Central retinal artery occlusion (CRAO) is a devastating and usually permanent cause of blindness.

We are working toward evaluating the efficacy of tPA for acute CRAO and our evidence preliminarily suggests this may be beneficial if administered early, within 4.5 hours of the onset of blindness.

We conducted a national survey to evaluate how CRAO is treated in academic centers in the USA, and discovered that practive was highly variable.  Some centers provide numerous treatments and thorough evaluation of stroke risk factors, while others conduct a brief outpatient evaluation only. 

Among our patients, we found that approximately 37% had concurrent acute strokes on MRI (often clinically silent), 37% had critical carotid artery disease and 20% had a critical finding on echocardiogram.  A full 25% of our patients required an acute surgery to address a stroke risk factor. In the year after CRAO, the rate of combined stroke, myocardial infarction and death was 25%, indicating the high rate of concurrent vascular risk in the CRAO population. 

Medial to lateral view of the vascular supply to the optic nerve and retina

The order of the major branches off the ophthalmic artery is variable; the most common configuration is shown at left.  The posterior segment of the optic nerve is supplied by the pial plexus primarily via branches from the ophthalmic artery.  The anterior segment of the optic nerve is supplied primarily by branches from the posterior ciliary arteries.  The retina is primarily supplied by the central retinal artery and in a minority of cases has additional supply from the cilio-retinal artery, a branch of the posterior ciliary artery.  Collateral arterial blood flow from the meningeal circulation is variable and in cases of chronic vascular disease may be the dominant arterial supply to the central retinal and posterior choroidal arteries.

Trends in CRAO treatment in the USA:

We identified university-associated teaching hospitals offering vascular neurology, neuro-ophthalmology and/or retina fellowships in the United States and asked the directors of the programs to respond to questions in an open response format to profile the acute management of CRAO at their institution. 

We found remarkable heterogeneity in the approach to acute treatment of patients with CRAO among the 45 institutions that responded to the survey.  Only 20% had a formal policy, guideline or white paper to standardize the approach to treatment.  The primary treating physician was an ophthalmologist, neurologist, or neuro-ophthalmologist 44, 27, and 7% of the time, respectively; 24% were co-managed acutely by neurology and ophthalmology.  Intravenous fibrinolysis was offered to selected patients in 53% of institutions, and was the preferred initial treatment in 36%; anterior chamber paracentesis, ocular massage and hyperbaric oxygen therapy were offered occasionally, while 9% of institutions offered no treatment.  At 35% of institutions, patients with acute CRAO were not referred to a general emergency room for initial treatment routinely, and overall the approach to risk modification was highly variable. 

Currently no consensus exists on how patients with acute CRAO ought to be managed, leading to widespread variability in treatment practices.  Due to the high rate of comorbid disease, it is essential that these patients be admitted for emergent inpatient evaluation, ideally with co-management by ophthalmology and vascular neurology.  We present an evidence-based protocol for the evaluation and management of acute CRAO.

tPA for acute CRAO

… and lack of efficacy of anterior chamber paracentesis, hemodilution and ocular massage

Central retinal artery occlusion  (CRAO) is a relatively rare disorder that is caused by interruption of blood flow to the retina, usually by a clot or some other embolus.  Despite around 150 years of research, no compelling treatment has been found for this disease.  Treatment with fibrinolytics has been used experimentally for a long time and some of the results have been encouraging.  We conducted a patient-level meta-analysis to aggregate all of this observational data and compare how patients with CRAO do when treated with fibrinolytics versus when they are treated with other approaches or not treated at all.  This type of analysis tries to maximize the usefulness of the best retrospective and observational data in aggregate to help guide clinical decision making and contribute to better design of clinical trials to hopefully improve the odds of having a successful trial. 
 
The biggest surprise in the data was the poor performance of conventional treatments at less than half the recovery rate of patients who were simply left alone.  While this result is limited by the retrospective, non-randomized study design, it raises enough doubt that I think ocular massage, anterior chamber paracentesis and hemodilution should be abandoned as treatments for acute CRAO.  The data is encouraging regarding the effectiveness of tPA for CRAO — but only in the first 4.5 hours from symptom onset.  This is not strong enough data to make a compelling recommendation that patients with CRAO should receive tPA.  However, many centers do treat CRAO off-label with tPA and for those centers I would recommend only treating within the first 4.5 hours.

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.

The key to treating this sort of stroke is to control the infection. Patients require long term antibiotics and many require surgical removal of infected material from the heart. It is also critically important to identify where the infection came from and try to treat that (infected teeth, infected kidney stones, infected ports, dialysis and injection drug use are common causes).

Our team is committed to providing cutting edge care for patients with cerebrovascular complications from infective endocarditis. This requires a multidisciplinary team and many patients will need care from infectious disease specialists, cardiologists and/or cardiothoracic surgeons, neurologists and psychiatrists.

What is cerebral amyloid angiopathy (CAA)

CAA is a disorder of the small blood vessels of the brain. A small, abnormal protein called β-amyloid accumulates in the brain during aging. In Alzheimer’s disease, this protein clumps together a forms toxic plaques in the brain; in CAA the same protein is deposited on small arteries. Once there, it unleashes a number of toxic effects — including activating the immune system to attack the blood vessels. This causes the blood vessels to become fragile and prone to breaking. It also makes it more difficult for the brain to regulate blood flow.

