What is Hippocampal Sclerosis?

   Today we will discuss Hippocampal Sclerosis (HS), which causes memory impairment similar to, and frequently confused as, Alzheimer’s disease (AD). HS is often misdiagnosed as AD because initial symptoms and rate of progression follow roughly the same pattern, but as the neurodegeneration continues the two disorders diverge. Memory impairment is severe in both HS and AD, but other fields of cognition, such as visuospatial processing and executive functioning, remain relatively unimpacted in most HS cases. This is because the atrophy in HS is highly localized to the memory encoding circuit: the hippocampus and nearby structures.

   HS was first observed in 1825 as a product of epilepsy, which remains a primary cause, HS presents in 30-45% of all epilepsy syndromes and in 56% of cases of Medial Temporal Lobe Epilepsy (MTLE). It is believed that seizures, particularly febrile seizures in childhood, damage the hippocampus and prime it for HS development later on. Another factor influencing HS is age. Some researchers even specify age-related HS as a separate disorder from HS induced by epilepsy, denoted as HS-Aging, which is what we will be focusing on in this blog.

   A study focusing on fine-tuning diagnostic classification of HS-Aging analyzed comprehensive data from 1,422 patients with various dementing illnesses. They determined that 68.1% of those diagnosed with HS-Aging post mortem were incorrectly diagnosed with probable AD prior to their death. This misclassification highlights the importance of understanding the differences between these disorders better, so that treatment can target AD or HS specifically. Luckily, some key differences in the clinical presentation of HS versus AD have been elucidated.

   HS patients show abnormal TAR-DNA Binding Protein 43 (TDP-43) in the hippocampus, with one study determining that 89.9% of patients with HS had abnormal TDP-43 compared to only 9.7% of HS-negative patients. Abnormal TDP-43 presents in other dementing disorders too, such as Frontotemporal Lobar Degeneration (FTLD) and AD, however,the age of death and clinical presentations between HS and FTLD differ significantly making TDP-43 a valuable tool for diagnosis. Unfortunately, abnormal TDP-43 presents in 23% of AD cases as well indicating the need for other differentiating factors for an accurate determination of AD versus HS.

   Psychometric testing can help differentiate between HS and AD in these cases. HS patients tend to have high verbal fluency but low delayed recall due to loss of hippocampal neurons with minimal dysfunction in other domains of cognition. This isolated memory problem in HS patients can often be compensated for with notes and an agenda; allowing them to function normally in social and occupational tasks. AD patients’ early memory dysfunction is not as severe as HS patients but the progression of their non-memory symptoms impact not only verbal fluency but also problem solving. AD patients who have low delayed recall should also have low verbal fluency, visuospatial processing, etc. leading to impaired social and occupational function, while an HS patient would have decreased delayed recall before showing any significant decrease in the other domains of thought (e.g. language, visuospatial function, and problem solving).

   These findings suggest there’s potential to better differentiate diagnoses between AD and HS, although further research is needed. Once accomplished we may develop the capability to treat, or even prevent, HS and removing a confounding disorder frequently categorized as AD will allow for more accurate research into AD as well.

Norwood, B. A., et al. Classic hippocampal sclerosis and hippocampal-onset epilepsy produced by a single “cryptic” episode of focal hippocampal excitation in awake rats [Internet]. Journal of Comparative Neurology. 2011. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894278/
Nelson, P. T., et al. Hippocampal sclerosis in advanced age: clinical and pathological features [Internet]. Brain. 2011. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097889/
Brenowitz, W. D., Monsell, S. E., Schmitt, F. A., Kukull, W. A., & Nelson, P. T. Hippocampal sclerosis of aging is a key Alzheimer’s mimic: clinical-pathologic correlations and comparisons with both Alzheimer’s disease and non-taupathic frontotemporal lobar degeneration [Internet]. Journal of Alzheimer’s Disease. 2015. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946156/
Amador-Ortiz, C., et al. TDP-43 IMMUNOREACTIVITY IN HIPPOCAMPAL SCLEROSIS AND ALZHEIMER’S DISEASE [Internet]. Annals of Neurology. 2007. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677204/
Nelson, P. T., et al. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease [Internet]. Acta Neuropathalogica. 2013. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889169/

