KNOPMAN, D. S. MD; PARISI, J. E. MD; SALVIATI, A. MD; FLORIACH-ROBERT, M. MD; BOEVE, B. F. MD; IVNIK, R. J. PHD; SMITH, G. E. PHD; DICKSON, D. W. MD; JOHNSON, K. A. BS; PETERSEN, L. E. BS; MCDONALD, W. C. MD; BRAAK, H. MD; PETERSEN, R. C. PHD, MD
It has been challenging to define a minimum threshold for the neuropathological diagnosis of Alzheimer disease (AD). In patients with a high burden of AD pathology there are firm grounds for claiming that AD caused the dementia. In any series there are typically a few cases with lower burdens of AD pathology that nonetheless are attributed to AD in the absence of a better alternative (1–4). When AD pathology of a lesser severity is present, causal attribution of dementia to the pathology becomes problematic. Defining a minimum threshold for AD pathology may be confounded by the presence of other common known pathologies (5).
To understand the pathological threshold for the development of dementia by AD, it may be more feasible conceptually to start with a definition of the maximum limit in cognitively intact individuals rather than with a minimum limit in demented individuals. If cognitive integrity can be assured at a time point close to death, there are few issues that can compromise the determination of a maximum limit for AD (or other) pathology in asymptomatic individuals.
Because prospective cognitive assessment is required to insure that so called normal subjects are cognitively intact immediately prior to their terminal illness, nondemented subjects can be identified only through large-scale, prospective longitudinal studies. Only a few series that could verify the cognitive integrity of their “normal” subjects have been reported (5–11). While the majority of cognitively intact individuals had little AD pathology, several of the series contained examples with high burdens of AD pathology (7, 8). These outlier subjects would appear to pose a major interpretive problem.
In light of the pivotal importance of studies of well-characterized nondemented individuals, as well as the variability of AD pathology of normal subjects in the recent studies (7, 8), we analyzed the neuropathological features in prospectively recruited, prospectively diagnosed, cognitively normal individuals in the Mayo Alzheimer's Disease Center and the Alzheimer's Disease Patient Registry projects in Rochester, Minnesota. We focused on the presence of AD pathology, but also evaluated the presence and the distribution of vascular lesions and the presence of Lewy Bodies (LB). We then analyzed associations between these pathological findings and demographics, cognitive status, and APOE genotyping.
MATERIALS AND METHODS
A total of 192 subjects who were recruited to the Mayo Alzheimer's Disease Patient Registry (12) and whose last clinical diagnosis was “normal” had died at the time of data analysis for the present study. All subjects had been residents of Rochester, Minnesota and were recruited from the Community Internal Medicine practice of the Mayo Clinic. Individuals with other neurological diseases such as Parkinson disease or stroke were excluded, even if they were cognitively normal. From this group there were 39 subjects who had had brain autopsies, who were originally enrolled as normal controls in the ADPR, and who were diagnosed as normal on their last clinical evaluation that occurred within 2 years of death.
All subjects were initially examined and interviewed by a study physician. The neuropsychological evaluations at the baseline included cognitive and behavioral scales, only 3 of which will be referred to in this report: the Mini-Mental State examination (13–15), Mattis Dementia Rating Scale (16–18), and the Wechsler Memory Scale, Revised, Logical Memory Subtest (WMS-LM) (19). A consensus committee of neurologists and neuropsychologists determined diagnoses and subjects were enrolled in the present study only if their histories and neuropsychometric assessments were consistent with normal cognitive function (12, 20). APOE genotyping was performed according to established methods (21) from a blood sample drawn either at the baseline examination or during clinical follow-up. The subjects were reevaluated on an annual basis with neuropsychological testing (12, 20). The examinations during their follow-up were discussed at the consensus conference. At their last clinical examination prior to death, they were considered by consensus conference to be cognitively intact/normal. All cases were examined cognitively within 2 years of death. Two cases were examined between 1.5 and 2 years, 9 within 1 and 1.5 years, and the remainder within 1 year. All subjects gave informed consent for participation. The study was approved by the Mayo Institutional Review Board.
