Background Accumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer’s Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBFVis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort. Methods 64 subjects participated in the present study. ΔCBFVis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) and [18F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI. Results ΔCBFVis.Act. correlated negatively (<InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2024_1652_Article_IEq1.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBFVis.Act. did not correlate with FDG SUVr (<InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2024_1652_Article_IEq2.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness (<InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2024_1652_Article_IEq3.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation (<InlineEquation ID="IEq4"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2024_1652_Article_IEq4.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex (<InlineEquation ID="IEq5"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2024_1652_Article_IEq5.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26). Conclusion We found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease.

The cerebral blood flow response to neuroactivation is reduced in cognitively normal men with β-amyloid accumulation

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2025年1月4日

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Mark Bitsch Vestergaard,
Aftab Bakhtiari,
Merete Osler,
Erik Lykke Mortensen,
Ulrich Lindberg,
Ian Law,
Martin Lauritzen,
Krisztina Benedek,
Henrik Bo Wiberg Larsson

摘要

Background

Accumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer’s Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBF_Vis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort.

Methods

64 subjects participated in the present study. ΔCBF_Vis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [¹¹C]Pittsburgh Compound-B (PiB) and [¹⁸F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI.

Results

ΔCBF_Vis.Act. correlated negatively ( $\beta$ $β$ = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBF_Vis.Act. did not correlate with FDG SUVr ( $\beta$ $β$ = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness ( $\beta$ $β$ = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation ( $\beta$ $β$ = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex ( $\beta$ $β$ = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26).

Conclusion

We found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease.