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We have developed an agar-embedding method for brain-slicing that minimizes the geometrical distortions which arise from handling and slicing the fixed postmortem brain. To facilitate postmortem brain-magnetic resonance imaging (MRI) co-registration, each hemisphere is processed separately. We embed the fixed brain hemisphere with reference markers in agar. The block containing the brain and markers is sliced at a fixed interval using a rotary slicer. Each slice is photographed with a high-resolution digital camera. The digital images are realigned as a 3-dimensional volume via a control point-based registration method for multi-slice registration. The realigned multiple slices of the reconstructed postmortem hemisphere are then co-registered to corresponding slices of an in vivo reference MRI-volume. We illustrate these postmortem MRI-brain co-registration methods to correlate in vivo T2-weighted MRI hyperintensities in gray and white matter with underlying pathology. For design-based stereology, the volume of interest (VOI) is defined using reproducible anatomical boundaries. This method is suitable for stereologic measures of structures ranging from defined nuclei to whole brain.

The goal of this study was to examine the relationship between subcortical vascular disease and brain atrophy in patients with Alzheimer's disease (AD) and mixed dementia (i.e., AD and subcortical vascular disease together). MRI was performed on 77 cognitively normal (CN) subjects, 50 AD and 13 mixed dementia patients. Subcortical vascular disease was determined by white matter hyperintensities (WMH) volume and presence of subcortical lacunes. Brain atrophy was measured using total brain cortical gray matter (CGM), entorhinal cortex (ERC) and hippocampal volumes. CGM volume, but not ERC or hippocampal volume was inversely related to WMH volume in patients and controls. In contrast, no relationship was detected between CGM, ERC, or hippocampal volumes and subcortical lacunes. Furthermore, no interaction was found between WMH and diagnosis on cortical atrophy, implying that WMH affect cortical atrophy indifferently of group. These results suggest that subcortical vascular disease, manifested as WMH, may affect cortical atrophy more than ERC and hippocampal atrophy. Further, AD pathology and subcortical vascular disease may independently affect cortical atrophy.

1) To determine the regional pattern of reduced N-acetylaspartate (NAA) in subcortical ischemic vascular dementia (SIVD); 2) to explore the relationship between NAA reduction and subcortical vascular disease; and 3) to test if MR spectroscopic imaging (MRSI) in combination with structural MRI improves differentiation between SIVD and Alzheimer disease (AD).Thirteen patients with SIVD (71 +/- 8 years old) and 43 patients with AD of comparable age and dementia severity were studied using MRSI and MRI. Patients were compared to 52 cognitively normal subjects with and without lacunes.Compared to controls, patients with SIVD had lower NAA by 18% (p0.001) in frontal cortex and by 27% (p0.003) in parietal cortex, but no significant NAA reduction in white matter and medial temporal lobe. Compared to patients with AD, patients with SIVD had lower NAA by 13% (p0.02) in frontal cortex and by 20% (p0.002) in left parietal cortex. Cortical NAA decreased in SIVD with increasing white matter lesions (r = 0.54, p0.02) and number of lacunes (r = 0.59, p0.02). Thalamic lacunes were associated with greater NAA reduction in frontal cortex than were lacunes outside the thalamus (p0.02) across groups, after adjusting for cognitive impairments. Adding parietal NAA to MRI-derived hippocampal atrophy improved separation between SIVD and AD (p = 0.02) from 79 to 89%.These results emphasize the importance of cortical dysfunction as a factor in SIVD and indicate a characteristic pattern of metabolite change that might serve as a basis for improved diagnosis.

Summary Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswanger's disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections. Brain imaging (computed tomography and magnetic resonance imaging) is essential for correct diagnosis. The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) and some forms of cerebral amyloid angiopathy have a genetic basis. Treatment is symptomatic and prevention requires control of treatable risk factors.

This study tested the hypothesis that the hippocampus has a relatively specific role in retaining information over delays. Thirty-seven subjects with probable Alzheimer's disease were evaluated with a verbal memory task and structural MRI. Cortical gray matter but not hippocampal volume predicted immediate free recall. In contrast, hippocampal volume was the best predictor of how well information was retained over a delay, even after controlling for levels of immediate recall. Results suggest that the role of the hippocampus is relatively specific to the consolidation of new memories. (JINS, 2004, 10, 639–643.)

