Testing for Dementia and Successful Therapies After Diagnosis

Testing for Dementia and Successful Therapies After Diagnosis

Testing for Dementia and Successful Therapies after Diagnosis

Testing for Dementia and Successful Therapies After Diagnosis

Alzheimer’s Dementia Case Study

Recently, I was asked to consult on a 70 y/o man who was diagnosed with AD. Ten years ago he was gainfully employed as an accountant but had rapidly progressive dementia thereby making work impossible, thus mandating retirement. After undergoing multiple specialty consults and workups, his 50 y/o children desperately brought the patient to me stating that I was their “last hope.” They were advised to seek out a care facility for AD as nothing else could be offered to this patient. The loving care at home has become challenging and beyond the family’s ability. The patient was finally placed in a long-term care facility. Of course, the family was told that there is no cure or treatment for AD. 

The patient’s current medications include cholesterol lowering medication, HTN medicine, major tranquilizers that caused significant weight gain, and BPH medicines. A baseline cholesterol level was normal, but the patient had a history of a prior MI and consequently was taking rosuvastatin. All inflammatory markers are markedly elevated, but a current LDL level was 35 on medication. However, the triglycerides were over 500 and the HDL was 30, apo-B was 200 (60-140), and HgBA1C was 6.4. The markedly elevated apo-B is probably due to the dyslipidemia, the treatment for which is optimal statin and PCSK-9 therapy to lower apo-B, which was not that effective in this case. 

Dietary control further improved cholesterol but not the other parameters. I discontinued cholesterol medication, finasteride, and BP med (HTN now controlled by restrictive diet), and psychotropics, all of which can increase IR. After one year of therapy, repeat FDG-PET showed decrease in beta-amyloid plaque, increased glucose uptake and metabolism on FDG-PET, and stable gray matter atrophy. Repeat apo-B level was 50, triglyceride 75, HDL 47, with normalization of inflammatory markers. 

Most importantly, however, and much to the amazement of the family, was the significant improvement clinically in dementia, confusion, agitation, sleep, demeanor, and combative behavior. Although it took over a year to realize improvement in signs and symptoms of dementia, the patient was able to return home and be cared for by his family. The patient continues to improve symptomatically as opposed to the significant deterioration experienced every year since the original diagnosis. I intentionally left out the on-treatment hormone levels so as to not scare you.

Are there any other ways to test for Dementia other than PET scans?

Previously, I mentioned that I had attended a lecture by Dale Bredesen, M.D. who has the reputation of being an expert in AD and dementia, which he proved is a multifactorial disease. One consistent theme I heard mentioned over and over again was that the process of dementia, whatever the cause, starts to occur 30 years before becoming manifest as clinical symptomatic dementia. The exception to that are the genetic causes of dementia, for which there is no cure or prevention. 

However, for the run of the mill usual dementia patient with either AD or vascular dementia, early signs are evident as can be seen on PET scans either as beta-amyloid protein on neurons or vascular dementia. However, other than performing PET scans on everyone, are there any simpler tests to run and treatments to implement that are cost-effective? Insulin resistance (IR) and dyslipidemia are such tests; however, most clinicians ignore or remain oblivious as to how to diagnose and treat these significant pathologies. Since there is no standard blood test for IR, most clinicians will not understand how to use SHBG, dyslipidemia, apo-lipoproteins, waist circumference, BMI, or LDL particle numbers to diagnosis IR or prediabetes because the common FBG and HgBA1C levels remain normal making the diagnosis elusive. However, it is early on that the insult to the brain, heart, blood vessels, pancreas, liver, and kidneys starts but this early disease onset is rarely diagnosed, appreciated, or aggressively treated. 

Well, if Bredesen says that most AD and dementia is a treatable and preventive disease, then why is the incidence of AD and dementia increasing yearly, just like the incidence of other metabolic diseases? For that matter, why is the percent of CVD increasing over the last 10 years when it was decreasing for the 10 years prior to that? And with all the drugs we have to throw at cholesterol, why is the % incidence increasing when it should be decreasing? What is it that we are missing? And metformin has not been shown to improve/reverse AD or symptoms. Hmmm. Oh look, there’s an elephant in the room.

Parenthetically, why is the incidence of dementia, NAFLD, type 2 DM, kidney disease, and cancer also increasing? Rather, why do we let the house burn down when there is so much that we can do to put out the fire? Somehow for CVD, the cholesterol-centric model is not working, coinciding with the recent conclusion from one study that CVD is not driven by cholesterol but more by IR, DM, obesity, HTN, and dyslipidemia from elevated triglycerides and low HDL. And that is driven by visceral fat with the resultant increase in systemic inflammation, endothelial dysfunction, and lipid laden macrophage infiltration of the blood vessel wall. 

