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.
OBJECTIVE: To determine the relationship between apolipoprotein E (apoE) genotype and neuropathologic lesions in Alzheimer’s disease (AD) and Lewy body variant (LBV). DESIGN: Retrospective genetic-neuropathologic study of AD and LBV cases. The main neuropathologic outcome measures were modeled as a function of apoE genotype, neuropathologic diagnosis, and gender. Age at death and duration of symptom effects were controlled for by ANCOVA. PATIENTS: One hundred twenty-seven cases with neuropathologically diagnosed AD (n = 84) or LBV (n = 43). MAIN OUTCOME MEASURES: Quantitative scores of neuritic plaques (NPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA) severity, and CAA prevalence were averaged across four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. RESULTS: The apoE epsilon 4 allele was associated with increased NPs within both AD and LBV. The epsilon 4 allele was associated with an increased frequency of CAA in the AD and LBV groups combined groups combined and in and in LBV alone. While CAA severity and NETs were increased in the epsilon 4/4 homozygous case when AD and LBV were combined, there were no significant effects within AD or LBV alone. CONCLUSIONS: The apoE epsilon 4 allele is strongly associated with increased NPs, but not neocortical NFTs, in both AD and LBV.
Objective. To examine the cross-sectional prevalence of neurological symptoms and signs in a large cohort of human immunodeficiency virus (HIV)-seropositive men, and determine the relationship of the symptoms to disease stage, immunologic markers, and independent variables from neuropsychological (NP) testing and psychiatric interview. Methods: One hundred-nine controls and 386 HIV-infected volunteers enrolled in the HIV Neurobehavioral Research Center (HNRC) longitudinal study. The majority, without acquired immune deficiency syndrome (AIDS), were screened for alcohol/substance abuse; previous diagnosis of HIV-associated dementia; and HIV-unrelated developmental, neurological, medical, and neurobehavioral conditions which potentially impair cognition; and underwent a structured neurological interview and examination, standardized NP testing, and psychiatric interview as part of a more extensive battery. A large subset (N = 377) underwent lumbar puncture for cerebrospinal fluid (CFS) examination. We examined the relationship of sixteen select but independent variables, using stepwise multiple regressions, from demographic/staging, immunological, NP, and psychiatric domains to neurological symptoms in an effort to identify possible predictors of subclinical nervous systems involvement. Results. All categories of neurological symptoms were significantly more prevalent among medically asymptomatic (CDC stage A) subjects than controls, with a further rise in prevalence in those with more advanced stages of infection. The most marked rise was seen in cognitive and sensorimotor complaints. In contrast, significant findings on neurological examination were evident in only the sicker (stage C) subjects. Stage of illness, serum β2-microglobulin, psychiatric indices of depressed mood or anxiety, and NP “motor” performance were the most significant independent variables associated with the presence of neurological symptoms. CSF pleocytosis was seen early (CDC stage A), and may reflect the presence of HIV in the central nervous system (CNS) at the least stages of infection. We also confirmed the value of CSF β2m and neopterin as important markers of advancing disease stage. Whether they predict subclinical CNS involvement is to be determined by longitudinal observations. Conclusion. Neurological complains are common in medically asymptomatic HIV subjects whereas signs are not. The symptoms correlate with commonly determined independent measures of depression, anxiety, NP tests of fine motor speed and strength, as well as indices of disease worsening (CDC stage, serum β2m).
We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2) High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD.
The authors examined the reports of MRI brain studies of 69 patients with DSM-III-R-diagnosed psychotic disorders (30 early-onset and 24 late-onset schizophrenia patients and 15 with other psychoses) and 41 normal comparison subjects. Participants’ ages ranged from 45 to 87 years. A qualitative rating scheme determined type and severity of clinically detectable abnormalities, including volume loss, infarcts, lacunae, and white matter hyperintensities. In this clinically well-characterized sample, the vast majority of the MRIs were within normal limits. There were no significant differences between psychosis patients and normal comparison subjects or between early-onset and late-onset schizophrenia patients in frequency, type, or severity of gross structural abnormalities. The results indicate that late-onset schizophrenia and related disorders can exist without clinically significant gross structural abnormalities in the brain.