Neuropathological examinations were performed according to the recommendations of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (1). After removal, the brain was divided into right and left hemi-brains. One hemi-brain was fixed in 10% buffered formaldehyde for 10 to 14 days and sectioned. Routinely sampled brain areas included middle frontal gyrus (Brodmann's area, BA 9), inferior parietal lobule (BA 39), superior temporal gyrus (BA 22), calcarine cortex (BA 17), anterior cingulate gyrus (BA 24), hippocampus at the level of the lateral geniculate body, amygdala, transentorhinal, and entorhinal cortices at the level of the mammillary bodies, nucleus basalis, cerebellum, dorsomedial thalamus with subthalamic nucleus, and midbrain with substantia nigra. Samples were processed in paraffin and stained with hematoxylin and eosin (H&E). Selected sections were stained with modified Bielschowsky silver and Gallyas and immunostained with antibodies to β-amyloid (clone 6F/3D, 1/10 dilution; Novocastra Vector Labs, Burlingame, CA); tau (clone AT8, 1/1,000 dilution; Endogen, Woburn, MA); α-Synuclein (clone LB509, 1/200 dilution; Zymed, South San Francisco, CA); αβ Crystallin (Rabbit polyclonal, 1/5,000 dilution; Chemicon, Temecula, CA); and ET3 (generously provided by Dr. Peter Davies, New York, NY).
The regions in which the counting was performed were selected macroscopically according to Duyckaerts et al (22) as the areas where the cortical ribbon was the thinnest (i.e. where the angle of section was the closest to 90° relative to the cortical pial surface). Pathological findings were recorded according to Dickson et al (23) from ×200 magnification fields, excluding fields at the crest of gyri or depth of sulci. Ten contiguous fields were examined for frontal, parietal, temporal, and calcarine cortex; 5 contiguous fields for amygdala, transentorhinal, entorhinal, and anterior cingulate cortices, and substantia nigra; 4 contiguous fields for subiculum and nucleus basalis; and 3 contiguous fields for hippocampus.
Quantification and Identification of Plaques
Three types of plaques were identified and counted and are described as follows: 1) Diffuse plaques: neuropil deposition of finely granular material on Bielschowsky-stained sections. 2) Dense core plaques: neuropil deposition of compact argyrophilic material, on Bielschowsky-stained sections. 3) Neuritic plaques: identified by the presence of dystrophic neurites, arranged radially forming a discrete spherical lesion averaging about 30 μm in diameter (23). Neuritic plaques were counted on tau immunostained sections.
Plaque counts were normalized and expressed as number of counts/mm2. The number of each type of plaque was also characterized according to the CERAD rating scheme of none, sparse (1–5 per ×100 field), moderate (6–15 per ×100 field), or frequent (>15 per ×100 field) (1). The score of the neocortical region with the highest count was used as the overall score for each subject.
Quantification of Neurofibrillary Tangles
Neurofibrillary tangles (NFTs) were identified as flame-shaped or globoid masses of intracellular argyrophilic fibers. Extracellular “ghosts” NFT were also recorded. NFTs were counted on both Bielschowsky and anti-tau stained slides. We will report only the staging of NFT distribution according to the scheme of Braak and Braak (24), which was completed primarily with Bielschowsky stained slides but supplemented by the anti-tau stained sections. Braak Stage I represents small numbers of NFTs confined to the trans-entorhinal cortex; stage II, moderate or larger numbers in transentorhinal cortex and few in hippocampus; stage III, frequent NFTs in transentorhinal and entorhinal cortices and moderate NFTs in hippocampus (CA1 and subiculum); stage IV, more severe hippocampal involvement and mild to moderate involvement of isocortex; stage V, frequent NFTs in association isocortex; and stage VI, NFTs in primary sensory cortices.
