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Vascular Cognitive Impairment Neuropathology Guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment

Published on Nov 1, 2016in Brain11.81
· DOI :10.1093/brain/aww214
Olivia Skrobot7
Estimated H-index: 7
(UoB: University of Bristol),
Johannes Attems44
Estimated H-index: 44
(Newcastle University)
+ 10 AuthorsSeth Love54
Estimated H-index: 54
(UoB: University of Bristol)
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Abstract
There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwet’s AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45–0.91) and microinfarcts (0.52–0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies—leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss—predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment. * Abbreviations : CAA : cerebral amyloid angiopathy MMSE : Mini-Mental State Examination ROC : receiver operating characteristic VCI : vascular cognitive impairment VCING : vascular cognitive impairment neuropathology guidelines
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  • References (68)
  • Citations (47)
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References68
Newest
Published on Jan 1, 2017in Journal of Cerebral Blood Flow and Metabolism6.04
Eseosa T. Ighodaro9
Estimated H-index: 9
(UK: University of Kentucky),
Erin L. Abner31
Estimated H-index: 31
(UK: University of Kentucky)
+ 13 AuthorsSarah E. Monsell18
Estimated H-index: 18
(UW: University of Washington)
Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinical-pathological correlations in the “oldest-old” compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyze...
Published on Jul 1, 2016in Brain Pathology6.16
J. Scott Miners16
Estimated H-index: 16
(UoB: University of Bristol),
Jennifer Palmer12
Estimated H-index: 12
(UoB: University of Bristol),
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol)
The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post-mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin-1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin-associated glycoprotein:pr...
Published on May 1, 2016in Acta Neuropathologica18.17
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol),
J. Scott Miners16
Estimated H-index: 16
(UoB: University of Bristol)
Cerebrovascular disease (CVD) and Alzheimer’s disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting fi...
Published on Feb 22, 2016in Journal of Alzheimer's Disease3.70
Emma L. Ashby9
Estimated H-index: 9
(UoB: University of Bristol),
James Scott Miners14
Estimated H-index: 14
(UoB: University of Bristol)
+ 1 AuthorsSeth Love54
Estimated H-index: 54
(UoB: University of Bristol)
Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid- (A) pathology. In contrast, anti- hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on A plaqu...
Published on Dec 1, 2015in Acta neuropathologica communications
Kirsty E. McAleese7
Estimated H-index: 7
(Newcastle University),
Michael J. Firbank46
Estimated H-index: 46
(Newcastle University)
+ 8 AuthorsJohn T. O'Brien97
Estimated H-index: 97
(University of Cambridge)
Introduction Cerebral white matter lesions (WML), visualized as white matter hyperintensities (WMH) on T2-weighted MRI, encompass structural damage and loss of integrity of the cerebral white matter (WM) and are commonly assumed to be associated with small vessel disease (SVD). However, it has been suggested that WM damage may also be the result of degenerative axonal loss that is secondary to cortical Alzheimer’s disease (AD) pathologies i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ)...
Published on Dec 1, 2015in Alzheimers & Dementia14.42
Giuseppe Tosto15
Estimated H-index: 15
(Columbia University),
Molly E. Zimmerman35
Estimated H-index: 35
(Albert Einstein College of Medicine)
+ 2 AuthorsAdam M. Brickman56
Estimated H-index: 56
(Columbia University)
Abstract Introduction It is unclear whether white matter hyperintensities (WMHs), magnetic resonance imaging markers of small-vessel cerebrovascular disease, promote neurodegeneration and associated clinical decline in Alzheimer's disease (AD), or simply co-occur with recognized pathogenic processes. Methods In 169 patients with mild cognitive impairment, followed for 3 years, we examined the association of (1) baseline regional WMH and cerebral spinal fluid–derived t-tau (total tau) with entorh...
Published on Apr 1, 2015in Brain11.81
Tl Thomas4
Estimated H-index: 4
(UoB: University of Bristol),
Scott Miners4
Estimated H-index: 4
(UoB: University of Bristol),
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol)
Perfusion is reduced in the cerebral neocortex in Alzheimer’s disease. We have explored some of the mechanisms, by measurement of perfusion-sensitive and disease-related proteins in post-mortem tissue from Alzheimer’s disease, vascular dementia and age-matched control brains. To distinguish physiological from pathological reduction in perfusion (i.e. reduction exceeding the decline in metabolic demand), we measured the concentration of vascular endothelial growth factor (VEGF), a protein induced...
Published on Jan 1, 2015in Brain Pathology6.16
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol),
J. Scott Miners16
Estimated H-index: 16
(UoB: University of Bristol)
Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the whit...
Published on Jul 1, 2014in Brain Pathology6.16
Scott Miners4
Estimated H-index: 4
(UoB: University of Bristol),
Hayley Moulding1
Estimated H-index: 1
(UoB: University of Bristol)
+ 1 AuthorsSeth Love54
Estimated H-index: 54
(UoB: University of Bristol)
In dementia with Lewy bodies (DLB), blood flow tends to be reduced in the occipital cortex. We previously showed elevated activity of the endothelin and angiotensin pathways in Alzheimer's disease (AD). We have measured endothelin-1 (ET-1) level and angiotensin-converting enzyme (ACE) activity in the occipital cortex in DLB and control brains. We also measured vascular endothelial growth factor (VEGF); factor VIII-related antigen (FVIIIRA) to indicate microvessel density; myelin-associated glyco...
