Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

Abnormal semantic processing in females with fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, affects fragile X (FMR1) gene premutation carriers in late life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. Sixty-one females (34 FXTAS, Mage = 62.7; 27 controls, Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated approximately 10-140 seconds later. N400 and P600 amplitude data were submitted to analysis of covariance. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. Event-related potential analyses showed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.

Patients with MCI and N400 or P600 abnormalities are at very high risk for conversion to dementia.

OBJECTIVE: We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI). BACKGROUND: Two ERP components, the P600 and N400, are sensitive to abnormal episodic/declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity. METHODS: Patients with amnestic MCI (n = 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD converters (within 3 years) vs nonconverters, using split-plot analyses of variance. RESULTS: A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F = 9.9, p = 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood. CONCLUSIONS: Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.

Anosmia is very common in the Lewy body variant of Alzheimer's disease.

BACKGROUND: Olfactory abnormalities are reported in Alzheimer's disease and Parkinson's disease. Anosmia appears to be common in dementia with Lewy bodies but not in pure Alzheimer's disease. OBJECTIVE: To determine whether anosmia improves discrimination between the Lewy body variant (LBV) of Alzheimer's disease and "pure" Alzheimer's disease. METHODS: 106 cases of necropsy confirmed pure Alzheimer's disease (n = 89) or LBV (n = 17) were reviewed. All had received butanol odour threshold testing. Anosmia was defined as a score < or = 1.0 on a 0-9 point scale. Logistic regression analysis was used to model potential predictors (for example, parkinsonism, smoking, hallucinations) of neuropathological diagnosis and anosmia. RESULTS: LBV cases had an increased prevalence of anosmia (65%) compared with Alzheimer's disease (23%; odds ratio (OR) = 6.3, p = 0.00045), or normal elderly people (6.7%). Within the dementia cases, the negative predictive value (92%) and specificity (78%) of anosmia were both good; sensitivity for detecting LBV was 65%, but the positive predictive value (PPV) was only 35%. Logistic regression models showed anosmia (OR = 5.4, p = 0.005) and visual hallucinations (OR = 7.3, p = 0.007) were strong independent predictors of Lewy body pathology. When anosmia was added as a core feature to consensus diagnostic criteria for probable Lewy body dementia, five additional cases of LBV were detected (29% increased sensitivity), but with four additional false positives (1% increased discrimination, 4% decreased specificity, 33% decreased PPV). CONCLUSIONS: Anosmia is very common in LBV. Adding anosmia as a core feature improved sensitivity for detecting LBV, but did not improve discrimination between Alzheimer's disease and LBV owing to a concomitant increase in false positives.

Abnormal verbal event related potentials in mild cognitive impairment and incipient Alzheimer's disease.

BACKGROUND: It has been reported that patients with amnesia have a reduced effect of word repetition upon the late positive component of the event related potential (ERP), which peaks at around 600 ms after word onset. OBJECTIVE: To study a word repetition ERP paradigm in subjects with mild cognitive impairment. SUBJECTS: 14 patients with mild cognitive impairment (mean mini-mental state examination score = 27); 14 normal elderly controls. METHODS: Auditory category statements were each followed by a single visual target word (50% "congruous" category exemplars, 50% "incongruous") while ERPs were recorded. N400 (an ERP component elicited by semantically "incongruous" words) and LPC amplitude data were submitted to analysis of variance. RESULTS: The latency of the N400 was slower in mild cognitive impairment. In normal controls, the ERPs to "congruous" targets showed a late positive component to new words, which was greatly diminished with repetition. This repetition effect in normal subjects started before 300 ms at right frontal sites, and peaked at approximately 600 ms post-stimulus over posterior sites. In contrast, the group with mild cognitive impairment had a reduced repetition effect (p < 0.02), which started around 500 ms, with a more central distribution. Further comparisons within the cognitive impairment group showed no appreciable congruous word repetition effect among seven individuals who subsequently converted to probable Alzheimer's disease. The congruous word repetition effect in the group with mild cognitive impairment was almost entirely accounted for by the non-converters. The amplitude of the congruous late positive component word repetition effect was significantly correlated (0.38 < or = r < or = 0.73) with several verbal memory measures. CONCLUSIONS: The congruous word repetition ERP effect appears sensitive to the memory impairment in mild cognitive impairment and could have value in predicting incipient Alzheimer's disease.

Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease.

OBJECTIVE: To determine the relation between concomitant small cerebral infarction and clinical progression of Alzheimer disease (AD). DESIGN: A retrospective clinicopathologic study of patients with AD. METHODS: We searched the databases of the University of California, San Diego, Alzheimer's Disease Research Center, La Jolla, for patients with an autopsy diagnosis of definite AD with or without a concomitant small cerebral infarction. Clinical and neuropsychologic data obtained during longitudinal follow-up were available for 201 subjects with AD neuropathologic features and 36 with AD and concomitant cerebral infarcts (volume, < 10 cm(3)). The rates of cognitive decline on the Mini-Mental State Examination and the Dementia Rating Scale were each calculated and compared between the 2 groups. RESULTS: The age at death was significantly (P = .05) higher and the Braak stage was lower in patients with mixed AD and infarct pathological features compared with those with AD pathological features only. The rate of cognitive decline over time was not significantly (P > or = .20 for all) different between the 2 groups. There was a trend for the presence of a cerebral infarct to be associated with more severe clinical dementia (P =.08) as measured by the Dementia Rating Scale, but no such trend for the Mini-Mental State Examination. CONCLUSION: This clinicopathologic correlation study suggests that concomitant small cerebral infarcts with a total volume of less than 10 cm(3) do not significantly influence the overall rate of global cognitive decline in patients with AD. Arch Neurol. 2000;57:1474-1479

Word repetition in amnesia. Electrophysiological measures of impaired and spared memory.