Quantification of Lewy Bodies
The presence of Lewy bodies (LBs) (25) was assessed in substantia nigra, amygdala, and cingulate cortex using α-synuclein-stained sections. In each region the total number of LBs was counted and an LB score according to McKeith et al (26) was recorded.
For the presence of argyrophilic grain disease, silver- and tau-positive medial temporal (amygdaloid, entorhinal, and hippocampal) grains and tau-positive white matter coiled bodies and ballooned amygdaloid neurons were required. We required grains to be present in both amygdala and hippocampus. Ballooned, neurofilament, and αβ-crystallin-positive neurons in amygdala also were recorded (27). Detection of grains was confirmed by staining for ET3, a selective 4R tau antibody (28).
The numbers and size of lacunar and large infarcts and the presence of meningeal or parenchymal amyloid angiopathy were recorded.
To compare quantitative and categorical aspects of the group differences we used t-tests and chi-squared tests. Pearson or Spearman correlations were used to assess the association between clinical and pathological features.
Descriptive data on the 39 subjects is given in Table 1. Only 5 (13%) subjects were less than 80 years old, while 9 subjects (23%) were 90 years or older at death. The MMSE at the last clinical evaluation was ≥27 in 32 subjects; 1 subject had an MMSE score of 24; 2 had scores of 25; and 4 had scores of 26. The DRS scores at last clinical evaluation (mean = 134.5) exceeded 130 (out of a maximum score of 144) in 29 of 39 cases. The lowest score accepted among subjects as not cognitively impaired was 122.
The 39 subjects who underwent autopsy differed from the nonautopsied cases who had been evaluated within 2 years of death (n = 95) slightly in age (mean 85.4 ± 5.4 yr vs 87 ± 6.4 yr), but not in education (13.1 ± 3.1 yr vs 12.8 ± 2.9 yr), final MMSE (28.0 ± 1.6 vs 27.8 ± 1.7), or percentage of women (61.5% vs 63%). An additional 58 subjects whose last diagnosis was “normal” had not been examined within 2 years of death. These subjects were older (89.2 ± 8.0 yr) than the 39 subjects in the present report.
Causes of death based on the complete autopsy, or on clinical impression if only a limited autopsy was performed, were obtained from the autopsy report. Cardiac disease, usually acute myocardial infarct, was the most frequent primary cause of death (17 subjects, 44%). Cancer-related illnesses caused 10 deaths (26%). Primary pulmonary causes of death, including pulmonary embolism, pneumonia, or bronchitis accounted for most of the remainder (13 subjects, 33%). Some patients had more than 1 principal cause of death listed. Head trauma was not part of the terminal illness in any subject. Recent stroke was not listed as the principal cause of death in any of the subjects, although acute and subacute cerebral infarcts were observed pathologically in 10 cases.
NFT distribution as described by Braak staging is given in Table 2 and Figure 1. Only 1 subject had no NFT pathology. Twenty-two subjects (56%) had Braak stage I or II and 11 (28%) had Braak stage III. Five (13%) subjects demonstrated Braak stage IV or higher, with 4 intermediate between Braak stages IV and V. One subject had Braak stage V.
Two of the 5 subjects with Braak stage IV or higher also had moderate numbers of tau-positive neuritic plaques. One was an 88-year-old woman (case 38) who had moderate numbers of neuritic plaques. Her last testing was 585 days prior to death, at which time her MMSE was 28 and DRS was 140. She was said to have abruptly declined cognitively in the last 4 months of her life by family reports, but she was also found to have multiple new cerebral infarcts at that time. The other subject (case 30) with Braak stage IV–V and frequent numbers of neuritic plaques in the temporal lobe and moderate numbers in other cortical regions was a 74-year-old woman last examined 284 days prior to death. She scored 29 on the MMSE and 134 on the DRS at the time. The other 3 subjects with higher Braak stages had only sparse neuritic plaques. These 3 subjects included an 89-year-old woman (case 25) who scored 128 on the DRS and recalled 2/16 on the WMS-LM at 329 days prior to death; an 82-year-old man (case 37) who scored 133 on the DRS 67 days prior to death; and an 88-year-old man (case 35) who scored only 122 on the DRS, but who recalled 16/18 on the WMS-LM at the same testing session 423 days prior to death.
