Mixed dementia: Neglected clinical entity or nosographic artifice?

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

“…Clinically, toward the termination of the AD process there is usually progressive forfeiture of the swallowing reflex (dysphagia) and the onset of inspirational pneumonia to which most AD patients succumb over a clinical course averaging about ∼5-12 years (Dinsmore, 1999;Ahluwalia and Vellas, 2003;DeTure and Dickson, 2019;von Arnim et al, 2019;Cao et al, 2020 1,2,3 ; last accessed 26 August 2020). 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 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.…”

Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes

“…From a neuropathological point of view, a frequent comorbidity of cerebrovascular and AD pathologies is confirmed in aged subjects [7][8][9]. At mechanistic level, a plethora of tissue and molecular events have been proposed to interplay between the neurodegenerative process and the cerebrovascular damage (blood-brain barrier leakage, inflammation, oxidative stress) [10,11], however, the complete knowledge of this potential cause-and-effect relation is still lacking [10]. Although AD can be frequently diagnosed with a considerable accuracy, the distinction between MixD, isolated AD and VaD remains controversial, being a difficult diagnostic challenge [11].…”