Clinical and imaging features of mixed Alzheimer and vascular pathologies

Chui and Ramirez-Gomez Alzheimer's Research & Therapy (2015)7: DOI 10.1186/s13195-015-0104-7 REVIEW Open Access Clinical and imaging features of mixed Alzheimer and vascular pathologies Helena C Chui* and Liliana Ramirez-Gomez Abstract The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia. Introduction Traditionally, Alzheimer disease (AD) and vascular dementia are recognized as the two most prevalent forms of dementia in late life. A combination of AD and vascular pathologies (so-called mixed dementia) is usually registered as a close third, moving up to first or second in rank in community-based studies of the oldest of old. Conceptualization and diagnosis of these entities has been evolving from clinical-pathological phenotypes, which could not be resolved until autopsy, to new research diagnostic criteria that incorporate molecular biomarkers (for example, amyloid-beta (Aβ) and phosphorylated tau), and in vivo structural, functional, and perfusion imaging. Neuropsychological features (for example, pattern and * Correspondence: Department of Neurology, University of Southern California, 1570 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA severity of impairment across principle cognitive domains) remain relevant to diagnosis and clinical care. Innovations are underway in computerized neuropsychological assessment (for example, computerized assessment with continuous measures, such as the National Institutes of Health tool box) and rethinking cognitive impairment in terms of functional neural networks. In this review, we consider mainly how recent advances in biomarkers and imaging have altered our conceptualization and diagnosis of mixed AD and vascular pathologies. Medically speaking, the approach to mixed AD and vascular pathologies should be tied to prevention and treatment. During the past 30 years, emphasis has moved from dementia to mild cognitive impairment to preclinical disease, in the hopes that prevention and treatment can be instituted earlier in the disease course. AD is currently conceptualized as a combined amyloidopathy and tau-related neurodegeneration. Mainstream © 2015 Chui and Ramirez-Gomez; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chui and Ramirez-Gomez Alzheimer's Research & Therapy (2015)7: strategies to prevent and treat AD target these misfolded proteins. The model for vascular cognitive impairment (VCI) adopted here posits that vascular risk factors (VRFs) lead to cerebrovascular disease (CVD), which leads to vascular brain injury (VBI), which leads to VCI (Figure 1). It is paramount to maintain focus on the type of CVD (the cause), as well as on the resulting VBI and VCI. For example, the prevention and treatment of cerebral amyloid angiopathy (CAA), which is intrinsically associated with AD, is likely to differ fundamentally from the prevention and treatment of atherosclerosis. It may pay off to pay some attention to terminology, rather than to lump all vascular dementias into the category of VCI. In this review of clinical and imaging features of mixed AD/VCI, we have chosen nuanced terminology to distinguish levels of vascular factors: mixed AD/VRFs, mixed AD/CVD, mixed AD/VBI, and mixed AD/VCI. We use the term VCI when clinical criteria are used to define groups, VBI when study groups are defined by infarcts/ hemorrhages noted by imaging/pathology, and CVD to refer to specific disorders of blood vessels (for example, atherosclerosis or amyloid angiopathy). Finally, we use the term VRFs to refer to traditional risk factors for atherosclerosis (for example, hypertension, diabetes mellitus, and hyperlipidemia) and not for amyloid angiopathy (for example, apolipoprotein E (ApoE) ε4 is mentioned distinctly and not included under the label VRF in this review). Page 2 of 13 The diagnosis of VCI is reflected in recent clinical criteria [1], which draw heavily on evidence of infarcts, white matter hyperintensities (WMHs) and microbleeds (MBs) using structural magnetic resonance imaging (MRI). Multiple autopsy studies have shown that microinfarcts (one type of VBI) are major risk factors for VCI; however, microinfarcts fall below the resolution of 1.5 and 3 T MRI. This is one of several gaps in in vivo detection that we must close going forward. For the diagnosis of AD in this review, we adopt research-level criteria for high likelihood of preclinical, mild cognitive impairment and dementia due to AD based on biomarker evidence [2-4]. This req (...truncated)