The majority of subjects had NFT distribution that fit well into the Braak staging system, but there were 9 instances in which the distribution of NFT in 1 region was discordant according to the Braak scheme, with the NFT burden in another region. These discrepancies (Table 3) usually involved difference between adjacent stages rather than more divergent stages. There was no correlation between Braak stage and age (r = 0.08), education (r = 0.010), last MMSE (r = −0.03), or last DRS (r = −0.24).
CERAD plaque count ratings for diffuse plaques, cored plaques, and neuritic plaques are given in Table 2 and Figure 2. Nineteen (49%) subjects had moderate or frequent diffuse plaques in at least 1 neocortical region, of whom 9 had frequent diffuse plaques. Seven (18%) subjects had moderate or greater cored plaques, one of whom had frequent cored plaques in at least 1 cortical region. There were no subjects with frequent neuritic plaque densities, but there were 2 (5%) who had moderate numbers of neuritic plaques (cases 30 and 38).
The group of 7 subjects with moderate or greater numbers of cored plaques, including 2 with moderate neuritic plaques, were comparable in age at death (mean = 84.9 years), months between last evaluation and death (mean = 9.5 months), MMSE score (mean = 28.6), and DRS score (mean = 137) compared to the other 32 subjects. The APOE e4 allele was present in only 1 (14%) of these 7 subjects, while it was present in 9 (28%) of the other 32 subjects (chi-square test, not significant). The group with moderate cored plaque densities did not have a substantially higher Braak stage (mean = 2.6) compared to the others (mean = 2.1) (t-test, not significant).
The subjects with moderate or frequent diffuse plaque burden (n = 19) were indistinguishable demographically (age, time between last MMSE and death) and cognitively (MMSE and DRS) from those with lesser diffuse plaque scores. Diffuse plaque burden was not associated with a difference in Braak stage. There were no differences in plaque burden of any type between those subjects who died with ischemic heart disease or from other causes. Among the 14 subjects with ischemic heart disease, 3 subjects (21%) had moderate or greater densities of cored plaques, compared to 5 (21%) of 24 subjects whose autopsy reports did not list ischemic heart disease.
Of the 23 subjects with Braak stage ≤II, only 4 had a maximum of moderate numbers of cored plaques. Five of these 23 had neither diffuse, cored, nor neuritic plaques. Of the 16 subjects with Braak stages >II, 3 had no plaque pathology of any type. Figure 3 shows the lack of striking relationships between plaque density and Braak stage.
By the National Institute on Aging–Reagan Institute criteria (NIA-RI) (29), none of our cases met criteria for high “likelihood” of AD. Four met NIA-RI criteria for intermediate “likelihood.” Because our subjects were not demented, the NIA-RI criteria should be interpreted strictly on quantitative terms, not for the likelihood of the pathological findings “explaining” the clinical syndrome. Seven cases met CERAD criteria for possible AD (1). Nineteen met Khachaturian criteria for AD (30).
Vascular Pathology (Table 4)
By virtue of enrollment criteria, no subject had clinical strokes except possibly during their terminal illness. Eighteen (46%) subjects had at least 1 small old infarct, and only 9 had more than one. Over half of the small infarcts were in the thalamus, putamen, or caudate (20/39 infarcts). The remainder of infarcts were in neocortical locations (11 infarcts in 6 subjects) or white matter (8 infarcts in 6 subjects). With one exception, none of the infarcts were greater than 0.5 cm in their greatest linear measurement and the majority were microscopic. The exception was Case 38, who in the 4 months prior to death suffered from multiple cerebral infarcts probably associated with a coagulopathy and pancreatic adenocarcinoma.