The combined effects of these problems often leads to slowing of processing speed on neuropsychiatric testing and patients and their families often report memory problems. These fragile blood vessels can often also lead to intracerebral hemorrhages.

This process usually progresses slowly and most patients with CAA are over age 60 (although there are rare exceptions).

How is CAA diagnosed?

The most useful test for diagnosing CAA is an MRI of the brain, particularly the susceptibility weighted sequence. This scan essentially puts blood products under a magnifying glass, enabling us to see microhemorrhages in the brain which are often 1mm or less in diameter. These show up on the scans as black dots and appear 2-3x larger on the scans than they actually are. In CAA, these microhemorrhages occur in a distinctive pattern — they are in the cortical grey matter or at the junction of the grey and white matter, but do not involve the deeper structures of the brain (the basal ganglia, pons or cerebellum). When we see this pattern in an older adult, it is strongly suggestive of CAA.

Neuropsychiatric testing can also help to make a diagnosis of CAA. Patients often have similar symptoms as those with Alzheimer’s disease, but with the addition of prominent slowing of processing speed. While neuropsychiatric testing cannot make the diagnosis of CAA on its own, it is a helpful test.

There are a few other tests which we do not obtain very often in the clinic unless a case is confusing. These include PET scans (FDG-PET, which shows us areas of the brain which are not as active as they shoud be), “Amyloid PET” (including the original beta-amyloid PET probe PiB; these show us how much beta-amyloid is in the brain and where it is) and cerebrospinal fluid testing of β-amyloid and tau levels. In a few cases, we also consider genetic testing.

How is CAA treated?

We do not have a treatment for CAA yet that specifically stops or slows β-amyloid deposition in the blood vessels. Treatment for each patient should be taylored to their particular needs and considers the other medical problems they have, so these are just general principles.

We primarily focus on three things to reduce the frequency of hemorrhages and protect memory:

1. We try to achieve tight blood pressure control. This is the only treatment for CAA that has been shown in a randomized controlled trial to reduce the frequency of hemorrhage. It is helpful for patients to check their blood pressure at home regularly and bring these measurements to their doctors.
2. Avoid blood thinners. We generally try to keep people off of drugs like coumadin/Warfarin, Eliquis, Xarelto, Pradaxa, etc. We also prefer patients to not take aspirin, plavix or other mild blood thinners that act on the platelets unless they absolutely need to. These decisions need to be made individually for each patient.
3. Avoid head trauma. To do this, we generally focus on lowering the risk of falls and avoiding a few trauma-prone activities and hobbies.

The rest of our treatments work to improve symptoms. We sometimes use memory enhancing drugs like those used in Alzheimer’s disease and we aggressively treat anxiety, depression and sleep disorders because this seems to make a big difference for our patients.

Is CAA genetic?

Usually not, most CAA is sporadic rather than inherited. There are a few families who have mutations which lead to CAA, but this is rare and generally causes a form of CAA which is severe and starts a decade or more earlier than typical CAA.

There are some genes that influence the risk of developing CAA, the most famous of which is ApoE4. These genes are important scientifically because they help us understand the disease better, but they do not change an individual person’s risk enough that we need to check them clinically.

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.

Fish oil was approved by the FDA to control high triglyceride levels in 2019. At lower doses, fish oil is used as a dietary supplement and like most supplements does not require a prescription. According to Healthline.com, omega-3 fatty acids, found in fish oil, “can fight age-related mental decline and Alzheimer’s disease.” Big claims like that are easy to make, but hard to prove with solid science. According to one large analysis, most studies did not find any statistically significant effect of omega-3 fatty acids against Alzheimer’s disease.¹ While shorter trials in the analysis may overlook long-term effects, a 3-year-long trial confirmed that omega-3 fatty acids are not effective against cognitive decline in the long term.² Moreover, omega-3 fatty acids might struggle to reach the brain,³ needing administration of higher doses to have a sufficient concentration there. However, higher doses mean a higher risk of side effects. A meta-analysis with a total of 24.5 thousand participants shows that omega-3 fatty acids had some adverse effects, even though it is generally well-tolerated.⁴ All in all, its dubious efficacy and risk of side effects do not support omega-3 supplementation as a treatment of Alzheimer’s disease.

Instead of taking omega-3 fatty acid supplements, a better approach is to incorporate fish into your diet regularly, particularly those rich in healthy fats (like salmon, herring, cod, or mackerel). If you are a vegetarian, Brussels sprouts and walnuts are good choices. However, omega-3 fatty acids in seed oils, such as flaxseed oil, have poor bioavailability, which greatly reduces its omega-3 effects.

Ginkgo biloba extract is a plant-based food supplement that comes from trees native to China. It is marketed as a cognitive enhancer for age-related neurodegenerative disorders such as Alzheimer’s disease. The active compounds in Ginkgo biloba extract are believed to dilate blood vessels and thus increase blood supply to the brain. However, a comprehensive analysis of the effect of Ginkgo biloba on Alzheimer’s disease concluded there was no significant difference with the placebo group,⁵ despite numerous claims of positive effects on cognitive function in other reports.^{6 7} Most “positive” studies of Ginkgo’s effect on memory are limited due to low quality of the evidence. Almost all studies agree that Ginkgo biloba extract supplementation is safe with very few side effects. Overall, while Ginkgo biloba extract is safe, there is no robust evidence to believe that it helps at all with dementia.

