MedicalResearch.com Interview with:
Lauren McCollum, MD
Cognitive and Behavioral Neurology Fellow
Penn Memory Center / Cognitive Neurology Division
MedicalResearch.com: What is the background for this study?
Response: Alzheimer’s Disease (AD) is a heterogenous condition, with considerable variability in cognitive symptoms and progression rates.
One major reason for this heterogeneity is “mixed pathology,” – i.e., both AD- and non-AD pathology. Examples of non-AD pathology include cerebrovascular disease (CVD), Lewy Bodies, and TDP-43. Pathologically, Alzheimer’s Disease is defined by characteristic amyloid plaques and neurofibrillary tangles, which can be assessed for in living patients with CSF- or PET-based biomarkers for amyloid and tau, respectively. Classically, amyloid deposition begins years or even decades before pathologic tau accumulation, which is in turn associated with brain atrophy and cognitive decline.
The recently developed NIA-AA “ATN” research framework allows for the classification of individuals with regard to 3 binary biomarkers: Amyloid (A), Tau (T), and Neurodegeneration (N). An individual’s ATN biomarker status indicates where along the “Alzheimer’s Disease continuum” they lie. Additionally, some ATN statuses are on the “typical AD” continuum, while others are not. Research has shown that 15-30% of cognitively normal older adults have elevated amyloid. It stands to reason that some portion of cognitively impaired individuals with elevated amyloid and neurodegeneration have something other than AD driving their neuronal injury. Within the context of the ATN research framework, this subset of people is the A+T-N+ group (i.e., people who have elevated amyloid and neurodegeneration, but are tau-negative), as amyloid alone (that is, amyloid without tau) is not thought to cause significant cognitive impairment or brain atrophy. Our hypothesis was that, compared to A+T+N+ (a set of typical-AD biomarkers), A+T-N+ have cognitive and neuroimaging profiles that deviate from a typical Alzheimer’s Disease pattern – i.e., with less memory loss and less atrophy in AD-signature regions – and may have biomarkers suggestive of alternate non-AD pathologies [e.g., white matter hyperintensities (WMHs), a marker of CVD].
MedicalResearch.com: What are the main findings?
Response: We performed two analyses using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The first analysis used a PET-based approach to compare amyloid-positive people with mild cognitive impairment (MCI) or AD based on tau status (i.e., A+T- vs A+T+). Amyloid status was determined based on a composite SUVR of 1.11 with florbetapir PET. Tau status was assessed using the tau PET tracer AV-1451, and a cut-off of 1.22 SUVR in the bilateral extrahippocampal mesial temporal lobes was determined based on analysis of amyloid-negative cognitively normal controls. 13 A+T- and 30 A+T+ individuals were identified and compared. (In this analysis, cognitive impairment was used as a proxy for neurodegeneration as the sample size was small.)
The main findings in this analysis were that verbal memory was less impaired in A+T- compared to A+T+ (5-minute delayed recall score 5.3 vs 2.7, p=0.024), while the groups were similarly impaired on executive function as assessed by Trails B time (146 vs 131 seconds, p=0.628).
In a second, larger analysis, amyloid and tau positivity were determined based on CSF using cut-off values for the Roche Elecsys platform (A-beta-42<980, pTau>24), and the neurodegeneration cut-off was set at the 90th percentile for mean ICV-and-age-adjusted hippocampal volume of 113 amyloid-positive individuals with dementia-level impairment. 29 A+T-N+ MCI, 87 A+T+N+ MCI, and 165 amyloid-negative cognitively normal controls were compared. The cognitive findings were similar to the first analysis, with A+T-N+ having less severe memory impairment compared to A+T+N+ (30-minute delayed recall score of 3.2 vs 1.6, p=0.004) and similar impairment in other domains, including executive function (Trails B time of 126 vs 124 seconds, p=0.899). Additionally, A+T-N+ had less severe posterior hippocampal atrophy compared to A+T+N+, and both MCI groups had similarly substantial burdens of WMHs.
MedicalResearch.com: What should readers take away from your report?
Response: Compared to the typical-AD biomarkers groups, both A+T- MCI/AD (from the first analysis) and A+T-N+ MCI (from the second analysis) displayed relative sparing of memory compared to executive functioning. Relative posterior hippocampal sparing in A+T-N+ MCI compared to A+T+N+ MCI may suggest non-AD pathology, as along the “hippocampal longitudinal axis” AD pathology (specifically, tau) preferentially affects the posterior hippocampus (while still involving the whole axis) and suspected TDP-43-opathies preferentially affect the anterior hippocampus.Both MCI groups had greater WMH burden than controls, suggesting CVD may contribute to symptoms in both.
Taken together, symptomatic patients who have elevated amyloid but not tau had features suggestive of alternative non-Alzheimer’s disease pathologies, including a less “Alzheimer’s-like” cognitive profile (i.e., with less memory loss), abnormal burden of WMHs, and relative sparing of the posterior hippocampus.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Future directions for this research will include cortical thickness analyses to assess for additional neuroimaging correlates of these distinct cognitive profiles. We will also be further assessing our hypothesis with longitudinal analyses.
I (Dr. McCollum) have no disclosures. Dr. Wolk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck, Jannsen, Eli Lilly and GE.
AAN 2019 abstract:
Cognitive Profiles in Amyloid-Positive Mild Cognitive Impairment and Alzheimer’s Disease with and without Tau (P2.1-030)
Lauren McCollum, Laura Wisse, Sandhitsu Das, Robin de Flores, Paul Yushkevich, David Wolk
First published April 9, 2019,
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