Lewy Body Pathology
By virtue of enrollment criteria, no subject had clinical Parkinsonism. Five (13%) subjects had Lewy bodies (Table 5). Four demonstrated Lewy bodies in substantia nigra. Only 1 subject (Case 38) had neocortical Lewy bodies. Two subjects, including case 38, had Lewy bodies in cingulate gyrus. Four had Lewy bodies in amygdala (with the fifth case missing sections from that region).
Argyrophilic Grain Pathology
Twelve (31%) subjects had the findings of argyrophilic grains confirmed on Bielschowsky-stained, tau-immunostained, and αβ-crystalline-immunostained sections. In a subset of 30 cases, grain disease was confirmed in 10 cases (33%) using the specific 4R-tau antibody ET3. A comparison of Gallyas and ET3-stained sections in these 30 cases showed that the 2 techniques were comparable for identifying grains. Of 10 cases, 9 were also Gallyas-positive. Only in 6 (20%) of these cases were there large numbers of grains.
The majority of our longitudinally followed, cognitively intact elderly individuals had low burdens of AD pathology. Depending upon the histologic finding used to define the AD pathologic burden, 5% (moderate numbers of neocortical neuritic plaques), 13% (Braak stages IV or higher) to 18% (moderate cored plaques) of the subjects showed greater AD pathology. Our findings add to the small number of cases that have been published previously (5–11), demonstrating the modal pattern and the outliers. We will argue that the outliers do not actually present an interpretive problem.
Studies across the age spectrum suggest that AD neuropathology precedes clinical symptomatology by several years or decades (31). Therefore, to derive a threshold for clinically silent AD pathology, the presence of a few cases with high burdens of AD pathology should be expected because there must be instances of incident AD in a cohort with a mean age of 85 years. In 80- to 84-, 85- to 89-, and 90- to 94-year-old cohorts, the annual incidence rates of AD in Rochester Minnesota were 1.9, 3.2, and 4.6 per 100 persons per year, respectively (32). Furthermore, because there may be a multi-year preclinical phase of AD that does not lead to scoring at an impaired level on cognitive testing (33–38), the numbers of subjects with higher grade AD pathology may reflect those who would have become incident cases not just 1 year later, but perhaps 2, 3, or even 4 years in the future. Thus, it would have actually been worrisome if a few of our subjects, given their ages, did not have higher burdens of AD pathology.
Taking into account the admixture in our series of individuals with what has been called preclinical AD (10), the cut-off points for clinical relevance of AD-type pathology derived from the present analysis are Braak stage ≥IV or numbers of neuritic plaques ≥ moderate (i.e. <6 per ×100 field in any neocortical region). Lower levels of AD pathology, even including frequent diffuse plaques, should not be sufficient to cause dementia. Correlational studies in demented patients have also shown the importance of increasing burdens of neuritic plaques (39) and neocortical NFTs (39, 40). An alternative hypothesis to the claim that there is a generalized threshold for AD pathology to produce dementia would be that there is inherent person-to-person variability in susceptibility to AD pathology. If this were the case, the implication is that one can never be certain whether AD pathology is clinically relevant or not. However, our results do not support this alternative explanation. The data show that most cognitively intact individuals have little AD pathology.
There was no relationship between the amount of AD pathology and any cognitive measure in our normal subjects. The lack of such a relationship could be due to inadequate power with only 39 subjects or to the insensitivity of the clinical instruments. With these caveats noted, the conclusion to be drawn would be that the burden of AD pathology on cognition is a discontinuous process. Until a certain threshold is reached, AD pathology appears to exert no dramatic influence on cognition. In addition, our findings do not support an association reported once before (41) between ischemic heart disease and greater burdens of AD plaque pathology.
