Alzheimer’s/Vascular Spectrum Dementia: Classification in Addition to Diagnosis

Abstract

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

Evidence for the Utility of Actuarial Neuropsychological Criteria Across the Continuum of Normal Aging, Mild Cognitive Impairment, and Dementia

“…Reducing diagnostic errors is likely to strengthen observed associations with regard to diagnosis, biomarker abnormalities, rates of progression and reversion, and drug or other intervention effects [33]. Relatedly, Emrani et al [34] recently discussed the importance of leveraging statistical modeling techniques based on neuropsychological test performance in AD diagnosis and classification schemes, in light of growing evidence for the heterogeneity of underlying neuropathological processes contributing to neuropsychological phenotypes observed along the AD continuum, including in the dementia stage.…”

microRNA-Based Biomarkers in Alzheimer’s Disease (AD)

“…The definitive diagnosis of AD is one of the most difficult and challenging in neurology (Arvanitakis et al, 2019;Fierini, 2020;Ghaffari et al, 2020;Guest et al, 2020;Habes et al, 2020;Turner et al, 2020). AD is more often than not accompanied by other multimodal dementing neuropathologies including neurovascular and/or cardiovascular disease involving vascularbased dementia, multiple infarct dementia (MID) and/or strokes or "mini-strokes, " frontotemporal dementia (FTD), hippocampal sclerosis, Lewy body disease, and several other dementing illnesses and comorbidities such as Down's syndrome (trisomy 21), epilepsy and prion disease [including bovine spongiform encephalopathy (BSE; mad cow disease), Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and other relatively rare human prion disorders] and other rare AD subtypes (Dinsmore, 1999;Lemcke and David, 2018;DeTure and Dickson, 2019;Checksfield, 2020;Fierini, 2020;Emrani et al, 2020;Habes et al, 2020;Williams et al, 2020 4 ; last accessed 26 August 2020). The accurate identification of AD is exacerbated by the global lack of routine diagnostic tools for identifying patients early enough in their disease course, i.e., the "prodromal" period, for designing a suitable intervention or prospective treatment regimen.…”

“…These include the significantly higher occurrence of AD in aged human females (about ∼2 times greater than that in males) and strong association with aging (Guerreiro et al, 2012;Bhattacharjee and Lukiw, 2013;Jiang et al, 2013;Cao et al, 2020;Dumurgier and Tzourio, 2020;Lukiw, 2020a,b). The wide variety of behavioral disorders, extreme heterogeneity in neurological disturbances, mnemonic and cognitive deficits including significant age-and genderbased differences, combined with supplementary neurological diseases such as neurovascular disease and ischemic and/or hemorrhagic stroke are extremely common, especially in the most elderly of LOAD patients (Dinsmore, 1999;Fierini, 2020;Emrani et al, 2020;Habes et al, 2020). Environmental factors and life style triggers such as occupational exposures to pesticides, organic solvents, environmental neurotoxins such as aluminum and mercury, anesthetics and/or food additives, education, smoking, increased body-mass index (BMI), obesity, metabolic syndrome and diabetes, microbial and gastrointestinal (GI) tract microbiome contributions such as highly proinflammatory Bacteroides fragilis lipopolysaccharides (BF-LPS) to the onset and development of AD are being increasingly recognized but their mechanism of pathological contribution are in most cases not well understood, and are currently under intense research investigation (Hill et al, 2014a,b;Altveş et al, 2020;Lukiw, 2020a,b;Rahman et al, 2020).…”

“…Using data-driven studies in the identification of the earliest signs of AD and the implementation of biomarker testing and PET and/or MRI neuroimaging during the prodromal or earliest stages of the disease is an urgent contemporary quest in AD diagnostics (Zhao et al, 2015;Fierini, 2020;Emrani et al, 2020;Habes et al, 2020). This current void may be in part filled by precise miRNA profiling of miRNAcontaining biofluids along the course of AD.…”

Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System

“…AD is the leading cause of dementia worldwide, accounting for 60-70% of cases (http://www.who.int/mediacentre/ factsheets/fs362/en/), although increasing evidence shows that mixed brain pathologies (AD and vascular) account for most dementia cases in the old age [34,35]. Previous intervention efforts focused on the management of single risk factors with relatively modest findings.…”