Lastly, vitamin E is another common food supplement often used against cognitive decline. Vitamin E is a fat-soluble antioxidant that detoxifies oxygen radicals that are thought to drive cellular aging and contribute to Alzheimer’s disease. The three high-quality, large-scale clinical trials of vitamin E treatment – two for Alzheimer’s disease and one for mild cognitive impairment – found no significant improvement in cognitive measures.^8,9,10 Importantly, the recommended daily allowance of vitamin E is around 22 international units, but the doses used in these studies were enormous – 2000 international units daily. At these doses, Vitamin E stops acting as antioxidants and may produce some toxicity. One large study found that a high dosage of these supplements (> 400 international units daily) may increase all-cause mortality.¹¹ Thus, it is clear that very high doses of vitamin E are a bad idea, but whether modest doses could make a difference remains to be seen.

For all three supplements, fish oil, Ginkgo biloba extract, and vitamin E, there is no definitive evidence that they slow cognitive decline in Alzheimer’s disease. While Ginkgo biloba extract is pretty safe, both omega-3 fatty acids in fish oil and vitamin E have a risk of side effects, especially in higher doses. While a good diet takes some good effort, it generally outperforms food supplements in improving overall health with fewer side effects.

References:

References

1. Canhada, S., Castro, K., Perry, I. S. & Luft, V. C. Omega-3 fatty acids’ supplementation in Alzheimer’s disease: A systematic review. Nutr. Neurosci. 21, 529–538 (2018).
2. Andrieu, S. et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 16, 377–389 (2017).
3. Arellanes, I. C. et al. Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial. EBioMedicine 59, 102883 (2020).
4. Chang, C.-H. et al. Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials. Prostaglandins Leukot. Essent. Fatty Acids 129, 1–12 (2018).
5. Birks, J. & Grimley Evans, J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst. Rev. CD003120 (2009) doi:10.1002/14651858.CD003120.pub3.
6. Yuan, Q., Wang, C., Shi, J. & Lin, Z. Effects of Ginkgo biloba on dementia: An overview of systematic reviews. J. Ethnopharmacol. 195, 1–9 (2017).
7. Yang, G., Wang, Y., Sun, J., Zhang, K. & Liu, J. Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr. Top. Med. Chem. 16, 520–528 (2016).
8. Dysken, M. W. et al. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. JAMA J. Am. Med. Assoc. 311, 33–44 (2014).
9. Sano, M. et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222 (1997).
10. Petersen, R. C. et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005).
11. Miller, E. R. et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37–46 (2005).

The FDA’s approval of aducanumab does not change the facts, and the facts in this case are daunting. The potential benefits of this drug, even assuming the most optimistic interpretations promoted by the drug developer are true, are small – so small they are miniscule. This is not a drug that gives people their memory back. More importantly, the risks are high. In some patients, the drug causes an immune reaction on the blood vessels of the brain compromising blood brain barrier function. As a result, more than one-third of patients treated with this drug developed swelling and/or bleeding of the brain. This side-effect has been widely downplayed, but the long-term effects have not been adequately studied. This drug has taken a tragically misguided pathway to become approved. The phase 3 trials were terminated prematurely for futility, then revived on the basis of a tenuous sub-group analysis. The approval of aducanumab comes in opposition to a near-unanimous recommendation against approval from the FDA’s scientific advisory committee and at the behest of intense pressure from advocacy groups.

One of the key arguments advanced in favor of approval was that approval would spur future drug development. I suspect this decision will promote the development of additional anti-amyloid therapies but it is likely to reduce the focus on developing novel drug targets. The amyloid cascade hypothesis has been tested and tested over the last decades to the exclusion of other meaningful ideas. The long series of clinical trial failures related to this hypothesis was building toward a major recalibration. If this is derailed by the actions of the FDA today, it will be a significant harm.

I want to point out three other surprising details in yesterday’s approval. First, aducanumab was approved for all patients with Alzheimer’s disease. Biogen’s trials only enrolled patients with early Alzheimer’s disease, so the approval including patients with advanced disease is hard to explain. Second, patients enrolled in the trials were proven to have β-amyloid in their brain. This is critical, because a diagnosis based only on symptoms is wrong a substantial portion of the time. However, the FDA does not require selection of patients with amyloid-PET scan or cerebrospinal fluid analysis. Finally, the FDA approved continuing treatment even in patients who developed severe brain swelling and hemorrhage once the acute episode has stabilized. This is a disturbing disregard for the significance of even the most severe spectrum of this important side effect. These decisions expose patients to unnecessary risks and introduce variables that will make effective post-market surveillance extremely difficult.

There is so much wrong with this data and this process. This isn’t the turning point in the fight against Alzheimer’s disease, in fact, I am very concerned that it may be a major setback. For the safety of our patients, we should proceed with great caution.