Background Depression symptoms may be associated with the development of Alzheimer disease (AD). Objectives To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. Setting Academic institutions with specialized memory clinics. Design Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. Participants A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. Main Outcome Measures Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. Results There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82). Conclusions Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Purpose: The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (ERC), and whole brain longitudinal change in cognitively normal elderly controls (C), non-demented subjects with cognitive impairment (CI), and demented (D) subjects. Methods: 16 C, 6 CI, and 7 D subjects of comparable age were studied with MRI twice, at least 1 year apart. Longitudinal change in total brain size was measured by several methods, including computerized segmentation, non-linear warping, and change in the fluid/tissue boundaries between cerebrospinal fluid (CSF) and brain. Change in hippocampal volume was measured by semi-automated methods, and ERC volumes were manually measured. Results: The annual rate of atrophy was greater in D versus C and D versus CI for cortical gray matter (cGM) (P=0.009 and 0.002), hippocampus (P=0.0001 and 0.002), and for the change in the fluid/tissue boundary (P=0.03 and 0.03). The annual rate of atrophy of ERC was greater in both CI and D versus C (P=0.01 and 0.0002). No significant differences between groups were found using non-linear warping. Conclusions: In CI, the greatest annual rates of atrophy were in ERC, while in D the greatest annual rates of atrophy were in hippocampus and cortex. Progressive ERC atrophy was observed with a greater degree of cognitive impairment, while hippocampal and cortical atrophy were only observed in demented subjects.

Alzheimer disease (AD) and Parkinson disease (PD) are associated with neuronal degeneration in major subcortical nuclei, but few studies have examined the neuronal degeneration in these nuclei concurrently.To identify clinical and pathological correlates of neuronal loss in the nucleus basalis (NB), locus coeruleus (LC), and substantia nigra pars compacta (SN) in AD and PD.The study sample comprised 86 cases with pathologically confirmed AD, 19 cases with PD, and 13 healthy elderly control subjects. The number of nucleolated neurons was counted in representative sections of the NB, LC, and SN. Effect sizes (ES) were computed to determine the standardized difference in cell counts relative to healthy controls.Cases of AD showed the greatest neuronal loss in the LC (ES = 3.16) followed by the NB (ES = 1.10), but variable loss in the SN (ES = 0.16). Cases of PD also showed the greatest neuronal loss in the LC (ES = 6.47), followed by the SN (ES = 2.58) and the NB (ES = 0.85). Significant correlations were found between the number of neurons in the NB and LC in PD (r = 0.54, P.05), as well as AD (r = 0.24, P.05). The duration of illness correlated with greater neuronal loss in the LC and NB in AD, and greater neuronal loss in the SN in PD.For both AD and PD the greatest neuronal loss was found in the LC. In AD, neuronal loss was most severe and best correlated with the duration of illness in the LC, rather than in NB as traditionally expected. Correlations between neuronal loss in the LC and NB (but not SN) in both PD and AD suggest that the former 2 nuclei may share common pathogenetic susceptibilities. Given the prominent loss of neurons in the LC, detection and treatment of noradrenergic deficiencies warrant attention in both AD and PD.

Objectives: To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects.Methods: Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 ± 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images.Results: Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 ± 4.3%/year for AD vs 1.4 ± 2.5%/year for CN [F1,42 = 25.6, p < 0.001]; right: 6.3 ± 3.3%/year for AD vs 1.4 ± 2.3%/year for CN [F1,42 = 25.6, p < 0.001]). Furthermore, increased ERC atrophy rate was correlated (r = −0.56, p = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (p < 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: r = −0.53, p < 0.01; right: r = −0.42, p < 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (p < 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (p < 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93.Conclusion: ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

A new strategy to register each slice of the postmortem brain to anatomically corresponding in-vivo MRI slices is presented. The approach relies on a recursive reslicing of the FVIRI volume using non-linear polynomial transformations. Simulation studies to validate the approach and results using real data are presented. The results suggest the feasibility and practicability of second- and third-order polynomials to register postmortem images on a slice-by-slice basis to corresponding MRI sections. Using this method, it is possible to investigate the pathology of a disease through routinely acquired MRIs and postmortem brain images.

