Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.
SchneiderJAArvanitakisZBangW, et al.
Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology2007;
69: 2197–2204.
2.
WardlawJMSmithEEBiesselsGJ, et al.
Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol2013;
12: 822–838.
3.
CaprihanAHillmerLErhardtEB, for Alzheimer’s Disease Neuroimaging Initiativeet al.
A trichotomy method for defining homogeneous subgroups in a dementia population. Ann Clin Transl Neurol2023;
10: 1802–1815.
4.
De GrootJCDe LeeuwFEOudkerkM, et al.
Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol2002;
52: 335–341.
5.
DeCarliCMurphyDGTranhM, et al.
The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology1995;
45: 2077–2084.
6.
YezhuvathUSUhJChengY, et al.
Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer’s disease. Neurobiol Aging2012;
33: 75–82.
7.
CantinSVillienMMoreaudO, et al.
Impaired cerebral vasoreactivity to CO2 in Alzheimer’s disease using BOLD fMRI. Neuroimage2011;
58: 579–587.
8.
GlodzikLRusinekHBrysM, et al.
Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab2011;
31: 671–679.
9.
ChungCCPimentel MaldonadoDAJor’danAJ, et al.
Lower cerebral vasoreactivity as a predictor of gait speed decline in type 2 diabetes mellitus. J Neurol2018;
265: 2267–2276.
10.
Jor’danAJManorBNovakV.Slow gait speed – an indicator of lower cerebral vasoreactivity in type 2 diabetes mellitus. Front Aging Neurosci2014;
6: 135.
11.
SorondFAGalicaASerradorJM, et al.
Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston study. Neurology2010;
74: 1627–1633.
12.
SilvestriniMPasqualettiPBaruffaldiR, et al.
Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke2006;
37: 1010–1015.
13.
VicenziniERicciardiMCAltieriM, et al.
Cerebrovascular reactivity in degenerative and vascular dementia: a transcranial doppler study. Eur Neurol2007;
58: 84–89.
14.
WiseRGHarrisADStoneAJ, et al.
Measurement of OEF and absolute CMRO2: MRI-based methods using interleaved and combined hypercapnia and hyperoxia. Neuroimage2013;
83: 135–147.
15.
MarshallOChawlaSLuH, et al.
Cerebral blood flow modulation insufficiency in brain networks in multiple sclerosis: a hypercapnia MRI study. J Cereb Blood Flow Metab2016;
36: 2087–2095.
16.
JahanianHChristenTMoseleyME, et al.
Measuring vascular reactivity with resting-state blood oxygenation level-dependent (BOLD) signal fluctuations: a potential alternative to the breath-holding challenge?J Cereb Blood Flow Metab2017;
37: 2526–2538.
17.
HalaniSKwintaJBGolestaniAM, et al.
Comparing cerebrovascular reactivity measured using BOLD and cerebral blood flow MRI: the effect of basal vascular tension on vasodilatory and vasoconstrictive reactivity. Neuroimage2015;
110: 110–123.
18.
de la TorreJC.Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol2004;
3: 184–190.
19.
DaiWLopezOLCarmichaelOT, et al.
Mild cognitive impairment and Alzheimer disease: patterns of altered cerebral blood flow at MR imaging. Radiology2009;
250: 856–866.
20.
AlbertMSDeKoskySTDicksonD, et al.
The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the national institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011;
7: 270–279.
21.
NasreddineZSPhillipsNABedirianV, et al.
The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc2005;
53: 695–699.
22.
GuralnikJMSimonsickEMFerrucciL, et al.
A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol1994;
49: M85–94.
23.
MorrisJC.The clinical dementia rating (CDR): current version and scoring rules. Neurology1993;
43: 2412–2414.
24.
O’BryantSEWaringSCCullumCM, et al.
Staging dementia using clinical dementia rating scale sum of boxes scores: a Texas Alzheimer’s research consortium study. Arch Neurol2008;
65: 1091–1095.
25.
De VisJBLuHRaviH, et al.
Spatial distribution of flow and oxygenation in the cerebral venous drainage system. J Magn Reson Imaging2018;
47: 1091–1098.
26.
MoriSWCeritogluCLiY, et al.
MRICloud: delivering high-throughput MRI neuroinformatics as cloud-based software as a service. Comput Sci Eng2016;
18: 21–35.