This advocacy position from the Alzheimer’s Association stands in stark contrast to a critical review from the scientific advisory committee which raised serious concerns about the safety and inadequately demonstrated efficacy of aducanumab. Two Phase 3 trials were stopped prematurely for futility. Only on later re-evaluation was a positive result observed in one of studies, while the second trial did not meet primary efficacy endpoints. The inconsistent results from these studies is concerning. Importantly, however, premature approval of this drug is not just a matter of potentially exposing patients to a drug that may not work, a remarkable 35% of treated patients developed swelling of the brain called ARIA-E and nearly 20% had bleeding associated with the swelling. The concerns around this side-effect have been widely downplayed, but the long-term risk of vascular cognitive impairment and/or intracerebral hemorrhage in patients who experience ARIA-E is not well understood and could be substantial.  

                The Alzheimer’s Association’s statement argued that “If approved, it would be the first treatment to potentially change the progression of Alzheimer’s. We believe the accumulated science, the publicly released data on aducanumab and the absence of other treatment justifies FDA approval, accompanied by a Phase 4 post marketing surveillance study.” This greatly concerns me. When they say, “it would potentially change the progression of Alzheimer’s,” it betrays that efficacy has not been adequately proven. Proving the efficacy and safety of aducanumab is Biogen’s responsibility – trying to accomplish this in a Phase 4 post marketing surveillance study would transfer the risk and the cost of developing this drug to our patients. This is aligned with corporate interests, but not the health and well-being of our patients.

                Alzheimer’s disease is a bad disease and the need for an effective treatment is clear and urgent, but I remember the famous saying that says “There is no problem so bad that you can’t make it worse by doing the wrong things.” Responsible advocacy should lead us to insist that treatments meet a high standard of safety and efficacy before they are distributed to potentially millions of our most-vulnerable patients.

Last month, we published the results of our cohort study from Vanderbilt University Medical Center evaluating the efficacy of early treatment with a “clot buster” called tPA or alteplase. We found that treating patients within 4.5 hours of onset resulted in three-times higher probability of recovery compared to patients who were untreated. To make sure this result was reproducible, we updated out 2015 patient level meta-analysis with patient level data from four new cohorts. This showed that treatment was highly effective at early timepoints across studies from all over the world. Importantly, early treatment also appears to be quite safe. Because alteplase is a potent blood thinner, it has the potential to cause bleeding. There have been a few incidences of significant bleeding in patients treated for CRAO, but most have been due to treatment at late timepoints or combining alteplase with other blood thinners. When administered according to established protocols, symptomatic bleeding is rare. We appreciate the recent blog from Dr. Richard Jackson reviewing this work. 

The next step in this effort is to establish a national registry to increase the statistical power of the study and to identify centers who treat large numbers of patients. The major obstacle to a successful clinical trial, in my opinion, is enrolling an adequate number of patients. This requires hospitals to have effective protocols in place for rapid triage, evaluation and treatment and robust collaboration among neurologists, ophthalmologists and emergency physicians. We are optimistic that we can identify a large-enough group of high-volume centers to conduct a trial in the near future. We discuss this issue in greater details here. If you would like to participate in such an effort, I’d be happy to hear from you at matthew.schrag@vanderbilt.edu. 

In the meantime, we are excited about two randomized clinical trials underway in Europe, the REVISION trial led by Sven Poli at the University of Tubingen in Germany and the THEIA trial led by Benoit Guillon at Nantes University in France, both of which will evaluate the efficacy of alteplase within 4.5 hours. We are also looking forward to the start of a trial of tenecteplase for CRAO led by colleagues in Norway (more on that later). 

As always, we are grateful to our national and global partners, including Brian Mac Grory at Duke University who is spearheading our registry efforts, Valerie Biousse at Emory University who has helped us foster interdisciplinary collaboration and Andrew Lee and Celia Chen who are leading the charge against CRAO in Australia, to recognize just a few of our key collaborators.  

According to the National Institutes of Health, vitamin D, which can be obtained both from an individual’s diet and from sun exposure, plays a prominent role in promoting intestinal calcium absorption, maintaining bone health and preventing osteoporosis. The vitamin is naturally found in only a few foods, such as the fatty components of salmon and tuna, fish liver oils, cheese, and egg yolks. However, many products, particularly milk, are fortified with vitamin D to ensure sufficient consumption of the vitamin. Additionally, exposure to ultraviolet (UV B) radiation from sunlight triggers vitamin D synthesis in the skin, though the amount of synthesis is dependent on factors such as time of day, cloud cover, shade, and age. As people age, their skin has a reduced ability to efficiently synthesize vitamin D. This, combined with the fact that older individuals generally spend less time outdoors and are less likely to consume an adequate amount of the vitamin in their diets, contributes to the tendency of older adults to develop vitamin D deficiencies (Office of Dietary Supplements, 2019). Beyond the issues with bone health associated with a deficiency in this vitamin, however, growing evidence suggests that inadequate levels of vitamin D in elderly individuals may also contribute to the development of dementia and mild cognitive impairment.