To determine the effects of subcortical ischemic vascular dementia (SIVD) and AD on entorhinal cortex (ERC) and hippocampus.Thirty-eight cognitively normal subjects, 18 patients with SIVD, and 22 patients with AD were included. Volumes of ERC and hippocampus were manually measured based on MRI. Global cerebral changes of cortical gray matter, subcortical gray matter, white matter, sulcal CSF, ventricular CSF (vCSF), and white matter signal hyperintensities (WMSH) were assessed.Patients with SIVD had 21.7% (p0.01) smaller ERC and 18.2% (p0.01) smaller hippocampi than cognitively normal subjects and 24.4% (p0.01) larger ERC and 11.1% (p0.05) larger hippocampi than patients with AD. In addition, patients with SIVD had less cortical gray matter and white matter and more vCSF and WMSH (all p0.01) than cognitively normal subjects and more vCSF and WMSH (p0.01) than patients with AD. The volumes of ERC and hippocampus were positively correlated to similar extents (p0.01) in SIVD and AD. Cortical gray matter loss was positively correlated (p0.01) with hippocampal atrophy, but not with ERC atrophy, in SIVD and AD. Hippocampal volume alone could classify 82% of patients with SIVD from cognitively normal subjects and 63% of patients with SIVD from subjects with AD. Adding global cerebral changes to hippocampus substantially improved the classification to 96% between patients with SIVD and cognitively normal subjects and 83% between subjects with SIVD and those with AD, whereas adding ERC change to hippocampus did not significantly improve the discrimination.The entorhinal cortex and hippocampus are less affected by subcortical ischemic vascular dementia than by AD.

Background: Causes of cognitive impairment in subcortical ischemic vascular disease (SIVD) are less well understood than in AD, but have been thought to result from direct effects of subcortical lacunes and white matter lesions, perhaps related to disruption of important cortical–subcortical pathways. Objective: To examine the relation between cognitive abilities and quantitative MRI measures of subcortical cerebrovascular disease and cortical and hippocampal atrophy. Methods: Subjects were 157 participants in a multicenter study of SIVD and AD who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunar infarcts. Dependent variables were neuropsychological tests of global cognitive function, memory, language, and executive function. Independent variables were quantitative MRI measures of volume of lacunar infarcts in specific subcortical structures, volume of white matter lesion (WML), volume of cortical gray matter (cGM), and total hippocampal volume (HV). Multiple regression analyses were used to identify MRI predictors of cognition. Results: Subcortical lacunes were not related to cognitive measures independent of effects of other MRI variables. WML was independently related to selected, timed measures. HV and cGM were strong and independent predictors of cognitive variables, with effects that did not differ in subjects with and without subcortical lacunes. Conclusions: Results suggest that cognitive impairment associated with subcortical ischemic vascular disease is primarily a result of associated hippocampal and cortical changes.

Importance Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. Objectives To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. Design, Setting, and Participants The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance–weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. Main Outcomes and Measures Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. Results Analysis confirmed the association of APOE with earlier AAO ( P = 3.3 × 10 −96 ), with associations in CR1 (rs6701713, P = 7.2 × 10 −4 ), BIN1 (rs7561528, P = 4.8 × 10 −4 ), and PICALM (rs561655, P = 2.2 × 10 −3 ) reaching statistical significance ( P APOE contributes to 3.7% of the variation in AAO ( R2 = 0.256) over baseline ( R2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation ( R2 = 0.242). Conclusions and Relevance We confirmed an association of APOE (OMIM107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO . In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Importance Because deposition of cerebral β-amyloid (Aβ) seems to be a key initiating event in Alzheimer disease (AD), factors associated with increased deposition are of great interest. Whether elevated serum cholesterol levels act as such a factor is unknown. Objective To investigate the association between serum cholesterol levels and cerebral Aβ during life early in the AD process. Design, Setting, and Participants A multisite, university medical center–based, cross-sectional analysis of potential associations between contemporaneously assayed total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cerebral Aβ, measured with carbon C11–labeled Pittsburgh Compound B (PIB) positron emission tomography. Seventy-four persons (mean age, 78 years) were recruited via direct outreach in stroke clinics and community senior facilities following a protocol designed to obtain a cohort enriched for cerebrovascular disease and elevated vascular risk. Three patients had mild dementia. All others were clinically normal (n = 33) or had mild cognitive impairment (n = 38). Results Cerebral Aβ was quantified using a Global PIB Index, which averages PIB retention in cortical areas prone to amyloidosis. Statistical models that controlled for age and the apolipoprotein E e4 allele revealed independent associations among the levels of LDL-C, HDL-C, and PIB index. Higher LDL-C and lower HDL-C levels were both associated with a higher PIB index. No association was found between the total cholesterol level and PIB index. No association was found between statin use and PIB index, and controlling for cholesterol treatment in the statistical models did not alter the basic findings. Conclusions and Relevance Elevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease. This finding, in living humans, is consistent with prior autopsy reports, epidemiologic findings, and animal and in vitro work, suggesting an important role for cholesterol in Aβ processing. Because cholesterol levels are modifiable, understanding their link to Aβ deposition could potentially and eventually have an effect on retarding the pathologic cascade of AD. These findings suggest that understanding the mechanisms through which serum lipids modulate Aβ could offer new approaches to slowing Aβ deposition and thus to reducing the incidence of AD.