Published on May 1, 2014in Brain11.81
Rachel Barker7
Estimated H-index: 7
(UoB: University of Bristol),
Emma L. Ashby9
Estimated H-index: 9
(UoB: University of Bristol)
+ 5 AuthorsSeth Love54
Estimated H-index: 54
(UoB: University of Bristol)
Little is known about the contributors and physiological responses to white matter hypoperfusion in the human brain. We previously showed the ratio of myelin-associated glycoprotein to proteolipid protein 1 in post-mortem human brain tissue correlates with the degree of ante-mortem ischaemia. In age-matched post-mortem cohorts of Alzheimer’s disease (n = 49), vascular dementia (n = 17) and control brains (n = 33) from the South West Dementia Brain Bank (Bristol), we have now examined the relatio...
Cited By47
Newest
Published on Feb 7, 2019in Acta neuropathologica communications
Yoshiki Hase9
Estimated H-index: 9
(Newcastle University),
Ren Ding1
Estimated H-index: 1
(Newcastle University)
+ 7 AuthorsRaj N. Kalaria39
Estimated H-index: 39
(Newcastle University)
Previous studies suggest white matter (WM) integrity is vulnerable to chronic hypoperfusion during brain ageing. We assessed ~ 0.7 million capillary profiles in the frontal lobe WM across several dementias comprising Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease with dementia, vascular dementia, mixed dementias, post-stroke dementia as well as post-stroke no dementia and similar age ageing and young controls without significant brain pathology. Standard histopathological me...
Published on 2019in Neuropathology and Applied Neurobiology6.88
Stefanie Schreiber16
Estimated H-index: 16
(Otto-von-Guericke University Magdeburg),
Annette Wilisch-Neumann6
Estimated H-index: 6
(Otto-von-Guericke University Magdeburg)
+ 7 AuthorsDavid J. Werring40
Estimated H-index: 40
(UCL Institute of Neurology)
Published on 2019in Brain Pathology6.16
Yoshiki Hase9
Estimated H-index: 9
(Newcastle University),
Tuomo Polvikoski28
Estimated H-index: 28
(Newcastle University)
+ 7 AuthorsRose Anne Kenny63
Estimated H-index: 63
(Trinity College, Dublin)
Autonomic dysfunction may affect brain blood flow and result in intermittent cerebral hypoperfusion, which is recognised as a cause of cognitive impairment and dementia. We assessed the burden of small vessel disease pathology in elderly subjects who had clinical evidence of autonomic dysfunction and had developed neurodegenerative dementias or vascular dementia (VaD). Clinical and neuropathological diagnosis in 118 subjects comprised dementia with Lewy bodies (DLB), Parkinson’s disease with dem...
Published on May 1, 2019in Lancet Neurology28.75
Joanna M. Wardlaw86
Estimated H-index: 86
(Edin.: University of Edinburgh),
Catherine Smith59
Estimated H-index: 59
(Medical Research Council)
+ 0 AuthorsMartin Dichgans74
Estimated H-index: 74
(LMU: Ludwig Maximilian University of Munich)
Summary Small vessel disease is a disorder of cerebral microvessels that causes white matter hyperintensities and several other common abnormalities (eg, recent small subcortical infarcts and lacunes) seen on brain imaging. Despite being a common cause of stroke and vascular dementia, the underlying pathogenesis is poorly understood. Research in humans has identified several manifestations of cerebral microvessel endothelial dysfunction including blood–brain barrier dysfunction, impaired vasodil...
Published on Apr 4, 2019in Brain11.81
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol),
James A. R. Nicoll57
Estimated H-index: 57
+ 6 AuthorsClive Holmes55
Estimated H-index: 55
Published on Jan 1, 2019in International Journal of Molecular Sciences4.18
Virginia Cipollini2
Estimated H-index: 2
,
Fernanda Troili , Franco Giubilei27
Estimated H-index: 27
Vascular pathology is the second most common neuropathology of dementia after Alzheimer’s disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers includin...
Published on Jun 1, 2019in Journal of Neurology, Neurosurgery, and Psychiatry8.27
Audun Osland Vik-Mo9
Estimated H-index: 9
,
János Bencze3
Estimated H-index: 3
(University of Debrecen)
+ 2 AuthorsDag Aarsland88
Estimated H-index: 88
Psychotic symptoms may occur in any dementia, including Alzheimer’s disease (AD), but are particularly common in Lewy body dementia (LBD). The mechanisms of psychotic symptoms are largely unknown. Psychosis has been found to be associated with more severe AD and Lewy body pathology in patients with AD and cerebrovascular disease-related vasculopathy.1 One form of vascular pathology, cerebral amylod angiopathy (CAA), is defined as deposits of amyloid in the vessel walls that increase risk of haem...
Published on May 21, 2019in British Journal of Pharmacology6.58
Pedram Honarpisheh (University of Texas at Austin), Louise D. McCullough52
Estimated H-index: 52
(University of Texas at Austin)
Published on May 15, 2019in International Journal of Molecular Sciences4.18
Jakub Hort20
Estimated H-index: 20
,
Martin Vališ14
Estimated H-index: 14
+ 1 AuthorsFrancesco Angelucci1
Estimated H-index: 1
Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectivel...
Published on May 1, 2019in Neuroscience Letters2.17
Eleni Gkanatsiou2
Estimated H-index: 2
(University of Gothenburg),
Erik Portelius39
Estimated H-index: 39
(University of Gothenburg)
+ 4 AuthorsGunnar Brinkmalm25
Estimated H-index: 25
(University of Gothenburg)
Abstract Cerebral amyloid angiopathy (CAA) is a type of vascular disease present in more than 50% of demented elderly and more than 80% of Alzheimer’s disease (AD) patients. Both CAA and AD are characterized by extracellular Aβ deposits with the distinction that CAA has vascular deposits while AD has amyloid plaques. In this study, we used immunoprecipitation (IP) in combination with mass spectrometry (MS) to test the hypothesis that the Aβ peptide pattern differs between subjects having Aβ plaq...
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