Back to the future: Alzheimer's disease heterogeneity revisited

Au, Rhoda; Piers, Ryan J.; Lancashire, Lee

doi:10.1016/j.dadm.2015.05.006

Cited by 44 publications

(39 citation statements)

References 17 publications

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“…Interestingly, when we measured the HKi/c levels in the plasma of 10 AD patients, two AD cases did not have more HKc than HKi, consistent with the less FXII activation determined by Western blot [14]. One explanation of lower HKi cleavage in some AD cases is that AD is a complex, heterogeneous disease that likely has different driving mechanisms for different patients [20,24]. It is possible that disease in these individuals is driven by a different mechanism, one that does not involve FXII activation or has FXII activation as a by-product.…”

Section: Discussionsupporting

confidence: 58%

A novel detection method of cleaved plasma high‐molecular‐weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

Yamamoto-Imoto

Zamolodchikov

Chen

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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Introduction Accumulation of β-amyloid is a pathological hallmark of Alzheimer's disease (AD). β-Amyloid activates the plasma contact system leading to kallikrein-mediated cleavage of intact high-molecular-weight kininogen (HKi) to cleaved high-molecular-weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed. Methods HKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate. Results We generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores. Discussion High levels of plasma HKc could be used as an innovative biomarker for AD.

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Section: Discussionsupporting

confidence: 58%

A novel detection method of cleaved plasma high‐molecular‐weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

Yamamoto-Imoto

Zamolodchikov

Chen

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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“…Although there are many potential alternate approaches to developing research guidelines in Alzheimer's disease [7][8][9][10][11][12] in 2018 the NIA relapsed back to a much narrow definition of the disease. This new Research Framework: Toward a biological definition of Alzheimer's disease headed by Clifford Jack (referred to as the Framework) [4] embraces a piecemeal framework that focuses on two biological markers correlated with Alzheimer's disease while discounting the clinical expression of the disease.…”

Section: The Problemmentioning

confidence: 99%

The argument against crowdfunding Alzheimer’s disease research

Garrett

2019

Adv Health Behav

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With pharmaceutical companies' repeated failures at finding effective interventions for Alzheimer's disease, together with an increasing reliance on the growing Federal funding for research, there is an emergent opportunity for financing alternate research through crowdfunding. Crowdfundingwhere funding is obtained from small donations from a large group of peoplehas become a new source of funding for medical research. By understanding how the research community has evolved to study Alzheimer's disease the pitfalls of this strategy can be highlighted. Alzheimer's disease research is complex. From its inception in the early 1900s, Alzheimer's disease has been at the center of movement within psychiatry to define the disease on the basis of its biology. Recent emphasisthrough the DSM (Diagnostic and Statistical Manual of Mental Disorders), RDoC (Research Diagnostic Criteria), RDoC (Research Domain Criteria) as well as the more recent Framework from the U.S. National Institute on Aginghave supported an exclusive emphasis on biology. But by excluding other aspects of the disease, such as its clinical expression, this research approach will be shown to be faulty and contradictory. So far this approach has resulted in 100% failures. By examining the historical and financial circumstances of the industry centered on Alzheimer's disease a strong warning is given to the public to mistrust crowdfunding Alzheimer's disease research. A broader and more inclusive approach is likely to generate a better understanding of the disease and therefore hold better promise for understanding the disease in the long term. Such a nuance approach competes badly with the more binary search for a cure and is less receptive to public support through crowdfunding.

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“…Alzheimer's disease (AD) is a complex neurodegenerative process with multiple etiologies and highly variable phenotypic presentations. [1] Regardless, there is clear consensus in the field that abnormally high levels of neocortical beta-amyloid (Aβ+) indicate AD pathology in persons with clinical evidence of dementia or mild cognitive impairment (MCI). [2][3][4][5] With the advent of in vivo detection of levels of cerebral beta-amyloid (Aβ) using positron emission tomography (PET) scans, [6] recent prospective studies have shown that, when followed prospectively, Aβ+ cognitively healthy older adults show an increased rate of decline in cognitive function, particularly in the domain of episodic memory, when compared to Aβ-healthy older adults.…”

Section: Introductionmentioning

confidence: 99%

3D printing of beta-amyloid protein deposits along capillary walls

Horowitz¹,

Snyder

2017

JBGC

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Abnormally high levels of neocortical beta-amyloid protein (A+) reflect Alzheimer’s disease (AD) pathology in persons with clinical evidence of dementia or mild cognitive impairment (MCI). The abnormal aggregation of beta-amyloid protein in the brain neuropil may lead to either diffuse plaques and/or concentrated neuritic plaques, with the latter form of deposits often present in the vicinity of the cerebral microvasculature. The A protein, with its crystalline molecular structure, infiltrates the vessel walls and compromises the blood-brain barrier (BBB). The physical basis for this was elegantly shown by Meyer and colleagues, in a 2008 publication showing two-dimensional (2D) confocal laser scanning microscopic imaging of vascular A protein deposits in APP23 transgenic mice. These investigators showed accumulations of “tuft-life structures”, also referred to as “pompons” with protruding spikes on – and embedded within – microvessels. These pompons of beta-amyloid protein “consist of fibrillar structures, [and] can encircle and constrict capillaries, and are often associated with distortion of capillaries”.We were struck by both the heuristic value of the imaging of Meyer and colleagues, in explaining the root cause of both the amyloid-related alterations in the vascular bed, and depicting minute protein deposits that are both geometrically complex, seemingly delicate and fragile, and yet tenacious in their embedding within small vessel walls. We re-created these images with standard 3D printing technology (extruded plastic) for both educational/teaching and artistic purposes.

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Back to the future: Alzheimer's disease heterogeneity revisited

Cited by 44 publications

References 17 publications

A novel detection method of cleaved plasma high‐molecular‐weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

A novel detection method of cleaved plasma high‐molecular‐weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

The argument against crowdfunding Alzheimer’s disease research

3D printing of beta-amyloid protein deposits along capillary walls

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