Many recent studies have examined the potential association between vitamin D levels and the development of Alzheimer’s disease. For instance, a 2014 study published in the journal Neurology tested 25-hydroxy-vitamin D concentrations in blood samples from healthy older adults. At a follow-up assessment approximately five years later, the researchers reassessed the participants’ vitamin D levels and evaluated whether they had developed dementia. They found a correlation between vitamin D deficiency and a higher risk of developing dementia (Littlejohns et al., 2014). A similar study by Oudshoorn et al. examined the relationship between vitamin D levels of elderly patients suspected to have Alzheimer’s and their performance on the Mini-Mental State Exam (MMSE), a test of cognitive function. They found that patients with sufficient levels of vitamin D scored significantly higher on the MMSE than patients with vitamin D deficiencies, implying a correlation between vitamin D levels and cognitive performance (Oudshoorn et al., 2008). These correlative studies do not prove that vitamin D deficiency caused dementia, nor do they explain the mechanism by which vitamin D might help prevent Alzheimer’s or other forms of dementia. A 2017 study found that that vitamin D decreased the production of toxic β-amyloid and increased its degradation in cultured neurons. They also found that vitamin D (and similar compounds) reduced the activity of β- and ?-secretase, two enzymes critical for the production of β-amyloid. Additionally, vitamin D was found to reduce the production of some inflammatory cytokines in this model, so it may work by suppressing some of the neuroinflammation which has been associated with Alzheimer’s disease (Grimm et al., 2017).

While there is fairly convincing evidence that vitamin D deficiency is not good for your brain, there is no convincing evidence that simply taking a supplementary pill will improve brain function. A 2018 meta-analysis comparing 73 studies that investigated the link between vitamin D and neurodegenerative disease, for instance, found no significant evidence of a neuroprotective benefit of vitamin D (Iacopetta et al., 2018). Again, while much of the available research does find an association between this vitamin and cognitive decline, this is correlational and does not clearly identify whether lower levels of vitamin D cause dementia or whether they are simply a symptom of it.

Nevertheless, avoiding vitamin D deficiency is reasonable as there are various health benefits beyond the prevention of Alzheimer’s disease and other forms of dementia and there is some potential for benefit related to cognition. We strongly encourage our patients to spend an adequate amount of time in outdoor activities. The added physical activity, social interaction and daylight exposure is unequivocally beneficial for the clear majority of patients. It is very easy as Alzheimer’s disease and dementia symptoms progress for people to become housebound, so for many patients and families, getting out of doors needs to be made a specific priority. For older adults, particularly those who do not spend ample time outdoors or consume a sufficient amount of vitamin D in their diets, vitamin D supplements may be beneficial. According to the NIH, the Recommended Daily Allowances for vitamin D are 600 International Units (IU) for most individuals under 70 years and 800 IU for adults over age 70. As a reference, one cup of fortified milk contains approximately 100 IU (Office of Dietary Supplements, 2019). While the data about the impact of this vitamin on Alzheimer’s disease remains incomplete, maintaining sufficient levels of vitamin D will, at minimum, support healthy bone development and promote brain health.

References

1. Grimm, M., Thiel, A., Lauer, A. A., Winkler, J., Lehmann, J., Regner, L., … Hartmann, T. (2017). Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation. International journal of molecular sciences , 18 (12), 2764. doi:10.3390/ijms18122764
2. Littlejohns, T. J., Henley, W. E., Lang, I. A., Annweiler, C., Beauchet, O., Chaves, P. H., … Llewellyn, D. J. (2014). Vitamin D and the risk of dementia and Alzheimer disease. Neurology , 83 (10), 920–928. doi:10.1212/WNL.0000000000000755
3. Iacopetta, K., Collins-Praino, L.E., Buisman-Pijlman, F.T.A., Liu, J., Hutchinson, A.D., & Hutchinson, M.R. (2018). Are the Protective Benefits of Vitamin D in Neurodegenerative Disease Dependent on Route of Administration? A Systematic Review. Nutritional Neuroscience, doi: 10.1080/1028415X.2018.1493807
4. Oudshoorn, C., Mattace-Raso, F. U. S., van der Velde, N., Colin, E. M., & van der Cammen, T. J. M. (2008). Higher Serum Vitamin D3 Levels Are Associated with Better Cognitive Test Performance in Patients with Alzheimer’s Disease. Dementia and Geriatric Cognitive Disorders. doi: https://doi.org/10.1159/000134382
5. Office of Dietary Supplements. (2019, August 7). Vitamin D: Fact Sheet for Health Professionals. Retrieved from https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/.

As clinical trial after clinical trial for Alzheimer’s disease fails to produce effective treatments, it is easy to get discouraged. Never-the-less, we have learned an incredible amount about Alzheimer’s disease over the last decades and our ability to help people with this disease is growing. The popular conception of Alzheimer’s disease is bleak — a relentless decline into madness and indignity. I want my patients to know that they can do better than that. At the same time, some people are promoting magical cures and announcing the End of Alzheimer’s Disease. We aren’t going to do that either, this isn’t about false hope.

I have had the incredible opportunity to watch many people (both patients and caregivers) gracefully navigate Alzheimer’s disease and they have taught me that good planning, committed families, strong faith, unflappable optimism and a sense of humor make a major difference in the experience of this disease. I want to share the insights and strategies that these families found most useful. The list below is a rough draft which I fully intend to update, but I hope it is a good starting point for people who are just starting to cope with Alzheimer’s disease.

1. Denial is the enemy.

2. Beware of quick fixes and easy cures

There are sadly lots of people willing to take advantage. At the moment there are no cures for Alzheimer’s disease, anyone who tells you otherwise is selling something.

3. Stay active

It is particularly important to stay physically active, but also socially and mentally active. Get out of the house every single day.