27.
Annexes A–D. Annals of the ICRP2009; 39: 47–70.
28.
SurSLinZLiY, et al.
Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance. Neurology2020;
95: e962–e972.
29.
PeresonSVandersteenADekeyserF, et al.
From innotest to the fully automated chemiluminescent b-amyloid(1-42) and total tau assays on the LUMIPULSE® G instrument series: taking quantification of Alzheimer’s disease CSF biomarkers to the next level. Alzheimer’s & Dementia2015;
11: P868.
30.
FazekasFChawlukJBAlaviA, et al.
MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol1987;
149: 351–356.
31.
RosenbergAÖhlund-WistbackaUHallA, et al.
β-Amyloid, tau, neurodegeneration classification and eligibility for anti-amyloid treatment in a memory clinic population. Neurology2022;
99: e2102–e2113.
32.
AlcoleaDPeguerolesJMuñozL, et al.
Agreement of amyloid PET and CSF biomarkers for Alzheimer’s disease on lumipulse. Ann Clin Transl Neurol2019;
6: 1815–1824.
33.
DumurgierJArtaudFTouraineC, et al.
Gait speed and decline in gait speed as predictors of incident dementia. J Gerontol A Biol Sci Med Sci2017;
72: 655–661.
DonahueMJDethrageLMFaracoCC, et al.
Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis. Stroke2014;
45: 2335–2341.
36.
DonahueMJStrotherMKLindseyKP, et al.
Time delay processing of hypercapnic fMRI allows quantitative parameterization of cerebrovascular reactivity and blood flow delays. J Cereb Blood Flow Metab2016;
36: 1767–1779.
37.
PetersenETZimineIHoYC, et al.
Non-invasive measurement of perfusion: a critical review of arterial spin labelling techniques. Br J Radiol2006;
79: 688–701.
38.
AslanSXuFWangPL, et al.
Estimation of labeling efficiency in pseudocontinuous arterial spin labeling. Magn Reson Med2010;
63: 765–771.
39.
MarshallOLuHBrissetJC, et al.
Impaired cerebrovascular reactivity in multiple sclerosis. JAMA Neurol2014;
71: 1275–1281.
GaoYZZhangJJLiuH, et al.
Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer’s disease and vascular dementia assessed by arterial spinlabeling magnetic resonance imaging. Curr Neurovasc Res2013;
10: 49–53.
42.
FicoBGMillerKBRivera-RiveraLA, et al.
Cerebral hemodynamics comparison using transcranial doppler ultrasound and 4D flow MRI. Front Physiol2023;
14: 1198615.
43.
CipolliniVSetteGBossùP, et al.
Neurovascular dysfunction in Alzheimer disease: assessment of cerebral vasoreactivity by ultrasound techniques and evaluation of circulating progenitor cells and inflammatory markers. Alzheimer Dis Assoc Disord2019;
33: 212–219.
44.
LimEYYangDWChoAH, et al.
Cerebrovascular hemodynamics on transcranial doppler ultrasonography and cognitive decline in mild cognitive impairment. J Alzheimers Dis2018;
65: 651–657.
45.
ShimYYoonBShimDS, et al.
Cognitive correlates of cerebral vasoreactivity on transcranial doppler in older adults. J Stroke Cerebrovasc Dis2015;
24: 1262–1269.
46.
StefaniASancesarioGPierantozziM, et al.
CSF biomarkers, impairment of cerebral hemodynamics and degree of cognitive decline in Alzheimer’s and mixed dementia. J Neurol Sci2009;
283: 109–115.
LikitjaroenYSuwanwelaNCPhanthumchindaK.Vasoreactivity induced by acetazolamide in patients with vascular dementia versus Alzheimer’s disease. J Neurol Sci2009;
283: 32–35.
49.
GucuyenerDOYenilmezCAyranciU, et al.
An analysis of changes in cerebral blood flood velocities in depressive pseudo-dementia and Alzheimer disease patients. Neurologist2010;
16: 358–363.
50.
MarmarelisVZShinDCTarumiT, et al.
Comparison of Model-Based indices of cerebral autoregulation and vasomotor reactivity using transcranial doppler versus near-infrared spectroscopy in patients with amnestic mild cognitive impairment. J Alzheimers Dis2017;
56: 89–105.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
