There is no doubt, however, that diet plays a role in healthy aging and this is certainly as important for brain health as it is for heart health.  We have also discovered that a deficiency in non-enzymatic antioxidants in the blood (particularly vitamins A, C, E and carotenoids) is very common among patients with AD and this is likely due to dietary deficiencies.  While it is not yet proven that correcting these deficiencies slows or reverses AD, it is reasonable and appropriate clinically to encourage patients to eat a healthy diet, rich in fruits, vegetables and nuts with natural antioxidants.  It may also be reasonable to consider gentle supplementation to correct specific deficiencies in specific nutrients for individual patients. 

I am particularly wary of supplementing non-enzymatic antioxidants to non-physiologic levels, because this may cause unexpected consequences.  Vitamin E in particular at high doses can behave in a pro-oxidant fashion and may actually decrease total antioxidant capacity of the blood (see here, here and here).  There is at least one meta-analysis which has associated high-dose vitamin E supplementation with all-cause mortality.  For these reasons, I am reluctant to encourage high-doses of any dietary supplement for my patients outside of a clinical study.

Read more in Oxidative stress in Alzheimer’s disease and CAA

The role of oxidative stress as it contributes to neuronal dysfunction in the context of aging and Alzheimer’s disease (AD) is of particular interest and has generated enormous observational and experimental literature. Despite this, large scale clinical trials of antioxidative therapy have not yet produced a compelling therapy for AD. Additionally, specific mechanisms which contribute to oxidative stress in the brain are not clear. The large volume of literature and heterogeneity of results makes a comprehensive understanding of the changes occurring in the human brain in Alzheimer’s disease elusive.

To address this, we are conducting analyses and meta-analyses to map the network of oxidative stress-related changes in the brain and blood in AD to try to better define the changes to determine if there is a broad dysregulation or a more-specific pattern to explain reported changes.

Read more in Diet and Alzheimer’s

Cerebral amyloid angiopathy is known to cause cerebrovascular fragility, but the specific molecular mechanisms that produce this outcome are not yet fully understood.  We discovered in previous work that intense late-complement activation on arterioles appears to contribute to lytic degeneration of vascular smooth muscle and this likely is a major contributor to hemorrhage and loss of vascular reactivity and autoregulation. 

In this new project, we are looking at three-dimensional imaging of the cerebrovascular network to better understand the structural changes occuring in cerebral microvessel affected by CAA and we are working to identify new molecular pathways which may help explain these changes.  We are approaching these goals using our modification of the CLARITY technique to obtain high-resolution 3D confocal microscopy in human brain tissue and using RNAseq to identify regulated pathways in patients with CAA.

Through this work, we discovered that there is extensive accumulation of lysosomes within dystrophic axon segments around β-amyloid plaques forming a halo around the plaques.

This neuropathological structure is present around essentially every β-amyloid plaque and is present from the earliest detectable stages of β-amyloid pathology. We also discovered that these lysosomes are abnormal, not just because of they accumulate within distended and dystrophic axon segments, but also because they are severely deficient in luminal proteases. Key proteins to AD neurobiology also accumulate in these structures, including β-secretase, amyloid precursor protein and presinilin, among others, which suggests that this is likely the site within neurons where β-amyloid is produced. These features make this structure of particular interest as a therapeutic target, but the precise role it plays in the neurobiology of AD and cognitive loss remains to be clearly defined. It is not clear why these lysosomes are in neuritic axons, why they are deficient in proteases or whether this is protective or harmful. We are working with an animal model which reproduces this pathological structure will enable us to test the role of this structure in AD and CAA.

Microhemorrhages can be mimicked by vessels viewed end on, so it is important to review adjacent imaging slices to make sure lesions are spheroid and not linear.  Calcium deposits can also induce susceptibility artifacts, this is most common in the basal ganglia, choroid plexus and in atherosclerotic vessels.  When the interpretation of the MRI is difficult, correlated with computed tomography can confirm whether a small lesion is calcium or iron.  Other rare mimickers of cerebral microhemorrhages are air embolism and mettallic emboli. 

Cerebral amyloid angiopathy and hypertension are widely recognized as common causes of cerebral microhemorrhages, but numerous other causes have been reported.  One of our ongoing projects is thoroughly document the causes of cerebral microhemorrhages and systematically determine the size and spacial pattern of these lesions.  To this end, we have assembled cohorts of patients with infective endocarditis and with aortic dissection and found that both of these are associated with cerebral microhemorrhages at a high frequency.