4. Plan!

Most people’s biggest worries are 1) losing autonomy and 2) being a burden on their family. Good planning can prevent both. Don’t put off making a will and living will. Communicate how you feel about nursing homes, “tube feeding” and other forms of life support to your family (in writing) long before these issues become reality.

5. Work on the Bucket List.

The silver lining is this disease usually progresses slowly. Think seriously about what you want to accomplish with the time you have and go get it done.

6. Don’t become isolated!

Family, friends, church, and other social groups are really important. This is still important when you can’t drive.

7. Recognize and avoid the crisis points.

Decide when to stop working, don’t wait until you can’t work. Decide when to stop driving, don’t wait until there is an accident. Decide when you need help at home, don’t wait until your family are at their wit’s ends.

8. Caregivers need regular breaks.

At the absolute minimum, caregivers need the bulk of one day off every week and a weekend off every three months.

9. Even at very advanced stages, people don’t lose their identity and do not have to lose their dignity.

10. Humor helps an awful lot.

Have thoughts about this list? I’d be happy to hear about it. Email me at matthew.schrag@vanderbilt.edu.

Enbrel is an anti-inflammatory drug approved by the FDA to treat rheumatoid arthritis by blocking an inflammatory molecule (cytokine) called TNF-alpha. There is a hypothesis that chronic inflammation of the brain may be part of the sequence of events which produces Alzheimer’s disease, so various anti-inflammatory treatments have been studied to see if they influence cognitive symptoms – so far none has. In the mid-to-late 2000s, a couple of low-quality scientific papers suggested that treatment with Enbrel could rapidly reverse Alzheimer’s disease, in some cases “within minutes”! In my experience, claims like this are often artifacts (“if it sounds too good to be true…). Not surprisingly, these studies were not independently replicated, but still some people promoted this expensive and potentially dangerous off-label treatment with Enbrel for Alzheimer’s disease in the hopes of a cure. This is widely criticized as exploitation of desperate patients with a treatment which is, at best, unproven.

Never-the-less, interest in a more-rigorous assessment of Enbrel for Alzheimer’s disease persisted and Pfizer eventually funded a phase II clinical trial to assess its potential. This trial used standardized, rigorous diagnostic criteria to select patients and was randomized and double blinded. It did not detect any clear beneficial effects of the treatment. In some secondary analyses, the authors of this study thought there was a trend toward better outcomes in treated patients, but the control patients worsened much faster than is typical, so even these weak trends were likely artifacts. The study was published in the respected journal Neurology in May of 2015. Around the same time, the internal study described in the Post article was completed, surprisingly showing a massive effect. This study was not blinded, not randomized and did not use rigorous diagnostic criteria, but rather was mined from insurance claim data. This type of data is useful for generating new ideas but should be viewed as exploratory and not the equivalent of a randomized controlled trial. The Post article suggests that Pfizer failed to investigate potential links between decreasing inflammation in the body and the progression of AD, but barely mentioned that they funded a clinical trial. Moreover, the article criticizes Pfizer for failing to share this data, but it is also clear that the data was made available to some external researchers.

Despite the sensational headline, Pfizer’s decisions in this case make sense. Regardless of motivations, the better-quality study showed little clinical effect. The insurance-claims-based data was too strong to be believable, particularly since the drug does not appear to cross the blood brain barrier and without further verification the data was probably not publishable. And importantly, the risk of promoting further off-label use of this treatment is real. Additional potential risks of taking Enbrel include that it lowers the body’s immune response leading to a greater chance of infection and the expense of the treatment which may be thousands of dollars a month. It should be emphasized that there is presently a lack of concrete, scientifically accepted evidence indicating that Enbrel is a viable treatment for AD and due to this lack of evidence patients should not be advised to use Enbrel as a therapeutic or preventive measure outside of a clinical trial.

Rowland, Christopher. “Pfizer had clues its blockbuster drug could prevent Alzheimer’s. Why didn’t it tell the world?” The Washington Post. 04 June 2019. WP Company. 20 June 2019 https://www.washingtonpost.com/business/economy/pfizer-had-clues-its-blockbuster-drug-could-prevent-alzheimers-why-didnt-it-tell-the-world/2019/06/04/9092e08a-7a61-11e9-8bb7-0fc796cf2ec0_story.html?utm_term=.89675cddbdae.

Butchart, Joseph et al. “Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial.” Neurology vol. 84,21 (2015): 2161-8. doi:10.1212/WNL.0000000000001617

“Enbrel® (etanercept) Financial Support Options.” Enbrel® (etanercept) Financial Support Options. 17 Jan. 2019. Amgen. 20 June 2019 https://www.enbrel.com/support/financial-support.

“Important Safety Information – Enbrel® (etanercept) HCP.” Important Safety Information – Enbrel® (etanercept) HCP. 2019. Amgen. 24 June 2019 https://www.enbrel.com/hcp/important-safety-information.

Novella, Steven. “Enbrel for Stroke and Alzheimer’s.” Science-Based Medicine. 8 May 2013. Science-Based Medicine. 20 June 2019 https://sciencebasedmedicine.org/enbrel-for-stroke-and-alzheimers/.

The study was profiled by Nature Reviews Neurology who concluded “[Perivascular spaces] showed associations with executive function and information processing speed performances beyond the other markers, suggesting that they might contribute to adverse cognitive health through a unique pathway.”

