https://www.medpagetoday.com/Neurology/AlzheimersDisease/68260#
Study is first to link subjective cognitive decline with brain tau levels
In
otherwise healthy older adults, self-reports of impaired cognition were
associated with greater buildup of tau protein in the entorhinal cortex,
researchers found.
In an analysis of data from the Harvard Aging Brain Study, those with more symptoms of subjective cognitive decline (SCD) had a higher burden of tau in this brain region, as measured in PET scans (β=0.35, P<0.001), Rebecca Amariglio, PhD, of Massachusetts General Hospital in Boston, and colleagues reported online in JAMA Neurology.
However, they didn't have greater tau buildup in the inferior temporal cortex, which is associated with later-stage disease -- suggesting that SCD could be an early indicator of tauopathy in clinically healthy older adults, the researchers said.
"Before tau spreads to the inferior temporal cortex, it has to pass through the entorhinal cortex, making the argument that the relationship with tau is a mix of people getting older and having more age-related complaints, and there may be a subset that likely represents the earliest path to Alzheimer's disease," Amariglio told MedPage Today.
Researchers have turned their attention to subjective cognitive complaints -- for instance, the feeling that your memory just isn't what it used to be -- as the field looks to identify earlier stages of disease in order to better prevent it. The term "subjective cognitive decline" has emerged as the leading concept, though there are not yet standard questionnaires and it is not recognized as a formal disease stage, like mild cognitive impairment (MCI).
Amariglio said her team's previous analyses of data from the Harvard Aging Brain Study have shown that healthy older adults with greater amyloid buildup had more cognitive complaints, as did those with greater hippocampal volume loss. And while other studies have tied greater cerebrospinal fluid (CSF) tau levels with worse cognitive complaints, this is the first to use imaging to get a direct assessment of tau deposition in the brain.
In this assessment, 133 clinically healthy participants (mean age 76, 56% women) had tau PET imaging with the flortaucipir 18F tracer (previously known as AV1451 and T807), along with amyloid PET imaging with Pittsburgh Compound B. Data were collected from June 2012 to April 2016.
The researchers assessed tau in the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with Alzheimer's-related pathologic mechanisms.
Since there's not yet a single gold-standard questionnaire for SCD, Amariglio and colleagues used a composite z-score from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire.
Overall, they found that higher SCD scores were associated with increasing entorhinal cortical tau burden (β=0.35, P<0.001) and greater amyloid burden (β=0.24, P=0.005) but not inferior temporal tau burden (β=0.10, P=0.27).
The association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for amyloid burden (β=0.36, P=0.001) and there was no interaction that influenced SCD, they reported.
An exploratory, post-hoc whole-brain analysis also showed that greater SCD was predominantly associated with greater tau burden in the entorhinal cortex, the researchers said.
The findings support a potential temporal sequence of events, with SCD marking one of the earliest behavioral changes among increasing pathologic changes in clinically healthy older adults, Amariglio and colleagues concluded, while conceding that SCD is still not predictive of progression to Alzheimer's disease.
In an accompanying editorial, Rik Ossenkoppele, PhD, of VU Medical Center in Amsterdam, and William Jagust, MD, of the University of California Berkeley, said the study is an "important advance in our understanding of SCD, but the interpretation is not straightforward because the independent variables (amyloid, tau, and depression) and the dependent variables (SCD) are complex and interrelated."
They cautioned that many older adults experience SCD, and doctors need better tools to assess it more completely and to better counsel their patients.
"A better understanding of how each specific molecular pathologic change is expressed in association with SCD at different stages of the development of Alzheimer's could lead to better methods of diagnosing Alzheimer's at preclinical stages, selecting individuals for early clinical trials, and ultimately effectively treating Alzheimer's at its earliest stages," they wrote.
Amariglio said a critical component for SCD evaluation going forward would be not just asking patients how their cognition is currently, but whether they've observed a change. Multiple questions are also necessary, as a lone benchmark every year may not be sensitive enough, she added.
In an analysis of data from the Harvard Aging Brain Study, those with more symptoms of subjective cognitive decline (SCD) had a higher burden of tau in this brain region, as measured in PET scans (β=0.35, P<0.001), Rebecca Amariglio, PhD, of Massachusetts General Hospital in Boston, and colleagues reported online in JAMA Neurology.