Amnesic patients often show improved performance when stimuli are repeated, even in the absence of conscious memory for those stimuli. Although these performance changes are typically attributed to perceptual or motor systems, in some cases they may be related to basic language processing. We examined two neurophysiological measures that vary with word repetition in 12 amnesic patients and 12 control subjects: (i) a late positive component of the event-related potential (ERP) linked to conscious memory and (ii) the N400 component that varies with language comprehension. In each trial, the subject heard a category name, then viewed a word, and then decided whether the word was semantically congruous or incongruous (e.g. 'yes' for 'baby animal: cub'; 'no' for 'water sport: kitchen'). Recall and recognition testing at the end of the experiment showed that control subjects had better memory for congruous than for incongruous words, as did the amnesic patients, who performed less well overall. In contrast, amnesic patients were unimpaired on the category decisions required in each trial and, like the control subjects, showed a large N400 for incongruous relative to congruous words. Similarly, when incongruous trials were repeated after 0-13 intervening trials, N400s were reduced in both groups. When congruous trials were repeated, a late positive repetition effect was observed, but only in the control group. Furthermore, the amplitude of the late positive repetition effect was highly correlated with later word recall in both patients and controls. In the patients, the correlation was also observed with memory scores from standardized neuropsychological tests. These data are consistent with a proposed link between the late positive repetition effect and conscious memory. On the other hand, the N400 repetition effect was not correlated with episodic memory abilities, but instead indexed an aspect of memory that was intact in the amnesic patients. The preserved N400 repetition effect is an example of preserved memory in amnesia that does not easily fit into the categories of low-level perceptual processing or of motor learning. Instead, the sensitivity of the N400 to both semantic context and repetition may reflect a short-term memory process that serves language comprehension in realtime.

Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4.

BACKGROUND: We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebrovascular lesions in Alzheimer disease (AD), which is particularly strong for microinfarcts, hemorrhages, and multiple lesion types. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis. OBJECTIVE: To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype. METHODS: We reviewed 306 cases of autopsy-confirmed AD (from the University of California, San Diego, brain autopsy series) to assess whether APOE genotype and other clinical risk factors were predictive of vascular lesions (VLs) in AD. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) and an average score was computed for each case. RESULTS: We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02). While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs. Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. Within strata of APOE genotype, the presence of severe CAA was associated with increased frequency of VLs (eg, within APOE4/4 homozygotes, VLs were present within 47% of the cases of severe CAA vs 9.5% of the cases of mild or absent CAA; P=.01). CONCLUSIONS: Severe CAA confers a greater risk of VLs in AD, even within strata of APOE genotype. Therefore, the association between severe CAA and VLs in AD is not a spurious one owing to APOE4. Overall, our cases of AD with APOE4 do not seem to be a more "vasculopathic" subtype of AD. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these are probably important in producing the common entity of "mixed" AD/vascular dementia. Arch Neurol. 2000.

Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer's disease.

In this brief review, we aim to describe the complex relationship between cerebral amyloid angiopathy (CAA), apolipoprotein E (ApoE), and cerebrovascular lesions in Alzheimer's disease (AD). First, we review the evidence that CAA is associated with, and may cause, specific types of vascular lesions (VLs). In addition to being a leading cause of lobar hemorrhages in the elderly, CAA has been implicated as a likely cause of small infarcts, microinfarcts, and incomplete infarctions in the deep white matter. We also review the role that ApoE4 (the major genetic risk factor for AD) has in predisposing toward CAA, coronary artery disease, and possibly toward cerebrovascular disease. Last, we provide evidence that the association between CAA and VLs is not a spurious one due to an increase in the ApoE4 genotype. Even within patient groups with the same ApoE genotype (specifically, E4/4 homozygotes and E3/3 homozygotes), our recent analyses have found significant increases in VLs in association with severe CAA. We discuss the implications of this finding as advancing a pathogenic role for severe CAA in producing many of the VLs commonly found in AD cases.

Relationship between auditory P300 amplitude and age of onset of schizophrenia in older patients.

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.

Cognitive decline is faster in Lewy body variant than in Alzheimer's disease.

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.

N400 abnormalities in late life schizophrenia and related psychoses.

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.

The impact of apolipoprotein E4 on cause of death in Alzheimer's disease.

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.

Lack of clinically significant gross structural abnormalities in MRIs of older patients with schizophrenia and related psychoses.

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.

The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant.

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.

Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV.

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.

Neurological Symptoms, Not Signs,Are Common in Early HIV Infection.

UNLABELLED: 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).

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.