Dr. Julie A. Schneider from Rush University Alzheimer’s Disease Center and Dr. Anand Viswanathan from the Massachusetts General Hospital Stroke Research Center commented in an editorial that accompanied the manuscript: “This study adds two important findings to the literature. First, it adds to a growing literature that EPVS are important markers of cognitive performance. Indeed, [enlarged perivascular spaces] had a dramatic effect, equivalent to 15 years of age in information processing. The second take-home message, and perhaps of greater importance, is that different types of vascular tissue injuries in aging have independent associations with cognitive performance. Therefore, looking at only one type of abnormality is likely to provide an incomplete picture of the magnitude of the vascular contributions.”

We do not know why these spaces form. One theory is that the spaces are enlarged because the brain cannot effectively clear waste products in the interstitial fluid. Another hypothesis is that perivascular spaces form as neurons die and the brain atrophies. Either way, the current study focuses new attention on this previously neglected MRI finding.

This study was featured in the March 22, 2019 issue of the VUMC Reporter.

Dr. Anthony Arnold from UCLA wrote an editorial discussing this discovery, arguing that patients with CRAO must have an urgent evaluation, just like a patient with TIA or stroke, to prevent future cerebrovascular events. He says, “The paradigm for management of acute retinal ischemia has changed.”

Neuroophthalmologist Valerie Biousse and Nancy Newman, Chair of ophthalmology at Emory University, echoed this sentiment in a correspondence to the Journal. “It is critical that the cause of CRAO be quickly and accurately identified in order to allow for appropriate secondary stroke prevention (which may require urgent surgical intervention) based on the mechanism of CRAO. … Eye care providers play an essential role in evaluating patients with acute visual loss urgently and by making the correct diagnosis of acute retinal ischemia. Once the diagnosis is established, they should follow existing guidelines and send these patients immediately to the nearest stroke center.”

Never-the-less, this conclusion has been controversial. Dr. Sohan Hayreh, ophthalmologist from the University of Iowa and noted expert in the management of vascular retinal disease, argues these patients should be treated in the ophthalmology clinic, saying “for proper management of non-arteritic-CRAO, urgent evaluations of carotid artery, heart, fasting lipid levels, and complete blood count constitute the most important investigations, rather than neurologic evaluations—unless, of course, there are neurologic symptoms. This has been my policy of management of these disorders for about half a century.”

Biousse and Newman respond to this controversy saying “these results clearly highlight the need to expedite the evaluation and treatment of CRAO patients. Unfortunately, this is still a matter of some debate in the United States and many ophthalmologists continue to delay this process by not sending acute CRAO patients immediately to an emergency department affiliated with a stroke center. … Urgent evaluation in an emergency department affiliated with a stroke center is not “controversial.” Rather, it is standard of care, as recommended by the American Heart Association and the American Stroke Association.”

We discuss these results and other aspects of our work on CRAO on The Retina Channel podcast, here.

Ketoflex

Dr. Dale Bredesen of UCLA describes the Ketoflex diet as a non-drug therapy that “reverses” cognitive decline in Alzheimer’s disease (AD). Limiting carbohydrate and calorie consumption induces a “mildly ketogenic state,” in which ketone bodies (e.g. acetoacetate) are metabolized as an alternative energy source over glucose. The Bredesen Protocol claims that this alternative pathway yields more energy in the form of ATP.[i]

Ketogenic diets have already shown efficacy as therapies in severe epilepsy.[ii] On the other hand, hyperketonemia and acidosis have been identified as risks for Type 1 diabetics on ketogenic diets. A growing body of literature suggests that, since metabolic dysregulation has been implicated in AD, fasting and/or ketogenesis may have neuroprotective effects in mouse and rat models.[iii] However, there is little evidence to support efficacy in slowing — let alone reversing — cognitive decline in human AD cases. A 2016 study conducted by Bredesen et al. showed “moderate to dramatic improvements” in 11 AD patients’ neuropsychological testing after 5-24 months of following Bredesen’s diet plan[iv]; however, its journal of publication, Aging, is of dubious reputation and was listed in librarian Jeffrey Beall’s compilation of predatory journals and publishers.[v]

The diet plan is part of the Bredesen Protocol, a “comprehensive, personalized program” heavily advertised to be capable of reversing cognitive decline. The program cost consumers a steep one-time payment of $4,000-20,000 in a New Zealand program.[vi]

Beta-XB

Dr. Fred Pescatore advertises the beta-XB supplement as a “brain-healing miracle” that restores cognitive function by “energizing” mitochondria. The product website claims that brain cells already use beta-XB to synthesize ATP, and that the cognitive decline associated with AD is a result of an “energy crisis” due to beta-XB deficiency.[vii]

Aside from references to plant extracts, the site does not further specify what the supplement actually contains.[viii] Anecdotal evidence of dramatic symptom reversal is not corroborated by any studies. The studies listed on the product website do not examine the effects of a specific “beta-XB” drug, but rather the impact of oral ketogenic compounds such as beta-hydroxybutyrate on neurodegeneration.[ix]

Beta-XB is included in a memory supplement package priced at $189.

