Background and Purpose—This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment ...

Vascular Contributions to Cognitive Impairment and Dementia A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.

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Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-b burden in Alzheimer’s disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer’s Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developinganimalmodels,andtheliteratureonthenaturalhistoryandpathologyofrelatedconditions.The

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Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Cerebral amyloid angiopathy (CAA) results from deposition of β-amyloid in the media and adventitia of small arteries and capillaries of the leptomeninges and cerebral cortex and is a major cause of lobar intracerebral hemorrhage and cognitive impairment in the elderly. CAA is associated with a high prevalence of magnetic resonance imaging markers of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Although advanced CAA is present in approximately ¼ of brains with Alzheimer disease (AD), fewer than half of CAA cases meet pathologic criteria for AD. This review will discuss the pathophysiology of CAA and focus on new imaging modalities and laboratory biomarkers that may aid in the clinical diagnosis of individuals with the disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.22516

Cerebral amyloid angiopathy in the elderly

Background and Purpose—Small asymptomatic cerebral hemorrhages detectable by gradient-echo MRI are common in patients with intracerebral hemorrhage (ICH), particularly lobar ICH related to cerebral amyloid angiopathy (CAA). We sought to determine whether hemorrhages detected at the time of lobar ICH predict the major clinical complications of CAA: recurrent ICH or decline in cognition and function. Methods—Ninety-four consecutive survivors of primary lobar ICH (age55) with gradient-echo MRI at presentation were followed in a prospective cohort study for 32.924.0 months. A subset of 34 subjects underwent a second MRI after a stroke-free interval of 15.86.5 months. Study endpoints were recurrent symptomatic ICH or clinical decline, defined as onset of cognitive impairment, loss of independent functioning, or death. Results—The total number of hemorrhages at baseline predicted risk of future symptomatic ICH (3-year cumulative risks 14%, 17%, 38%, and 51% for subjects with 1, 2, 3 to 5, or 6 baseline hemorrhages, P0.003). Higher numbers of hemorrhages at baseline also predicted increased risk for subsequent cognitive impairment, loss of independence, or death (P0.002) among subjects not previously demented or dependent. For subjects followed after a second MRI, new microhemorrhages appeared in 17 of 34 and predicted increased risk of subsequent symptomatic ICH (3-year cumulative risks 19%, 42%, and 67% for subjects with 0, 1 to 3, or 4 new microhemorrhages, P0.02), but not subsequent clinical decline. Conclusions—Hemorrhages identified by MRI predict clinically important events in survivors of lobar ICH. Detection of microhemorrhages may be useful for assessing risk in ICH patients and as a surrogate marker for clinical studies. (Stroke. 2004;35:1415-1420.)

Hemorrhage Burden Predicts Recurrent Intracerebral Hemorrhage After Lobar Hemorrhage

To explore the clinical effects of inflammation associated with vascular deposits of the amyloid beta peptide (A beta), we analyzed 42 consecutive patients with pathologically diagnosed cerebral amyloid angiopathy (CAA) for evidence of an inflammatory response. Inflammation with giant-cell reaction surrounding amyloid-laden vessels was identified in 7 of the 42 cases. The clinical symptoms in each of the seven were subacute cognitive decline or seizure rather than hemorrhagic stroke, the primary clinical presentation in 33 of 35 patients with noninflammatory CAA (p < 0.001). Inflammatory CAA also was associated with radiographic white matter abnormalities, significantly younger age at presentation, and a marked overrepresentation of the apolipoprotein E epsilon 4/epsilon 4 genotype (71% vs 4%, p < 0.001). Of the six inflammatory CAA patients with available follow-up information, five demonstrated clinical and radiographic improvement after immunosuppressive treatment. The syndrome of CAA-related perivascular inflammation appears to represent a subset of CAA with clinically distinct symptoms that may respond to immunosuppressive treatment. These data add to evidence that inflammation against A beta can cause vascular dysfunction, a potential mechanism for the toxic response recently observed in clinical trials of A beta immunization.

Kyungchan Choi

Papers

Clinical manifestations of cerebral amyloid angiopathy-related inflammation.