However, they didn't have greater tau buildup in the inferior temporal cortex, which is associated with later-stage disease -- suggesting that SCD could be an early indicator of tauopathy in clinically healthy older adults, the researchers said.
"Before tau spreads to the inferior temporal cortex, it has to pass through the entorhinal cortex, making the argument that the relationship with tau is a mix of people getting older and having more age-related complaints, and there may be a subset that likely represents the earliest path to Alzheimer's disease," Amariglio told MedPage Today.
Researchers have turned their attention to subjective cognitive complaints -- for instance, the feeling that your memory just isn't what it used to be -- as the field looks to identify earlier stages of disease in order to better prevent it. The term "subjective cognitive decline" has emerged as the leading concept, though there are not yet standard questionnaires and it is not recognized as a formal disease stage, like mild cognitive impairment (MCI).
Amariglio said her team's previous analyses of data from the Harvard Aging Brain Study have shown that healthy older adults with greater amyloid buildup had more cognitive complaints, as did those with greater hippocampal volume loss. And while other studies have tied greater cerebrospinal fluid (CSF) tau levels with worse cognitive complaints, this is the first to use imaging to get a direct assessment of tau deposition in the brain.
In this assessment, 133 clinically healthy participants (mean age 76, 56% women) had tau PET imaging with the flortaucipir 18F tracer (previously known as AV1451 and T807), along with amyloid PET imaging with Pittsburgh Compound B. Data were collected from June 2012 to April 2016.
The researchers assessed tau in the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with Alzheimer's-related pathologic mechanisms.
Since there's not yet a single gold-standard questionnaire for SCD, Amariglio and colleagues used a composite z-score from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire.
Overall, they found that higher SCD scores were associated with increasing entorhinal cortical tau burden (β=0.35, P<0.001) and greater amyloid burden (β=0.24, P=0.005) but not inferior temporal tau burden (β=0.10, P=0.27).
The association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for amyloid burden (β=0.36, P=0.001) and there was no interaction that influenced SCD, they reported.
An exploratory, post-hoc whole-brain analysis also showed that greater SCD was predominantly associated with greater tau burden in the entorhinal cortex, the researchers said.
The findings support a potential temporal sequence of events, with SCD marking one of the earliest behavioral changes among increasing pathologic changes in clinically healthy older adults, Amariglio and colleagues concluded, while conceding that SCD is still not predictive of progression to Alzheimer's disease.
In an accompanying editorial, Rik Ossenkoppele, PhD, of VU Medical Center in Amsterdam, and William Jagust, MD, of the University of California Berkeley, said the study is an "important advance in our understanding of SCD, but the interpretation is not straightforward because the independent variables (amyloid, tau, and depression) and the dependent variables (SCD) are complex and interrelated."
They cautioned that many older adults experience SCD, and doctors need better tools to assess it more completely and to better counsel their patients.
"A better understanding of how each specific molecular pathologic change is expressed in association with SCD at different stages of the development of Alzheimer's could lead to better methods of diagnosing Alzheimer's at preclinical stages, selecting individuals for early clinical trials, and ultimately effectively treating Alzheimer's at its earliest stages," they wrote.
Amariglio said a critical component for SCD evaluation going forward would be not just asking patients how their cognition is currently, but whether they've observed a change. Multiple questions are also necessary, as a lone benchmark every year may not be sensitive enough, she added.
The authors
disclosed financial relationships with Avid, Abbvie, Biogen, Bracket,
Genentech, Lundbeck, Roche, Sanofi, Eli Lilly, Janssen, Bayer, GE
Healthcare, Siemens Medical Solutions, Genzyme, Novartis, ISIS Pharma,
AZTherapy, and Navidea.
Jagust disclosed financial relationships with Bioclinica, Genentech, Biogen, and Novartis.
Jagust disclosed financial relationships with Bioclinica, Genentech, Biogen, and Novartis.
Primary Source
JAMA Neurology
Source Reference: Buckley RF, et al "Region-specific association of subjective cognitive decline with tauopathy independent of global amyloid burden" JAMA Neurol 2017; DOI: 10.1001/jamaneurol.2017.2216.Secondary Source
JAMA Neurology
Source Reference: Ossenkoppele R, Jagust WJ "The complexity of subjective cognitive decline" JAMA Neurol 2017; DOI: 10.1001/jamaneurol.2017.2224.
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