Background Alzheimer disease (AD) and vascular dementia are among the most frequently occurring causes of dementia in the world, and their accurate differentiation is important because different pharmaceutical strategies may modify the course of each disease. Objective To determine which of 10 neuropsychological test scores can accurately differentiate patients with probable AD from those with subcortical ischemic vascular dementia (SIVD) for use in evidence-based clinical practice. Design Patients with suspected dementia were referred to the study by family physicians, geriatricians, and neurologists. All participants received a thorough assessment according to standard diagnostic guidelines. Diagnoses of probable AD (n = 31) and probable SIVD (n = 31) were made according to consensus criteria. The diagnosticians were blind to the results of the 10 neuropsychological test scores. Results There were no significant differences between the groups in age or Mini-Mental State Examination scores. Logistic regression analyses identified 2 neuropsychological tests that best distinguished the groups (sensitivity = 81%; specificity = 84%; positive likelihood ratio = 5.1). These were the recognition memory subtest of the Rey Auditory Verbal Learning Test and the Controlled Oral Word Association Test. The AD group performed better on the oral association test, whereas the SIVD group did better on the recognition memory test. Conclusion Patients with probable AD and probable SIVD can be distinguished with a high degree of accuracy using these 2 neuropsychological tests.

Objectives—To explore volume changes of the entorhinal cortex (ERC) and hippocampus in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) compared with normal cognition (NC); to determine the powers of the ERC and the hippocampus for discrimination between these groups. Methods—This study included 40 subjects with NC, 36 patients with MCI, and 29 patients with AD. Volumes of the ERC and hippocampus were manually measured based on coronal T1 weighted MR images. Global cerebral changes were assessed using semiautomatic image segmentation. Results—Both ERC and hippocampal volumes were reduced in MCI (ERC 13%, hippocampus 11%, p

Vascular dementia (VaD) incorporate different vascular mechanisms and changes in the brain, and have different causes and clinical manifestations. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current clinical definitions of VaD have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Thus current criteria for VaD select an etiologically and clinically heterogeneous group. This definitional heterogeneity may have been a factor in “negative” clinical trials. An alternative for clinical drug trials is to focus on a more homogenous group, such as those with subcortical (ischemic) VaD. This designation incorporates two small vessel clinical entities “Binswanger’s disease” and “the lacunar state”. It comprises small vessel disease as the primary vascular etiology, lacunar infarct(s) and ischaemic white matter lesions as the primary type of brain lesions, and subcortical location as the primary location of lesions. The subcortical clinical syndrome is the primary clinical manifestation, a definition which still requires additional empirical data. We expect that subcortical VaD show a more predictable clinical picture, natural history, outcome, and treatment responses. We propose a modification of the NINDS-AIREN criteria as a new research criteria for subcortical VaD.

Twenty-six Alzheimer's disease (AD) and 42 healthy control (NC) subjects were evaluated with neuropsychological and apraxia batteries. ADs produced a greater range of error types, but did not differ from NCs in their most frequent error types. Hand sequencing ability contributed significantly to AD praxis with no predictors for NCs. Although groups did not differ in gesture time, the AD group had significantly longer response latencies for periods prior to gesture execution and the effect was prominent for transitive tasks and nondominant hand use. Results illustrate the sensitivity of timing measures in identifying abnormal praxis in early stages of AD.