Prevagen

Manufactured by Quincy Bioscience, Prevagen contains apoaequorin, a calcium- and cholesterol-binding protein found in jellyfish. Apoaequorin intake has been shown to protect rat hippocampal neurons from glucose deprivation.[x] A company-published study of 218 adults with self-reported memory issues reported improvements in verbal memory and executive function in the treatment group after 90 days of taking 10 mg apoaequorin.[xi]

Apoaequorin’s mechanism of action remains to be studied. It is dubious as to whether the ingested protein can retain its structure and function during digestion, then pass through the blood brain barrier to reach its neuronal targets. Apoaequorin’s efficacy as a “memory supplement” has not been confirmed in any peer-reviewed publications. In 2017, the FTC charged Quincy Bioscience with fraud for falsely advertising the supplement as a memory booster.[xii] Several online patient communities have reported headaches, nausea, and severe hypertension as adverse effects of taking apoaequorin supplements.[xiii]

Prevagen’s listed price is about $60.

After reviewing these findings, I would advise my patients against using any of the treatments. The most effective “natural” ways to enhance memory is to make sure you get high-quality sleep, eat a diet rich in fruits and vegetables to make sure you are getting plenty of antioxidants and stay physically, mentally and socially active.

References

[i] https://drlonsdorf.com/pdf/ReCODE-Report-MPI-Cognition-NUTRITIONAL-GUIDELINES.pdf ]

[ii] A. van Berkel, D. IJff, J. M. Verkuyl. Cognitive benefits of the ketogenic diet in patients with epilepsy: A systematic overview. Epilepsy & Behavior, 87 (2018), pp. 69-77, https://doi.org/10.1016/j.yebeh.2018.06.004.

[iii] A. Paoli, A. Bianco, E. Damiani, G. Bosco. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases. BioMed Research International, 2014 (2014), pp. 10, https://doi.org/10.1155/2014/474296.

[iv] D. Bredesen, E. Amos, J. Canick, M. Ackerley, C. Raji, M. Fiala, J. Ahdidan. Reversal of cognitive decline in Alzheimer’s disease. Aging, 8 (2016), pp. 1250-1258, https://dx.doi.org/10.18632%2Faging.100981.

[v] https://beallslist.weebly.com

[vi] https://www.noted.co.nz/health/health/professor-dale-bredesens-alzheimers-treatment-now-on-offer-in-new-zealand/

[vii] http://betaxb.com

[viii] https://pro.ovhlearning.com/p/OV3SFPA1A/WOV3TC02/?h=true

[ix] H. White, K. Venkatesh, B. Venkatesh. Systematic Review of the Use of Ketones in the Management of Acute and Chronic Neurological Disorders. Journal of Neurology and Neuroscience 8 (2018), https://dx.doi.org/10.21767/2171-6625.1000188

[x] J. Detert, E. Adams, J. Lescher, J-A Lyons, J. Moyer Jr. Pretreatment with Apoaequorin Protects Hippocampal CA1 Neurons from Oxygen-Glucose Deprivation. PLOS ONE 8 (2013), https://doi.org/10.1371/journal.pone.0079002.

[xi] K. Lerner et al. Madison Memory Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of Apoaequorin in Community-Dwelling, Older Adults. Quincy Bioscience, LLC (2016), https://www.prevagen.com/wp-content/uploads/2017/02/ClinicalTrialSynopsis-cmk816.pdf.

[xii] https://www.nbcnews.com/health/health-news/jellyfish-memory-supplement-prevagen-hoax-ftc-says-n704886

[xiii] The ALSUntangled Group. Apoaequorin (Prevagen). Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14 (2013), pp. 78-79, https://doi.org/10.3109/17482968.2012.727302.

We were somewhat surprised to find that our patients seemed to be at high risk for strokes, heart attacks and other serious medical problems, making us think that the CRAO may be the tip of the iceberg. In our newly published manuscript in the American Journal of Ophthalmology we describe over 100 patients who came to the hospital with a CRAO. Over 30% of our patients had a stroke on their MRI, 37% had critical narrowing of the carotid artery, 20% had an acute heart attack or other critical heart disease and 25% needed an urgent surgery.  Over the following two years, 32% of patients with a CRAO had experienced another stroke, had suffered a heart attack or had died. Many of the underlying risk factors for these patients are treatable.

Based on this study we strongly encourage patients to develop sudden loss of vision to come immediately to the emergency room. While we are continuing to work on ways to rescue sight for patients with CRAO, we are already able to address most of the underlying medical risk factors that lead to bad outcomes, so long as we find them in time.  

Full text of this new manuscript is available on our pre-print server. https://schraglab.com/lab-and-projects

American Journal of Ophthalmology: https://www.sciencedirect.com/science/article/pii/S0002939418304793?via%3Dihub

The published version of this manuscript is available here … https://www.sciencedirect.com/science/article/pii/S0891584917312637.

We found that risk factor screening was most-thorough when acute CRAO management involved both ophthalmologists and neurologists in collaboration.  We also found that a little over half of programs were willing to treat appropriate patients with acute CRAO with tissue plasminogen activator (tPA).  As we consider whether or not a clinical trial of intravenous tPA for acute CRAO is justified, this finding importantly establishes that there is equipoise regarding the potential efficacy of fibrinolysis for acute CRAO.  Finally, we believe the that high-degree of variability found in this survey should ideally prompt the formulation of multidisciplinary guidelines to guide the treatment and risk factor screening of patients with acute CRAO.

The full manuscript has been posted under the “Lab and Projects” tab.

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.