Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease

Acta Neuropathol (2016) 131:659–685 DOI 10.1007/s00401-016-1571-z REVIEW Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease Raj N. Kalaria1 Received: 11 February 2016 / Revised: 23 March 2016 / Accepted: 24 March 2016 / Published online: 9 April 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Vascular dementia (VaD) is recognised as a neurocognitive disorder, which is explained by numerous vascular causes in the general absence of other pathologies. The heterogeneity of cerebrovascular disease makes it challenging to elucidate the neuropathological substrates and mechanisms of VaD as well as vascular cognitive impairment (VCI). Consensus and accurate diagnosis of VaD relies on wide-ranging clinical, neuropsychometric and neuroimaging measures with subsequent pathological confirmation. Pathological diagnosis of suspected clinical VaD requires adequate postmortem brain sampling and rigorous assessment methods to identify important substrates. Factors that define the subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes. Atherosclerotic and cardioembolic diseases appear the most common substrates of vascular brain injury or infarction. Small vessel disease characterised by arteriolosclerosis and lacunar infarcts also causes cortical and subcortical microinfarcts, which appear to be the most robust substrates of cognitive impairment. Diffuse WM changes with loss of myelin and axonal abnormalities are common to almost all subtypes of VaD. Medial temporal lobe and hippocampal atrophy accompanied by variable hippocampal sclerosis are also features of VaD as they are of Alzheimer’s disease. Recent observations suggest that there is a vascular basis for neuronal atrophy in both the temporal and frontal lobes in VaD that is entirely independent of any Alzheimer pathology. Further knowledge * Raj N. Kalaria 1 Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK on specific neuronal and dendro-synaptic changes in key regions resulting in executive dysfunction and other cognitive deficits, which define VCI and VaD, needs to be gathered. Hereditary arteriopathies such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or CADASIL have provided insights into the mechanisms of dementia associated with cerebral small vessel disease. Greater understanding of the neurochemical and molecular investigations is needed to better define microvascular disease and vascular substrates of dementia. The investigation of relevant animal models would be valuable in exploring the pathogenesis as well as prevention of the vascular causes of cognitive impairment. Keywords Alzheimer’s disease · Cerebral amyloid angiopathy · Cerebrovascular degeneration · Dementia · Neuropathology · Small vessel disease · Vascular dementia Introduction Cerebrovascular disease (CVD) is the second most common cause of age-related cognitive impairment and dementia, which is widely recognised as vascular dementia (VaD). VaD culminates from global or localised effects of vascular disease, which incurs stroke injury and other tissue perfusion changes. VaD is characterised as a neurocognitive disorder, but also incorporates behavioural symptoms, locomotor abnormalities and autonomic dysfunction. Vascular cognitive impairment (VCI) results from all causes of CVD including cardiovascular that lead to early and late plus severe forms of dementia syndromes. Within CVD, the most common vascular contributor to dementia is likely cerebral small vessel disease (SVD), which describes a range of clinical, neuroimaging and pathological features. 13 660 Acta Neuropathol (2016) 131:659–685 SVD has taken precedence as a radiological concept, but refers to an intracranial disorder that encompasses pathological changes within and at the surfaces of brain microvessels including perforating arteries and arterioles, capillaries and venules. SVD involves tissue injury in both the cortical and subcortical grey and white matter (WM). SVD, however, may often coexist with atherosclerosis involving large extracranial vessels and embolic disease [103]. In this article, I review the brief history of our current understanding of VaD, various criteria incorporating clinical, neuropsychological and pathological features that have been proposed over the years and key vascular lesions and tissue changes, which contribute to dementia. I convey some opinions about brain sampling and consider some of the rarer causes of VCI and VaD and how these can be investigated. It is clear that despite the strong and unambiguous evidence that vascular factors and vascular disease contribute to the global burden of brain disease, dementia prognosis and research has mostly focused on Alzheimer’s disease (AD). Vascular causes of dementia and their contribution to neurodegenerative processes have not been widely emphasised. Further descriptions of distinct pathological changes in cerebral vessels were another step forward towards classification of subtypes. In 1937, W Schultz had described drusige entrartung or congophilic amyloid angiopathy in some patients. More recently, C. Miller Fisher recognised for his profound proposal indicated that cerebrovascular dementia is a matter of both large and small strokes and provided clear accounts of lacunar syndromes [56]. Multiple small infarcts in association with hypertension (état lacunaire) are the commonest pathological changes linked to VaD. It is characterised by abrupt episodes, which lead to weakness, slowness, dysarthria, dysphagia, small-stepped gait, brisk reflexes and extensor plantar responses. All these signs are largely present by the time mental deterioration occurs [73]. The recognition of subtypes of clinical VaD was clearly an important step towards current pathological classifications based on vascular aetiology. It was subsequently recognised that multi-infarct dementia predominantly results from cortical infarcts attributed to large vessel disease, whereas dementia associated with subcortical ischemic lesions or Binswanger’s disease involving subcortical structures and the WM results from changes in intracranial small vessels (Table 1). Historical aspects and nosology The continuum of VCI and vascular cognitive disorder One could begin with Thomas Willis and apoplexy, but the concept that gradual strangulation of the brain causes cognitive and behavioural deficits was distinguished just over 100 years ago [18]. Both Alzheimer and Kraeplin had reasoned that old age-associated progressive hardening of the arteries lead to arteriosclerotic dementia. The label arteriosclerotic dementia attributed to cerebral softening with loss of relatively large volume (50–1 (...truncated)