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J Alzheimers Dis. 2018;62(3):1417-1441. doi: 10.3233/JAD-170803.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease.

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Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg Sweden and Memory Clinic at Department of Neuropsychiatry, Sahlgrenska University, Hospital, Gothenburg, Sweden.
Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.
Weill Cornell Medical College, Cornell University, New York, NY, USA.
Neuropathology Department, West Wing, John Radcliffe Hospital, Oxford, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, Oxford, UK.
Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
1st Department of Neurology, Neurochemistry Unit, National and Kapodistrian University of Athens, Athens, Greece.


Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.


Cerebral small vessel disease; cerebrospinal fluid; classification; cognitive impairment; diagnostic imaging; genetics; metabolism; pathology; pathophysiology; symptoms

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