Review: Vascular dementia: clinicopathologic and genetic considerations

Vinters, Harry V.; Zarow, Chris; Borys, Ewa; Whitman, Jeffrey D.; Tung, Steve; Ellis, William G.; Zheng, Ling; Chui, Helena C.

doi:10.1111/nan.12472

Cited by 86 publications

(58 citation statements)

References 146 publications

(181 reference statements)

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“…This was corroborated by low vascular pathology scores and SI values in DLB subjects without clear evidence of autonomic dysfunction. Whereas the highest burden of SVD pathology consisting of microinfarcts, lacunar infarcts, severe arteriolosclerosis, WM rarefaction and perivascular spacing was present in VaD, it was rather surprising that subjects diagnosed with neurodegenerative dementias including PDD, DLB and AD exhibited these similar microvascular changes particularly severe arteriolosclerosis and perivascular spacing. SI values were higher by 45%–50% signifying moderate‐severe arteriolosclerosis in dementia cases with autonomic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Large vessel disease may also contribute to SVD type of changes in the WM and to microinfarcts . In comparison to the neurodgenerative dementias, VaD subjects bear greater degrees of large vessel disease, that is, intracranial and extracranial atherosclerotic disease.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we tested the hypothesis that there is increased small vessel disease (SVD) or microvascular pathology in patients with clinical evidence of autonomic dysfunction or in those with repeated unexplained falls or syncope and progress to dementia. We performed clinicopathological studies to explore the extent of SVD pathological changes in patients exhibiting signs of autonomic dysfunction and had developed dementia.…”

Section: Introductionmentioning

confidence: 99%

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Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

et al. 2019

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We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD‐DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α‐synuclein pathology. We found moderate‐severe vascular changes and high‐vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub‐set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α‐synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging‐related neurodegenerative disorders and characterize their end‐stage clinical syndromes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

et al. 2019

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“…Complementarily, feature occlusion studies illustrated that the central amyloid core is the most discerning feature of a cored plaque's correct identification, and that its occlusion transforms a CNN model's classification to diffuse plaque. Importantly, the crucial features emerging from these machine learning introspection techniques-dense compact amyloid centers for cored plaques, ill-defined amorphous amyloid deposits for diffuse plaques, and amyloid within the media of the cortical vessels for CAAs -all a gree with key features used by experts 1,11,62,63 .…”

Section: Discussionmentioning

confidence: 99%

Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline

Tang

Chuang

DeCarli

et al. 2018

Preprint

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Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies.Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization.We report a proof-of-concept deep learning pipeline identifying specific neuropathologies-amyloid plaques and cerebral amyloid angiopathy-in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotated >70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieved strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualized morphology distributions for WSIs at high resolution. Resulting plaque-burden scores correlated well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrated that networks learned patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist's ability may suggest a route to neuropathologic deep phenotyping. KeywordsMachine learning, Alzheimer's disease, amyloid, deep learning, deep phenotyping, interpretability, explainable AI, convolutional neural networks, dementia, immunohistochemistry, plaques, pathology.Extracellular deposition of amyloid beta (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD) 1,2 , a common neurodegenerative disease. Amyloid plaques have a diverse range of morphologies and neuroanatomic distributions 1 . The current consensus criteria for a neuropathological diagnosis of AD [3][4][5] incorporate protocols assessing plaque density and distribution; some researchers have hypothesized that plaques may be an initiating event in AD 5,6 . More precise measures of plaque morphologies (such as cored, neuritic, and diffuse) can serve as a basis for understanding disease progression and pathophysiology, providing guidance and insight into disease mechanisms 2,7-10 .For neuropathologic diagnosis, established semi-quantitative scales are used to assess plaque burden ( Fig. 1a ) 4,8,11,12 . The standard semi-quantitative criteria put forth by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) based on the manual assessment of the highest density of neocortical neuritic plaques 4,13 . Diffuse plaques, which may be the initial morphological type of Aβ 14,15 , can account for over 50% of plaque burden in preclinical cases but are not included in CERAD 16 . Furthermore, data on anatomical location ( i.e. Thal amyloid phase) are based on the presence of plaques regardless of type or density 5 . The potential for neuropathologic deep phenotyping efforts that account for anatomic location, diverse sources of proteinopathy, and quantitative pathology densities motivates the development of effective and scalable quantitative methods to differentiate pathological subty...

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“…In addition to NAMs, antagonists at 5-containing GABA A receptors have also been shown to produce enhancements in cognitive functioning [44,74]. For example, an antagonist, S44819, has recently been shown to be active in rodent models of vascular cognitive impairment [75], a disorder of high prevalence in the geriatric community [76]. S44819 has been studied in healthy humans where it was shown to increase cortical excitability [77].…”

Section: Figurementioning

confidence: 99%

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

Witkin¹,

Golani²,

Cerne³

et al. 2019

obm geriatr

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Major depressive disorder is a highly-prevalent and debilitating disorder in the aged population. Accumulating clinical evidence suggests a key role for social support in helping to mitigate depression. Preclinical data are reviewed that indicate that selective negative allosteric modulation of 5-containing GABA A receptors, as with RY-080, might rapidly impact depression in patients. Further, preclinical data in transgenic mice modeling neurodegenerative diseases has suggested that this mechanism might also function to reduce agitation and aggression. These data are discussed in terms of the concept of

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Review: Vascular dementia: clinicopathologic and genetic considerations

Cited by 86 publications

References 146 publications

Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

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