Search

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer's disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P=0.012), provoked hallucinations or delirium (P=0.042), or the presence of any of these noncognitive symptoms of DLB (P<0.0001). Letter fluency (P=0.007) was significantly lower and Wechsler Logical Memory I (P=0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD., ((c) 2008 Elsevier Inc. All rights reserved.)

This study sought to identify altered brain activation patterns in amnestic mild cognitive impairment (MCI) that could precede frank task impairment and neocortical atrophy. A high-accuracy lexical decision (LD) task was therefore employed. Both MCI and normal seniors (NS) groups completed the LD task while functional magnetic resonance imaging (fMRI) was performed. Accuracy on the LD task was high (> or =89% correct for both groups), and both groups activated a network of occipitotemporal regions and inferior frontal cortex. However, compared with the NS group, the MCI group showed reduced fMRI activation in these regions and increased activation in bilateral portions of anterior cingluate cortex. The results from a voxel-based morphometry analysis indicated that altered activations in the MCI group were not within regions of atrophy. Receiver operating characteristic curves demonstrated that reduced fMRI response in the left and right midfusiform gyri accurately discriminated MCI from NS. When activation magnitude in both fusiform gyri were included in a single logistic regression model, group classification accuracy was very high (area under the curve = 0.93). These results showed that a disrupted functional response in the ventral temporal lobe accurately distinguishes individuals with MCI from NS, a finding which may have implications for identifying seniors at risk for cognitive decline., (2010 Wiley-Liss, Inc.)

We evaluated the association between mini-mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression-based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer's disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high-functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP-43-related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.

Background: Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical-pathologic correlation., Methods: We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies., Results: Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 +/- 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 +/- 8.6 and 10.6 +/- 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p < 0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE-death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology., Conclusions: Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the 'Pubmed Era'. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer's disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer's Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical-radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2.

We studied Alzheimer's disease (AD) pathology in the precuneus and surrounding brain areas. Anatomically, the precuneus corresponds to the medial portion of human cerebral cortical Brodmann Area 7. This study utilized patients from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Data from 47 brains were used comprising patients of differing antemortem cognitive impairment severities, each with longitudinal clinical data and extensive neuropathological data. We assessed whether the precuneus and surrounding areas are differentially vulnerable to AD-type pathological lesions (diffuse amyloid plaques, neuritic amyloid plaques, and neurofibrillary tangles). Eleven areas of brain were evaluated for each case: amygdala, hippocampal CA1, subiculum, entorhinal cortex, frontal cortex, superior and middle temporal gyri, inferior parietal lobule, occipital cortex, posterior cingulate gyrus, Brodmann Area 31, and the precuneus proper. Like other areas of neocortex, the precuneus demonstrated increased diffuse and neuritic amyloid plaques early in the evolution in AD, and increased neurofibrillary tangles late in AD. Correcting for the antemortem cognitive status of the patients, there was no evidence of an increase in the density of AD-type pathology in the precuneus or neighboring areas relative to other areas of cerebral neocortex. Our results are not consistent with the idea that the precuneus is involved in a special way with plaques or tangles relative to other areas of neocortex.

Dementia can be caused by different diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or both (AD + DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD + DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n = 156). Patients with important concomitant pathology (n = 5) or patients that were profoundly demented at recruitment (intake MMSE < 20; n = 86) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients with pathologically-diagnosed AD + DLB (n = 25) lost cognitive capacity faster than patients with AD alone (n = 40). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline.

Objective: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic., Methods: Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented., Results: The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test)., Conclusions: The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic., (Copyright 2008 S. Karger AG, Basel.)

Objective: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD)., Background: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI., Methods: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years., Results: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal., Conclusion: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

A previous autopsy study of patients with amnestic-type mild cognitive impairment (MCI) suggested an overrepresentation of argyrophilic grain disease (AGD). We studied 34 patients who had diagnoses of amnestic MCI during progression to dementia and who came to autopsy. Neuropathologic evaluation included routine histochemical and immunohistochemical methods, including a 4-repeat tau-specific marker (ET3). AGD was found in association with a variety of neuropathologic diseases in 18 (53%) cases but was the primary pathologic finding in only one (3%) case. ET3 allowed the detection of AGD in 5 additional cases missed using standard techniques. Cases with AGD were significantly older than those without (mean, 94 vs 84 years; p < 0.004, rank sum test). No significant differences were found between groups for other demographic variables, association of AGD with neuropathologic findings of Alzheimer disease, Lewy body, or cerebrovascular disease, or global measures of cognitive function, although there was a nonsignificant trend towards worsening cognitive status in cases with AGD. AGD is a common pathologic finding in subjects who have been diagnosed with amnestic MCI.

