Thinking Outside the Box: Alzheimer-Type Neuropathology That Does Not Map Directly Onto Current Consensus Recommendations
Open accessAbstract
The brains of many cognitively impaired patients fall into neuropathologic diagnostic categories that cannot be defined explicitly by guidelines of the National Institute on Aging and Reagan Institute. Here, 2 specific case categories are considered: i) "tangle-intensive" patients with the highest density of neurofibrillary tangles (as graded by the Braak staging system) but only moderate density of neuritic amyloid plaques (as graded by the Consortium to Establish a Registry for Alzheimer's Disease); and ii) "plaque-intensive" patients with intermediate severity neurofibrillary tangles and high density of neuritic amyloid plaques. To understand these technically unclassifiable cases better, we analyzed 1,677 cases with antemortem diagnoses of dementia from the National Alzheimer's Coordinating Center Registry; this registry includes both clinical and pathologic data from the National Institute on Aging-funded Alzheimer Disease Center. To evaluate the diagnostic tendencies of Alzheimer Disease Center neuropathologists, we assessed how the plaque-intensive and tangle-intensive cases were diagnosed. Tangle-intensive cases were more likely to be designated "high likelihood" that the dementia was due to Alzheimer disease, whereas plaque-intensive cases were typically designated as "intermediate likelihood." Only the Braak Stage VI tangle-intensive cases had lower final Mini-Mental State Examination scores than the plaque-intensive cases (p < 0.02). We conclude that more explicit diagnostic categories and a better understanding of the pathology in earlier phases of the disease may be helpful for guiding neuropathologists in the diagnosis of Alzheimer disease.
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NIA-Reagan provides instructions for classification of only 3 of 25 possible combinations of CERAD neuritic plaque density and Braak stage.
“Because of 25 possible combinations of CERAD neuritic plaque density and Braak neurofibrillary stage, NIA-Reagan provides instructions for classification of only 3 (32, 38).”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [32]
The Introduction (page unavailable) describes three NIA-Reagan likelihood categories and says off-diagonal plaque–tangle pairings are not clearly addressed. It does not support the count of 25 possible combinations: it describes four CERAD tiers and Braak stages 0–VI. The three categories also cover ranges of Braak stages, rather than just three individual combinations. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDue to idiosyncratic assignment of NIA-Reagan categories from case to case, we instead stratified by all relevant combinations of CERAD neuritic plaque density and Braak stage.
“Due to the idiosyncratic assignment of these categories from case to case (32), we instead stratified by all relevant combinations of the deterministic histopathological scores, consisting of the CERAD-defined neuritic plaque density score (29) and the Braak neurofibrillary tangle stage (33).”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [32]
The Results report relatively low consistency in NIA-Reagan category assignments for cases outside the guidelines, supporting the concern behind the citing authors’ choice. But they also report high consistency for cases that match the guidelines, so the source does not support describing assignments as idiosyncratic across cases generally. The decision to stratify by CERAD and Braak scores is the citing authors’ own method, not a finding attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEvaluation of AD status was conducted using National Institute on Aging Reagan Institute guidelines including evaluation of neurofibrillary tangles and neuritic senile plaques.
“Evaluation of AD status was conducted by the AD Center Neuropathology and Clinical Cores using guidelines set forth by the National Institute on Aging Reagan Institute that included evaluation of neurofibrillary tangles and neuritic senile plaques [36–38].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [38]
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“In a recent examination of NACC data, Nelson et al estimated that 18% of subjects with dementia fell outside of the NIA-Reagan guidelines (32); here, we found that when controls with no dementia were not included, 33% of subjects were not classifiable.”
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Self-citationHippocampal sclerosis in advanced age: clinical and pathological features
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“Evaluation of AD status was conducted by the AD Center Neuropathology and Clinical Cores using guidelines set forth by the National Institute on Aging Reagan Institute that included evaluation of neurofibrillary tangles and neuritic senile plaques [36 – 38].”
Cerebrovascular disease, beta-amyloid, and cognition in aging
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ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status
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Self-citationCriteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp?
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- Authors
- Nelson, P. T., Kukull, W. A., & Frosch, M. P.
- Affiliations
- University of Kentucky HealthCare (US)
- Harvard University (US)
- Corresponding author
- Nelson, Peter T.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05
- Volume
- 69
- Issue
- 5
- Pages
- 449-454
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC2892786
- OpenAlex
- W2057057871
- Cited by
- 37
- References
- 6
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 4 · 2013: 2 · 2012: 4
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30AG028383, U01AG016976, P50AG005134)
- National Institute of Neurological Disorders and Stroke (R01NS061933, K08NS050110)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neuropathology, neurofibrillary tangles, Braak staging, dementia diagnosis, diagnostic categories, cognitive impairment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Consensus Statements as Topic, Dementia, Female, Humans, Male, Psychiatric Status Rating Scales, Risk Factors, Severity of Illness Index, Cohort Studies, Geriatric Assessment, Neurofibrillary Tangles, Consensus
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