OBJECTIVES: To identify the percentage of patients with Alzheimer's disease (AD) in a general clinic population who would be provisionally eligible for randomized clinical trials and the extent to which these patients represent the overall clinic-based population. BACKGROUND: Many randomized clinical trials have restricted enrollment criteria that may limit generalizability, i.e., AD patients who fulfill selection criteria for phase III clinical trials may not be representative of other AD patients in clinical settings. DESIGN AND SETTING: Patients diagnosed as probable or possible AD from the nine clinical sites of the State of California's Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) were selected on the basis of their provisionally fulfilling the inclusion and exclusion criteria of two typical AD clinical trials at the time of their first visit (ECG and brain imaging criteria were not available). RESULTS: From a sample of 3470 subjects with possible or probable AD, overall, only 4.4% or 7.9% would have been provisionally eligible for each of two trials. Patients provisionally eligible were younger, relatively underrepresented by women, better educated, wealthier, and more likely to be white than ineligible patients. The major independent demographic predictors for eligibility were (1) income greater than $15,000 per year, (2) male gender, and (3) college education. More than 60% of probable AD patients were excluded because of significant behavioral problems; approximately one-quarter each were excluded because of significant medical or neurological problems. Allowing patients with probable or possible AD to enroll would have resulted in 10.6% being eligible. CONCLUSION: Selection criteria for AD clinical trials result in a demographically and clinically constrained subgroup that is not representative of the overall clinic population. J Am Geriatr Soc 45:923–928, 1997.

We conducted a case-control study of the possible association of occupations with likely exposure to electromagnetic fields and Alzheimer's disease (AD) with patients from the Alzheimer Disease Treatment and Diagnostic Center, Rancho Los Amigos Medical Center, Downey, CA. Patients with definite or probable AD were the case subjects (86 male, 240 female). Patients with cognitive impairment/dementia other than vascular dementia were control subjects (76 male, 76 female). The study was limited to patients who were at least age 65 at the time of their first examination at Rancho Los Amigos. The odds ratio for both sexes combined was adjusted for sex, education, and age at onset. The odds ratio for males was adjusted only for age at onset, and the odds ratio for females was adjusted for both education and age at onset. The adjusted odds ratio for both sexes was 3.93 (p = 0.006), 95% CI = (1.5 to 10.6). For males the adjusted odds ratio was 4.90 (p = 0.01), 95% CI = (1.3 to 7.9), and for females the adjusted odds ratio was 3.40 (p = 0.10), 95% CI = (0.8 to 16.0). These results are consistent with previous findings regarding the hypothesis that electromagnetic field exposure is etiologically associated with the occurrence of AD.

Background Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers (ARBs) may also prevent cognitive decline. Objective To evaluate the impact of treatment with ARBs on the neuropathology of Alzheimer disease (AD) in the National Alzheimer Coordinating Center database, which includes aggregated data and brain autopsies from 29 AD centers throughout the United States. Design Multiple logistic regression was used to compare the pathologic findings in hypertensive subjects taking ARBs with those taking other antihypertensive treatments as well as with hypertensive subjects who did not receive antihypertensive medications. Setting Neuropathologic data included neuritic plaque and neurofibrillary tangle measures and vascular injury markers. Patients Data were collected from participants who were self-referred or provider-referred and included those with and without cognitive disorders. Our sample included only hypertensive participants and excluded cognitively and neuropathologically normal participants (N = 890; mean age at death, 81 years [range, 39-107 years]; 43% women; 94% white). Results Participants with or without AD who were treated with ARBs showed less amyloid deposition markers compared with those treated with other antihypertensive medications (lower Consortium to Establish a Registry of Alzheimer Disease score: odds ratio, 0.47, 95% CI, 0.27-0.81; Alzheimer Disease and Related Disorders Association score: odds ratio, 0.43, 95% CI, 0.21-0.91; Braak and Braak stage: odds ratio, 0.52, 95% CI, 0.31-0.85; neuritic plaques: odds ratio, 0.59, 95% CI, 0.37-0.96). They also had less AD-related pathology compared with untreated hypertensive subjects. Participants who received ARBs were more likely to have had a stroke; hence, they had more frequent pathologic evidence of large vessel infarct and hemorrhage. Conclusion Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs on cognitive decline in those with dementia or AD needs further investigation.

Objective: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). Background: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. Methods: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. Results: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. Conclusions: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.

Approximately 50% of older hypertensive individuals have difficulties in executive function, the cognitive domain that controls complex tasks.1 Hypertensive individuals with executive dysfunction have a high rate of conversion to dementia.2 To date, no study has investigated therapeutic options for executive dysfunction. Recent evidence suggest that the renin angiotensin system plays a central role in linking hypertension to cognitive function offering new therapeutic options for cognitive protection.3 In the brain, angiotensin receptor blockers (ARB) block the type 1 but not type 2 whereas angiotensin converting enzyme inhibitors (ACEI) decrease activation of both receptors. Activating the type 2 receptor may provide cognitive protection.4 We therefore hypothesized that an ARB-based regimen would be superior to other antihypertensive regimens in cognitive protection, especially executive function, and conducted a 12-month double blind randomized clinical trial comparing candesartan, lisinopril, and HCTZ in hypertensives with early executive dysfunction.

Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.

CONVERGING LINES OF EVIdence have implicated 1 member of the vacuolar proteinsorting 10 family—the sortilin-related receptor, low-density lipoprotein receptor class A repeat-containing protein (SORL1) (GenBank 6653)—in the pathogenesis of Alzheimerdisease (AD).1-3 Pathological studies4,5 have documented reduced SORL1 expression in the brains of some patients with AD. Association between the risk of AD and multiple SORL1 single-nucleotide polymorphisms (SNPs) has been demonstrated in several studies3,6-10 that included populations of diverse ethnic background, used various study designs(ie, clinic case-control, family-based, or population-based), and relied on clinical or pathological criteria for AD, whereas the evidence of the association was equivocal in another study.11 One hypothesis for the role of SORL1 in the pathogenesis of AD is that SORL1 modulates subcellular trafficking of the amyloid precursor protein (APP). Reduced expression of SORL1 may lead to routing of APP into compartments where it is cleaved by the presenilin 1 complex to generate the amyloid β peptide.3 The role of SORL1 in APP processing is strongly supported by the fact that SORL1 interacts with endogenous APP holoproteins3,12 but does not bind to APP C-terminal fragments or to other type I membrane proteins.3 The SORL1 protein also belongs to a superfamily of low-density lipoprotein receptors (SorLA/LR11) that bind apolipoprotein E (APOE) and are implicated in cholesterol metabolism13 and atherogenesis.14 Human macrophages exposed to SORL1 have elevated lipid levels, and mice genetically deficient for SORL1 show signs of thickening arteries and macrophage infiltration relative to SORL1 knockout controls. These observations suggest a role for SORL1 in the development of atherosclerosis14 and raise the intriguing possibility that, like APOE and other cholesterol metabolism genes (eg, paraoxonase15), SORL1 may also increase dementia risk through effects on cerebrovascular abnormalities. Indeed, cerebrovascular disease increases the odds of dementia16 and potentially interacts with AD pathologic mechanisms to alter memory.17 Neurodegenerative and cerebrovascular processes can be linked to the known protein structure of SORL1 (Figure). Figure Inferred biochemical basis for the role of the sortilin-related receptor SORL1 in Alzheimer disease and cerebrovascular disease. The SORL1 protein contains several functional domains. The N-terminus region of the protein contains the vacuolar protein ... The possibility of multiple mechanisms of action associated with distinct SORL1 polymorphisms is supported by previous association studies. The SNPs associated with AD are located in 2 regions in SORL1 separated by a mean (SD) of 100 (15) kilobases that contain areas of tight linkage disequilibrium in white and African American subjects.3,18 Associations with SNPs in the region near the 5′ end have been reported in white European subjects, Hispanic subjects from the Dominican Republic, and Israeli-Arab subjects,3,6 whereas SNPs in the region closer to the 3′ end show association in African American, Han Chinese, and some white European and Hispanic subjects.3,6,8,10 Furthermore, associations with a specific 3-SNP haplotype in each of these locations have been replicated in multiple data sets representing several ethnic groups.3,6 These results suggest the existence of AD predisposing variants in different functional domains of SORL1 and thus raise the possibility for variable effects of intragenic polymorphisms on the biochemical properties of SORL1, on its cell-type–specific patterns of expression, or on both. To further elucidate how SORL1 gene variants influence processes leading to AD, we evaluated the association of SORL1 SNPs with brain magnetic resonance imaging (MRI) findings in a multiethnic group of families containing at least 1 sibpair discordant for AD. In addition, we compared SORL1 haplotypes with analogous measures of severity of AD and vascular abnormalities in a separate group of deceased individuals with pathologically confirmed AD.

While the pathogenetic mechanisms responsible for Alzheimer's Disease (AD) remain unknown, blood vessel deformities, thickened vascular basement membrane (VBM), and amyloid fibrils emanating from the VBM all suggest vascular involvement. The present study immunocytochemically localized the VBM constituent heparan sulfate proteoglycan (HSPG), which is said to play a role in filtration of anionic and neutral proteins. In addition, thioflavine S was used to double-label each tissue section for the presence of amyloid. Samples were taken from frontal, temporal and parietal lobes of 8 patients who exhibited the neuropathologic lesions of AD and 6 patients who did not. HSPG immunolabeled the capillary bed in all samples. Tissue from patients with AD, however, exhibited severe microangiopathic changes: ragged and irregular outer capillary walls, both thickened and attenuated capillary diameters, and regionally increased capillary density. In addition, plaque-like extravascular accumulations of HSPG were seen in all patients with AD. These accumulations were found in the vicinity of capillaries, and were commonly colocalized with amyloid. Neither extravascular clouds of HSPG immunoreactivity nor fluorescing accumulations of amyloid were found in non-AD patients. The pattern of HSPG immunostaining confirms: (1) the high incidence of microangiopathy in AD; (2) the close anatomic relationship between plaque constituents and capillaries; and (3) the colocalization of HSPG with extravascular amyloid. The cerebral vasculature, and specifically the VBM, may thus be actively involved in the pathogenesis of AD.

