Changes in Brain Function Occur Years before the Onset of Cognitive Impairment

Beason‐Held, Lori L.; Goh, Joshua Oon Soo; An, Yang; Kraut, Michael A.; O’Brien, Richard; Ferrucci, Luigi; Resnick, Susan M.

doi:10.1523/jneurosci.1402-13.2013

Cited by 220 publications

(154 citation statements)

References 45 publications

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“…In interpreting our 15 O-water PET results, we propose that longitudinal decrements in rCBF in brain regions mediating higher-order cognitive processes, such as the superior temporal and medial frontal cortices, represent early signatures of failing synaptic function related to lower SPARCL1 gene expression [52–54]. Conversely, brain regions showing longitudinal increases in rCBF may represent compensatory changes in neuronal activity that may be recruited to maintain normal cognitive function in at-risk individuals [55–57]. In this context, it is striking that minor allele carriers of SPARCL1 show greater longitudinal increases in rCBF in the precuneus and inferior temporal cortex, which are brain regions especially vulnerable to Aβ deposition and tau accumulation, respectively [58, 59].…”

Section: Discussionmentioning

confidence: 97%

SPARCL1 Accelerates Symptom Onset in Alzheimer’s Disease and Influences Brain Structure and Function During Aging

Seddighi

Varma

et al. 2017

JAD

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We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer’s disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

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Section: Discussionmentioning

confidence: 97%

SPARCL1 Accelerates Symptom Onset in Alzheimer’s Disease and Influences Brain Structure and Function During Aging

Seddighi

Varma

et al. 2017

JAD

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“…Evidence from a 2013 PET study suggests that those who later develop MCI demonstrate a greater increase in perfusion over time in orbitofrontal, medial frontal and anterior cingulate regions, compared to those who do not develop MCI, and that MCI converters show greater CBF decreases in parietal, temporal and thalamic regions (Beason-Held et al 2013). A 2015 study also found that, compared to cognitively stable participants, those who showed subtle cognitive decline at an 18-month follow-up demonstrated reduced CBF at baseline, most notably in the posterior cingulate cortex, an area commonly associated with AD.…”

Section: Cbf In Cognitive Riskmentioning

confidence: 99%

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

2016

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There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease-modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment (MCI) and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.

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“…Beason-Held and colleagues recently demonstrated that resting CBF is sensitive to predict conversion to MCI [49]. Compared to individuals who remained cognitively normal, adults who later developed MCI showed hyperperfusion in orbitofrontal, medial frontal and anterior cingulate regions over time, with decreased CBF in parietal, temporal and thalamic regions.…”

Section: Resting Cbf As a Predictive Toolmentioning

confidence: 99%

“…This suggests that increases and decreases in CBF take place years before the onset of cognitive symptoms in individuals who eventually develop cognitive impairment. Most of these changes were seen in areas that reflect early AD pathology and are thought to be associated with maintaining cognitive function, suggesting a connection between early changes in CBF and AD pathology [49]. …”

Section: Resting Cbf As a Predictive Toolmentioning

confidence: 99%

Cerebral Blood Flow Measured by Arterial Spin Labeling MRI as a Preclinical Marker of Alzheimer's Disease

Wierenga

Hays

Zlatar

2014

JAD

192

165

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There is growing recognition that cerebral hypoperfusion is related to the pathogenesis of Alzheimer’s disease (AD), implicating the measurement of cerebral blood flow (CBF) as a possible biomarker of AD. The ability to identify the earliest and most reliable markers of incipient cognitive decline and clinical symptoms is critical to develop effective preventive strategies and interventions for AD. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) measures CBF by magnetically labeling arterial water and using it as an endogenous tracer. Studies using ASL MRI in humans indicate that CBF changes are present several years before the development of the clinical symptoms of AD. Moreover, ASL-measured CBF has been shown to distinguish between cognitively normal individuals, adults at risk for AD, and persons diagnosed with AD. Some studies indicate that CBF may even be sensitive for predicting cognitive decline and conversion to mild cognitive impairment and AD over time. Taken together, evidence suggests that the current staging models of AD biomarker pathology should incorporate early changes in CBF as a useful biomarker, possibly present even earlier than amyloid β accumulation. Though still a research tool, ASL imaging is a promising non-invasive and reliable method with the potential to serve as a future clinical tool for the measurement of CBF in preclinical AD.

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Changes in Brain Function Occur Years before the Onset of Cognitive Impairment

Cited by 220 publications

References 45 publications

SPARCL1 Accelerates Symptom Onset in Alzheimer’s Disease and Influences Brain Structure and Function During Aging

SPARCL1 Accelerates Symptom Onset in Alzheimer’s Disease and Influences Brain Structure and Function During Aging

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

Cerebral Blood Flow Measured by Arterial Spin Labeling MRI as a Preclinical Marker of Alzheimer's Disease

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