Impact of multiple pathologies on the threshold for clinically overt dementia

Abstract

Longitudinal clinical-pathologic studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In-vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical-pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.

Spinal Arteriolosclerosis Is Common in Older Adults and Associated With Parkinsonism

“…1, 14–16 There are a handful of prior studies which have examined postmortem indices of spinal cord in older adults, but these examined a small numbers of cases, or have generally focused on larger arteries such as the anterior spinal artery or meningeal arteries. 3, 17, 18 The current study provides novel data about the accumulation of microvascular pathologies in spinal cords of older adults and lends support to several observations made in past smaller autopsy studies.…”

“…6, 29–32 Thus, like clinical AD dementia, the phenotype of parkinsonism in older adults may be commonly caused by mixed neuropathologies. 16 Finally, the finding that spinal arteriolosclerosis may be a common unrecognized cause of parkinsonism in older adults, suggests that the health burden of CNS microvascular pathologies may be underestimated in our aging population. 1, 33 Approaches which allow for antemortem identification and treatment of at risk individuals are needed to prevent late-life motor impairment.…”

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

“…(Love and J. S. Miners, 2016) and more atherosclerosis in intracranial vessels than age matched controls (Roher et al, 2004). Community-based pathological studies of clinically diagnosed AD have revealed that AD pathology (plaques and tangles) and ischemic lesions frequently coexist in the same brain (Schneider et al, 2007; Toledo et al, 2013), and that ischemic lesions lower the threshold for clinical dementia (Kapasi et al, 2017). Resting CBF is reduced and hemodynamic responses to neural activation are attenuated in the presymptomatic phase of AD (reviewed in (Kisler et al, 2017a)), suggesting early involvement in the disease process.…”

The multi-morbid old brain

“…Kapasi and colleagues now try to clarify this assumption and review data from large community-based cohorts to evaluate the influence of multiple pathologies on the clinical phenotype [6].Despite recent advances in the development of biomarkers for neuropathological lesions, such as Aβ and tau by both imaging methods and cerebrospinal fluid assessment, cerebral multi-morbidity is not accurately reflected in clinical diagnoses. This has a detrimental impact on clinical cohort studies as cohorts are assumed to be homogenous, while they are in fact highly heterogenous; e.g., a clinical AD cohort will have patients with (i) Aβ and tau pathology only; (ii) Aβ, tau, and α-syn pathology (over 40%); and (iii) Aβ, tau, and TDP-43 pathology (over 50%).…”

“…Kapasi and colleagues now try to clarify this assumption and review data from large community-based cohorts to evaluate the influence of multiple pathologies on the clinical phenotype [6].…”