Background Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability. Objective To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ( DSM-IV ). Methods Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the κ statistic. Results The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from κ = 0.30 (ADDTC) to κ = 0.61 (original HIS). Conclusions Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.

MR scanning is used in the clinical evaluation of patients with dementia but lacks a reliable method of visual inspection. Two neurologists conducted multiple pilot trials of alternate methods for visual inspection of MRIs, including methods that produced at least 75% interrater agreement in repeat trials, and selected a final method for rating ventricular:brain ratio (VBR), cortical atrophy, and white matter changes. Two other neurologists, new to the method, tested interrater reliability for each component of the method after a brief training session. The correlation of VBR measurement was 0.884 (p = 0.0001). The weighted kappa scores were 0.68 for overall frontal lobe atrophy, 0.38 for right temporal lobe atrophy, 0.20 for left temporal lobe atrophy, and 0.54 for parietal lobe atrophy. The weighted kappa scores were 0.77 for overall periventricular white matter hyperintensities and 0.72 for centrum semiovale hyperintensities. The proposed method may provide a rapid and reliable way to assess VBR, frontal lobe atrophy, parietal lobe atrophy, and white matter changes on brain MRIs in the evaluation of dementia, but it was less reliable for the assessment of temporal lobe atrophy.

There are standardized criteria to assist in the diagnosis of Alzheimer's disease (AD), a disorder that lacks unique clinical, morphologic, or biochemical features. Diagnostic reliability of single groups of investigators using these criteria is moderate to substantial. In this study, seven clinicians at separate sites established a criteria-based diagnosis in 42 consecutive memory disorder patients participating in a national genetic epidemiologic study using a quantitative multiaxis AD rating scale (ADRS) that incorporates NINCDS/ADRDA criteria, reliability of information, and comorbidity. Reliability, measured by a generalized kappa statistic for more than two raters, was substantial (0.63 ± 0.13) when the subjects were grouped as “AD” (probable or possible) versus “not AD,” but somewhat lower (0.52 ± 0.10) when subjects were classified as probable AD, possible AD, or not AD. There was unanimous agreement for two-thirds of the subjects using a dichotomous classification scheme. These findings suggest that the ADRS is a useful diagnostic instrument for multicenter studies.

Accurate diagnosis of vascular dementia is important for the recognition of underlying pathophysiology and the institution of appropriate therapy. It is also important for the determination of the incidence and prevalence of not only vascular dementia but also Alzheimer's disease (AD), since differentiating between these two entities is often problematic. The State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) herein propose criteria for the diagnosis of ischemic vascular dementia (IVD). These criteria broaden the conceptualization of vascular dementia, include the results of neuroimaging studies, emphasize the importance of neuropathologic confirmation, refine nosology, and identify areas that require further research. Parallel use of the proposed definitions of “possible” and “mixed” categories in the diagnosis of both AD and IVD would ensure compatibility between the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for AD and the ADDTC criteria for IVD. Uniform classification of subtypes of IVD will improve the generalizability of individual studies and aid in multicenter collaborations.

A 66-year-old man with progressive supranuclear palsy is described. Although generally apathetic, withdrawn, and aspontaneous in speech and behavior, he had sudden episodes of agitation, during which he was verbally threatening and physically abusive. Treatment with thiothixine and then with carbamazepine was ineffective in controlling his violent behavior. He responded temporarily to trazodone, and a recurrence of aggressive behavior was suppressed by increasing the dose of trazodone; this response may be related to trazodone's putative effect on the serotonin system. Although both carbamazepine and trazodone have been advocated for the control of aggression in organically impaired patients, they were not equally effective in this case. ( J Geriatr Psychiatry Neurol 1989;2:109-112).