OBJECTIVE: We tested the hypothesis that the apolipoprotein E epsilon 4 (apoE4) allele is associated with an increased proportion of vascular-related mortality in Alzheimer’s disease (AD). BACKGROUND: ApoE4 is associated with an increased risk of developing AD, with an earlier onset, and may predispose to vascular dementia as well. In the general population, apoE4 has been associated with increased coronary artery disease and shorter lifespan. There is a paucity of data regarding the effect of the apolipoprotein E (apoE) genotype upon the contributing causes of death in AD. METHODS: Death certificates of 114 AD cases were reviewed blind to apoE genotype. Deaths due to ischemic heart disease (IHD), cerebrovascular disease (CVD), vascular disease (either IHD or CVD), pneumonia, and other causes were analyzed as a function of apoE genotype. Logistic regression analyses were employed to control for age and gender effects. RESULTS: The likelihood of vascular disease contributing to death increased in association with the epsilon 4 allele (29% in cases without an epsilon 4 allele, 43% in cases with one epsilon 4 allele, 53% in epsilon 4/4 homozygous cases; p = 0.035 after corrections for age and gender). This increase appeared largely due to an increase in ischemic heart disease, which was reported more frequently on death certificates of cases with one or more epsilon 4 allele (adjusted odds ratio [OR] = 1.85 per epsilon 4 allele; p < 0.05). There were nonsignificant trends for apoE4 to be associated with increased mortality related to cerebrovascular disease (OR = 1.45) and decreased mortality related to pneumonia (OR = 0.77) and AD itself (OR = 0.72). The epsilon 4/4 cases had significantly earlier age of onset (mean = 64.5 yr), earlier death, and longer duration of disease (mean = 10.1 yr). Cases with one or more epsilon 4 allele tended to have lower mean MMSE scores prior to death (6.6 versus 9.5) and were more often female (54% versus 45%). CONCLUSIONS: The apoE4 allele appears to increase the risk of vascular and ischemic heart disease-related death in patients with AD.
The N400, an event-related brain potential (ERP) sensitive to semantic congruity, has been reported to have increased latency and/or reduced amplitude in young adults with schizophrenia. Little is known, however, regarding the N400 in older schizophrenia patients, especially those with late onset. We studied 18 middle-aged and elderly patients with schizophrenia and related psychoses (nine with early-onset psychosis (EOP) and nine with late-onset psychosis (LOP)), and nine normal comparison (NC) subjects. Subjects read words which were semantically incongruent (50%) or congruent (50%) with a preceding spoken phrase which defined either an antonymic or categorical relationship. The LOP group had a significantly later peak latency of the N400 congruity effect compared to the NC group. Seven of 18 psychosis patients, but none (0/9) of the normal subjects, had an abnormal latency or amplitude (p = 0.04), measured at T6 (right temporal). Smaller amplitudes were associated with more severe negative symptoms (rp = 0.58; p = 0.01). N400 abnormalities in older schizophrenia patients likely reflect abnormal processing of semantic information.
Auditory P300 amplitude reductions are well-established in young adults with schizophrenia. Little is known, however, regarding the P300 in older schizophrenia patients, especially those with late onset. We studied 28 middle-aged and elderly (mean age = 62.7 years) patients [14 with early onset schizophrenia (EOS) and 14 with late onset schizophrenia (LOS)] and 14 normal comparison (NC) participants using an auditory oddball paradigm. Event-related potentials were recorded from 15 scalp electrodes and six non-scalp sites. There were no significant differences between EOS and LOS groups in neuroleptic dosage, symptom severity, reaction times, target-detection accuracy, or N100 and N200 ERP measures. The EOS, but not the LOS, group had significantly smaller auditory oddball P300 amplitudes than the NC group. Twelve of the 14 LOS patients had P300 amplitudes in the normal range. Smaller P300 amplitudes were associated with earlier age of onset (r = 0.48), longer duration of illness (r = -0.49) and more severe alogia (r = -0.50). We conclude that P300 abnormalities in schizophrenia may be a marker for a disease subtype with early onset and more severe information-processing deficits.
OBJECTIVES: To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer’s disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD. BACKGROUND: Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases. METHODS: We searched the databases of the University of California-San Diego Alzheimer’s Disease Research Center and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE — final MMSE. Methods were devised to reduce floor effects on the MMSE. RESULTS: The average rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0 points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3 +/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11). CONCLUSIONS: This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.
Prominent psychotic symptoms, particularly hallucinations and delusions, have been estimated to occur in approximately 60% of patients with dementia with Lewy bodies (DLB). Many of these individuals experience psychotic symptoms before the onset of other features characteristic of DLB. To facilitate consistent diagnosis of DLB, an international consortium recently created consensus guidelines for the clinical and pathological diagnosis of this disease. Accurate diagnosis of DLB is particularly important as these patients may have greater neuroleptic sensitivity than other elderly patients. Currently there is no verified treatment specifically for psychotic symptoms in DLB. However, if neuroleptic treatment cannot be avoided, low doses of atypical antipsychotics may prove beneficial, while minimizing anticholinergic and extrapyramidal side effects.