Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-β–related cognitive decline

Hua, Jun; Lee, Seung Wook; Blair, Nicholas I.S.; Wyss, Michael; Bergen, Jiri M.G. Van; Schreiner, Simon J.; Kagerer, Sonja M.; Leh, Sandra E.; Gietl, Anton; Treyer, Valérie; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Lu, Hanzhang; Zijl, Peter van; Albert, Marilyn; Höck, Christoph; Unschuld, Paul G.

doi:10.1016/j.neurobiolaging.2019.01.001

Cited by 12 publications

(26 citation statements)

References 112 publications

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“…A reduction of rCBV was found in patients with AD and mild cognitive impairment [97,98]. By contrast, one study used a method to assess arteriol rCBV and found an increase in several brain regions in patients with mild cognitive impairment compared to cognitively unimpaired controls [99]. This demonstrated that the contribution of different vascular compartments to rCBV changes should be more thoroughly investigated.…”

Section: Dysregulation Regional Rcbf and Volumementioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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Section: Dysregulation Regional Rcbf and Volumementioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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“…The iVASO MRI approach can measure CBV in small pial arteries and arterioles (CBVa) 28,48 , the primary regulator of local tissue perfusion. The iVASO method has been used to measure neurovascular abnormalities in human brains of several disease conditions, such as brain tumors 52 , HD 15 , Parkinson's disease 53 , Alzheimer's disease dementia 53,54 , and schizophrenia 55 . In the current study, we demonstrated that CBVa was significantly increased at premanifest stage in heterozygous zQ175 mice, while structural MRI measures showed significant striatal atrophy later, indicating that iVASO CBVa measures may be a sensitive biomarker for assessing therapeutic response in the premanifest HD clinical trials.…”

Section: Discussionmentioning

confidence: 99%

HTTsilencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

Liu

Zhang

et al. 2020

Preprint

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Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

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“…This second cohort was recruited at the University of Zurich, Switzerland. The current study uses recently published MRI and clinical data of this cohort ( 13 ). The published MRI data was reanalyzed using a different method in the current study (see Data Analysis).…”

Section: Methodsmentioning

confidence: 99%

“…Cerebrovascular abnormalities including altered cerebral blood flow (CBF), cerebral blood volume (CBV), and blood–brain barrier permeability ( 7 – 10 ) have been linked with pathophysiology in various dementias ( 11 , 12 ). Following those reports( 13 ), we previously used advanced neuroimaging methods to show increased volumes of small pial arteries and arterioles (arteriolar cerebral blood volume, CBVa) in several brain regions such as the orbitofrontal cortex and the hippocampus in elderly adults with mild cognitive impairment (MCI) compared with the volumes of those in age-matched elderly controls. Cerebral vascular risk factors have also been associated with PDD.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the measurement of changes in CBVa may provide a more sensitive marker than measurement of changes in total CBV and CBF, which include both arteriolar and venous vessels. Hua et al ( 13 ) have previously reported on the MCI without movement disorder cohort and their data has been reanalyzed here with a different approach (see Methods). Based on the literature discussed previously, CBVa in preselected brain regions was calculated and compared in patients and matched controls in each cohort, with the goal of finding brain regions with altered CBVa that are specific to PD with normal cognition, PD with impaired cognition, and MCI without movement disorder.…”

Section: Introductionmentioning

confidence: 99%

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Differential Changes in Arteriolar Cerebral Blood Volume between Parkinson’s Disease Patients with Normal and Impaired Cognition and Mild Cognitive Impairment (MCI) Patients without Movement Disorder—An Exploratory Study

Paez

Rajan

et al. 2020

Tomography

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Cognitive impairment amongst Parkinson’s disease (PD) patients is highly prevalent and associated with an increased risk of dementia. There is growing evidence that altered cerebrovascular functions contribute to cognitive impairment. Few studies have compared cerebrovascular changes in PD patients with normal and impaired cognition and those with mild-cognitive-impairment (MCI) without movement disorder. Here, we investigated arteriolar-cerebral-blood-volume (CBVa), an index reflecting the homeostasis of the most actively regulated segment in the microvasculature, using advanced MRI in various brain regions in PD and MCI patients and matched controls. Our goal is to find brain regions with altered CBVa that are specific to PD with normal and impaired cognition, and MCI-without-movement-disorder, respectively. In PD patients with normal cognition (n=10), CBVa was significantly decreased in the substantia nigra, caudate and putamen when compared to controls. In PD patients with impaired cognition (n=6), CBVa showed a decreasing trend in the substantia nigra, caudate and putamen, but was significantly increased in the presupplementary motor area and intracalcarine gyrus compared to controls. In MCI-patients-without-movement-disorder (n=18), CBVa was significantly increased in the caudate, putamen, hippocampus and lingual gyrus compared to controls. These findings provide important information for efforts towards developing biomarkers for the evaluation of potential risk of PD dementia (PDD) in PD patients. The current study is limited in sample size and therefore is exploratory in nature. The data from this pilot study will serve as the basis for power analysis for subsequent studies to further investigate and validate the current findings.

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Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-β–related cognitive decline

Cited by 12 publications

References 112 publications

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

HTTsilencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

Differential Changes in Arteriolar Cerebral Blood Volume between Parkinson’s Disease Patients with Normal and Impaired Cognition and Mild Cognitive Impairment (MCI) Patients without Movement Disorder—An Exploratory Study

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