As demonstrated in the last Annual Summit (Hormones and Beyond 2021), reducing apo-B levels does not completely prevent the disease, rather removing apo-B off of the blood vessel wall by HDL/apo-A has a much greater effect in reducing the disease. So, what can we do to remedy this? If Bredesen preaches that those early signs and symptoms are evident at least 30 years before clinical disease becomes manifest, then what are those signs and symptoms that we can utilize and how do we aggressively treat those signs and symptoms? Bredesen mentions that beta-amyloid plaque can be seen on PET scans in young patients, but he doesn’t mention the most appropriate work-up or lab tests that we should do in our 40 y/o patients that present 30 years before the clinical disease of dementia becomes evident. For me, Bredesen failed to connect the dots. Come Monday morning, how do we best diagnose and treat and confront all those various disease drivers? How can we diagnose and treat the cause of the disease before the house burns down? Good question, but Bredesen left us hanging. Don’t wait until we smell smoke.

Pharmaceutical Industry and Alzheimer’s Drugs

In order to prove a therapy efficacious, we must rely on outcome studies and not just surrogate markers of disease like beta-amyloid plaque. In addition, we must also prove/demonstrate clinical improvement from our interventions. The recent published studies on aducanumab demonstrate mild reduction in plaque seen on PET scans but there is no clinical symptomatic improvement in dementia. I could spend the entire 3 days of the 7th Academic Summit: Breakthroughs in Brain Health, CVD, and Autoimmunity presenting all the studies of beta-amyloid plaque reversal by a multiple of other therapies, all published in peer review Neurology and Alzheimer Disease journals that are seemingly ignored because the therapies are not profitable or patented medications.  

A persistent endeavor by the pharmaceutical industry is to find that patented drug that reverses beta-amyloid plaque and that also improves symptoms. That does not explain, however, the consistent rejection and avoidance by medical societies of all the published literature demonstrating prevention and reversal of AD. The improvement on PET scans demonstrating significant reduction in plaque, improvement in glucose uptake and metabolism via Fluorodeoxyglucose-PET scans, and improvement in clinical symptoms, are so very impressive but inexplicably ignored by Neurology and medical academies. Other than politics and economics, I can’t explain it. If it is not a new, profitable and patentable drug, then we’re not interested. What a shame. 

As an aside, recent evidence indicates that the initial disease process involves tau tangles and aggregates that occur inside the cell and that results in cell death. The concept that AD is due to beta-amyloid plaque deposition outside the cell has not been demonstrated. Perhaps the plaque seen on the outside of the neuron is the result of the disease and not the cause of the disease. That too may be the reason for failure of any monoclonal antibody to improve symptoms of dementia in any study.

After multiple failed drug studies with monoclonal antibodies, one would think that the pharmaceutical industry would just give up on trying to come up with the magical drug that removes beta-amyloid plaque and that cures AD. As Bredesen mentioned, the pharmaceutical industry has thrown over 40 billion dollars at trying to come up with the drug that reverses and cures AD, but we are no further along at finding a cure than we were 20 years ago. Stupidity is defined as doing the same experiment over and over again expecting, and hoping for, different results. But the results are consistently the same, no improvement or benefit after $40 billion. 

My take is that the pharmaceutical industry is trying to put out the fire after the house has burned down. Once the damage is done, it makes no sense to remove beta-amyloid plaque from the outside of the neuron when the tau tangles and aggregates have destroyed the inside of the neuron which is now dead or non-functioning. There is no ischemic penumbra as with strokes where the tissue might be salvageable. The key should be to prevent the fire from occurring in the first place as well as put out the fire in the early stages, long before the ravages of beta-amyloid plaque and tau tangles destroy the house from the inside. 

Successful Therapies to be Utilized

I’ll connect the dots utilizing the medical literature and outcome studies demonstrating that which has been successful and should be utilized and not ignored. Measuring improvement in glucose utilization by FDG uptake on PET scans, as demonstrated in multiple studies showing reversal of AD, should be the outcome test of choice rather than PET scans that measure only beta-amyloid plaque. That assumes that removal of the plaque reverses the disease process, but we should never assume. Once the neuron is dead, not much can be offered to resuscitate the dead neuron. The key is to catch the disease process early on before the fire starts which makes perfect sense. The problem is that we clinicians are not trained, nor do we understand how to accomplish this, until it is too late. 

How do we diagnose and treat all these patients that would benefit? Unfortunately, patients are not aware of the need to diagnose and prevent the causative factors either as what patient conceptualizes the need to make an appointment to diagnose and treat early markers of AD disease? I think that is wishful thinking on Bredesen’s part. The intent of the upcoming 7th Academic Summit: Breakthroughs in Brain Health, CVD, and Autoimmunity is to review all that we should know in regard to evaluation and treatment before the fire starts, a training that we just don’t receive in any residency program or medical specialty guideline.

Which leads me into the main story of the next newsletter. Now that aducanumab is FDA approved, administration of the medication involves mandatory enrollment in an IRB study. One of the approved treatment sites is in Palm Springs and is connected to the neuro-imaging center. I recently attended the introduction lecture to the IRB study during which the researchers attempted to recruit patients and doctors. You will find the interaction most enlightening, politics and economics at their finest. 

Until next time, stay safe. Neal

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