculature. Further study with regard as to how AA may cause ischemia and its role in the neuropathologic and clinical progression of AD is needed.