• Histopathologic studies of the cerebral cortex, hippocampus, and three subcortical nuclei were performed in four patients with Parkinson's disease whose mental status had been evaluated by neuropsychologic testing. Clinicopathologic correlations suggest that dementia with marked visuospatial disturbance as well as severe aphasia may be associated with severe neuronal loss in subcortical nuclei, without significant numbers of plaques or tangles in the hippocampus and cerebral cortex. Furthermore, memory loss may not be consistently related to neuronal loss in the nucleus basalis of Meynert, particularly in non-Lewy body parkinsonism.

Fifty-four patients with Alzheimer's disease performed on the Dementia Assessment Battery that comprised of finger tapping, forward digit span, naming, verbal memory, visual memory, Token Test, digit cancellation, word-list generation, symbol-digit substitution, and copying geometric designs. Four forms of the battery were administered at weekly intervals. The equivalence of the forms, the relative difficulty of the tests, retest reliability, and factorial composition of the battery are presented. Performance improved with repetition. Impairments in visuo-spatial and verbal abilities were independent of each other. The fragility of the patients' working memory was identified as a main cause for their poor recall. The importance of "component analysis" in individual assessment is illustrated.

A meta-analytic review of flash and pattern reversal visual evoked potential research indicates that elderly demented patients have longer P100 latencies than age-matched control subjects. In the present empirical research, patients with research diagnoses of probable Alzheimer's disease were compared with sex- and age-matched control subjects using P100 latencies of visual evoked potentials (VEP) elicited by flash and pattern reversal. As compared to control subjects, Alzheimer's disease patients showed significantly longer P100 latencies of the VEP elicited by pattern reversal; the flash P100 only marginally distinguished them. These findings are discussed within the context of VEP recording practices, patient selection, sex and age matching of control subjects, and the visual system.

Defects of the serotonergic neurotransmitter system have been identified consistently in both Parkinson’s disease (PD) and depression, including decreased 5hydroxyindole acetic acid (5HIAA) in cerebrospinal fluid (CSF) (e.g., Asberg et al. 1976; Mayeux et al. 1984). Depression, the most common mental disturbance in PD, occurs in nearly one-half of patients and is not related to the severity of motor symptoms or changes in dopamine metabolism (Mayeux et al. 1984). The decrease in CSF 5-HIAA seems to be more marked in PD patients who also are clinically depressed, supporting a serotonergic hypothesis for depression in PD (Mayeux et al. 1984). Recently, decreased ‘H-imipramine binding density was reported in both putamen (Raisman et al. 1986) and cerebral cortex (Cash et al. 1985) from PD patients. 3H-Imipramine binds to a site associated with serotonin uptake, and its distribution parallels brain serotonergic innervation (Langer et al. 1987). Therefore, decreased binding density may rep

Two family members with hereditary pressure-sensitive neuropathy are reported. One patient presented atypically with acute brachial plexus neuropathy following transaxillary removal of the first rib. Electrophysiological studies showed slowing of motor nerve conduction in clinically affected and unaffected nerves. In vitro recording of the compound action potential of the subclinically involved sural nerve showed pronounced slowing in conduction of large and small myelinated fiber groups. These alterations correlated with morphological studies of the sural nerve that showed tomacula with acute and healed segmental demyelination. An inherited, generalized neuropathy manifested by a morphological abnormality of myelination may render peripheral nerves unduly susceptible to mechanical trauma, including positional pressure or traction effects during general anesthesia.

Decreased platelet 3H-imipramine binding density and decreased monoamine oxidase (MAO) activity have been considered as biological characteristics of several neuropsychiatric disorders, and may be related to central serotonin defects. Since serotonin system defects occur in Alzheimer's disease (AD), and decreased brain 3H-imipramine binding density, and increased brain and platelet MAO activity are reported also, we studied platelet 3H-imipramine binding density (Bmax) and platelet MAO activity in AD outpatients without antecedent psychiatric disorder. AD subjects with significant symptomatic behavioral disorder, predominantly agitation and delusions, and AD subjects without symptomatic behaviors were compared with controls. Age, sex, mini-mental state examination score, and illness duration did not distinguish the two AD groups. The agitated/delusional group showed significantly lower Bmax values than uncomplicated AD subjects or controls. MAO activity was significantly increased among female AD subjects without symptomatic behaviors compared to those who were agitated or to controls. These results indicate that 3H-imipramine binding and MAO activity may distinguish AD subjects with agitation or delusions from those without symptomatic behaviors, and suggest the existence of a biologically based Alzheimer's behavioral subtype.