Background: The pathologic outcome of patients diagnosed with mild cognitive impairment (MCI) following progression to dementia is poorly understood., Objective: To determine the pathologic substrates of dementia in cases with prior diagnosis of amnestic MCI., Design and Setting: Community-based cohort., Patients: Thirty-four subjects followed up prospectively as part of a community-based study who were diagnosed with amnestic MCI, progressed to clinical dementia, and underwent subsequent postmortem brain analysis., Main Outcome Measures: Neuropathologic analyses resulted in assignment of a primary pathologic diagnosis and included staging of Alzheimer pathologic abnormalities and identification of contributing vascular disease, Lewy bodies, and argyrophilic grains., Results: Although the majority of subjects progressed both clinically and pathologically to Alzheimer disease (AD), 10 (29%) of them developed non-AD primary pathologic abnormalities. All of the cases were found to have sufficient pathologic abnormalities in mesial temporal lobe structures to account for their amnestic symptoms regardless of the cause. Most subjects were found to have secondary contributing pathologic abnormalities in addition to primary pathologic diagnoses. No significant differences between subjects with and without neuropathologically proven AD were detected in demographic variables, apolipoprotein E genotype, or cognitive test measures at onset of MCI, onset of dementia, or last clinical evaluation., Conclusions: The neuropathologic outcome of amnestic MCI following progression to dementia is heterogeneous, and it includes AD at a high frequency. Complex neuropathologic findings including 2 or more distinct pathologic entities contributing to dementia may be common in community-based cohorts. Neither demographic variables nor cognitive measures had predictive value in determining which patients diagnosed with MCI will develop the neuropathologic features of AD.

Background: The neuropathologic substrate of amnestic mild cognitive impairment (aMCI) is not known., Objective: To determine the neuropathologic features of patients who died while their clinical classification was aMCI., Design: Cohort study., Setting: Community based., Participants: Sixty-six individuals, including 15 who had memory impairment beyond that allowed for aging but who were not demented, were studied along with 28 clinically healthy individuals and 23 patients with probable Alzheimer disease (AD) for comparison., Main Outcome Measures: Standard neuropathologic techniques and classification according to Khachaturian, Consortium to Establish a Registry for Alzheimer Disease, and National Institute on Aging-Reagan criteria were used to analyze autopsy tissue from 15 individuals who died while their clinical diagnosis was aMCI. For comparison, autopsy data on age-matched groups of clinically healthy individuals and patients with probable AD were analyzed., Results: Most patients with aMCI did not meet the neuropathologic criteria for AD, but their pathologic findings suggest a transitional state of evolving AD. All the patients with aMCI had pathologic findings involving medial temporal lobe structures, likely accounting for their memory impairment. In addition, there were many concomitant pathologic abnormalities, including argyrophilic grain disease, hippocampal sclerosis, and vascular lesions., Conclusions: The neuropathologic features of aMCI matched the clinical features and seemed to be intermediate between the neurofibrillary changes of aging and the pathologic features of very early AD.

Background: It remains unknown whether depression and apolipoprotein E genotype are risk factors for incident mild cognitive impairment (MCI)., Objective: To determine whether elderly individuals with depression (measured by the short Geriatric Depression Scale) are at increased risk of developing incident MCI., Design: Prospective cohort study., Setting: Primary care clinic., Participants: A cohort of 840 cognitively normal elderly subjects without depression at recruitment who were followed up prospectively for a median of 3.5 years (range, 0.4-12.8 years). Subjects who developed depression (score of >/=6 on the short Geriatric Depression Scale; depression cohort) were compared with all remaining subjects (referent cohort)., Main Outcome Measures: Incidence of MCI (primary outcome) and incidence of MCI or dementia (composite secondary outcome)., Results: Individuals in the depression cohort were at significantly increased risk of subsequent incident MCI (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1) after adjusting for age (time scale), sex, and education, and considering dementia as a competing outcome. The association was stronger in men but did not vary by severity of depression. We observed a synergistic interaction between apolipoprotein E genotype (epsilon3/epsilon4 or epsilon4/epsilon4) and depression (joint effect HR, 5.1; 95% CI, 1.9-13.6; test for additive interaction, P = .03). We found a similar association between depression and the subsequent composite outcome of incident MCI or dementia (HR, 2.6; 95% CI, 1.6-4.3)., Conclusions: Cognitively normal elderly individuals who develop depression are at increased risk of subsequent MCI. We found a synergistic interaction between depression and apolipoprotein E genotype.

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. [ABSTRACT FROM AUTHOR]