The major difficulty of testing AD pathological thresholds in dementia patients is the presence of other pathologies—particularly vascular and synucleinopathic—that might act synergistically with AD pathology (42). These other pathologies include both what can be measured by standard evaluations, for example the CERAD (1) or NIA-RI (29) approaches, but also what must be sought by considerably more arduous means, such as microvascular disease (43). Thus, in a dementia patient with AD pathology of, for example, Braak stage III and only sparse neuritic plaques, we assert that AD pathology should not be considered to be the sole etiologic agent.
Interpretation of cerebrovascular pathology is more difficult because of the multifocal nature of stroke. In addition, individuals with clinical strokes were excluded from the study group. A large number of our cases had some infarcts, but most were of the lacunar type, that is, very small in terms of volume. There were no instances of major vessel distribution infarcts. In the British neuropathology study, 8% of nondemented subjects had infarcts or lacunes, while 33% had infarcts, lacunes, and small vessel disease “consisting of diffuse pallor of myelin staining in white matter associated with hyaline degeneration of subcortical arteries and arterioles, microinfarcts or a combination of these features” (5). Compared to dementia patients in our population series with vascular dementia clinically (44), the abundance of cerebrovascular pathology in the normal subjects in the present series was substantially less.
Approximately 13% of our cases had Lewy bodies, consistent with the work of others. Age-specific prevalence rates of incidental Lewy body disease have shown rates of 12.5% for 70- to 79-year-old individuals and 18.2% for 80- to 89-year-old individuals (25). Our results confirm that nigral or amygdala Lewy bodies do not necessarily impair cognition.
A rather large proportion of our cases had argyrophilic grain disease. The relevance of these grains to cognitive function is uncertain, particularly in light of the high numbers observed in cognitively intact subjects. The high number of cases in our series compared to others (27) may be due to reasons of technique as well as our heightened awareness of this entity.
The strengths of this study lie in the number of cases studied, the prospective nature of the clinical evaluations and diagnoses, and the uniformity of the neuropathological evaluations. Perhaps the main weakness of our study was the possibility that we failed to recognize cognitive decline in some of our subjects due to the insensitivity of the cognitive instruments. Other potential weaknesses include the possibility that the study subjects were not representative of a community sample, and that as a result, there were biases in who was recruited. Any autopsy study is susceptible to some biases because of the low rate of autopsy. We were able to define the universe of subjects from which the current sample was obtained and found that the only difference between autopsied and not autopsied subjects was that autopsied patients were slightly younger. The age of our subjects is advanced and clearly comparable to the peak of dementia, but it would have been more informative had we had a greater representation of individuals under age 80, and especially under age 70 years. Another weakness is that we included subjects whose interval from last testing to death extended beyond 1 year. One of the 2 subjects in our series, Case 38, with neuropathological measurements in the range consistent with AD, was last examined 1.6 years prior to death. Had she consented to evaluation 6 months or less prior to death, she might have declined from her rather high DRS score of 140 that she achieved 1.6 years prior to death. Another potential criticism could be that we have reported ranges of pathology rather than actual counts of NFTs or plaques in cortical regions. We performed quantitative measurements of NFTs and plaques, but semiquantitative counts have been shown to improve reliability and to increase comparability to other studies (1).
This work is dedicated to the memory of Emre Kokmen, MD, one of the founders of the Mayo Alzheimer's Disease Patient Registry. Dr. Kokmen personally examined a number of the subjects in this report. We would also like to thank the participants of the Registry for their willingness to be part of this research project. We also thank Dr. Peter Davies and Marisol Espinoza for the ET3 antibody. A preliminary version of this work was presented at the 73rd Annual Meeting of the American Association of Neuropathologists, Pittsburgh, PA, June 11–15, 1997, and the 50th Annual Meeting of the American Academy of Neurology, Minneapolis, MN, April 1998.
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