Blood Tests May Be the Future of Diagnosing Alzheimer’s


   Two primary biomarkers are produced in the brains of those with Alzheimer’s disease (AD). They are misfolded versions of proteins called amyloid-β (Aβ) and tau. Despite having known this for quite some time, there has long been a lack of effective and cost-efficient testing to determine the presence of these proteins for a definitive AD diagnosis. The primary method of diagnosis is currently a scan of the brain called an Aβ-PET which uses radioactivity to show the location and concentration of misfolded Aβ in the brain. These PET scans cost thousands of dollars and are generally not covered by insurance. Alternatively, lumbar punctures (LP) to collect cerebrospinal fluid (CSF) can also determine an AD diagnosis, and while less costly than a PET scan, are more invasive with a higher degree of potential side effects. Due to the risks and discomfort involved for the patient with an LP it is not a routine practice. A long-awaited, simpler, safer, and less costly diagnostic test for AD may finally be on the horizon, and in the form of a simple blood test.

   Blood-based testing for Aβ had already shown promise, but Aβ alone couldn’t accurately predict an AD diagnosis. To add further complexity to the issue, multiple forms of tau are present throughout the body in varying concentrations that don’t all accurately correlate to the amount of misfolded tau in the brain. For example, one such sub-type called p-tau181 had elevated levels in the blood of participants with AD and mild cognitive impairment (MCI). Unfortunately, this alone doesn’t mean that the concentration of p-tau181 in the blood sufficiently correlates to p-tau181 levels in the brain and CSF to be a useful diagnostic tool for AD. Furthermore, increased concentration of this protein, while correlated with presence of AD and MCI, was not as closely tied to the other piece of the puzzle, Aβ pathology, as was desired. Testing for tau has been quite elusive; until now that is!

   Another sub-type called p-tau217, which does correlate well with Aβ pathology, was recently investigated to determine if it could be an effective blood-based biomarker for AD. At first, blood concentrations of p-tau217 were so low that they were undetectable. Luckily, scientists were able to purify and concentrate the sample to 800-fold, allowing for accurate detection of both p-tau181 and p-tau217 in the blood. Concentrations of both tau proteins correlated well to tau levels in CSF, and more importantly, were elevated in Aβ-positive individuals (those with the other biomarker of AD) in comparison to Aβ-negative individuals. This determined that it was more accurate to detect potential AD by using p-tau217 than p-tau181. A second study also confirmed that p-tau217 was an effective blood biomarker.

   In this study, researchers used the p-tau217 blood test to attempt to determine the presence of AD in patients who had a prior diagnosis of AD by Aβ-PET, CSF, or post-mortem analysis of the brain directly. In this way, they could determine whether or not it was truly an effective test and where any shortcomings might be. Interestingly, this tau blood test was able to distinguish those with AD from patients with other neurodegenerative disorders quite accurately. In patients with a PSEN1 mutation who remain asymptomatic much longer than those without the mutation, this test predicted an AD diagnosis roughly 20 years before onset of symptoms. This means that not only could this blood test become the new gold standard for AD diagnosis, but it could also become a preventative test to determine risk for AD. With this premature detection researchers could easily and accurately find participants for preventative AD trials which, hopefully, will lead us more quickly to a disease modifying treatment for AD, preventing symptom onset.  

Fyfe, I. Tau species has potential for Alzheimer disease blood test [Internet]. 2020. Available from: https://www.nature.com/articles/s41582-020-0401-z
Palmqvist, S., Janelidze, S., Quiroz, Y. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders [Internet]. Available from: https://jamanetwork.com/journals/jama/article-abstract/2768841

Virtual Activities for Social Isolation


Older adults and those with chronic health conditions are at higher risk of contracting Covid-19. Although social distancing precautions are very necessary to help flatten the curve and promote the health and safety of our communities, it can contribute to increased isolation and mental hardships. 

Staying mentally and physically active during social distancing and isolation can be challenging for families with loved ones experiencing Alzheimer’s disease. Covid-19 has created additional stress for those acting as caregivers leading to an increased risk of burnout.

When we are faced with spending long periods of time indoors it becomes necessary to find creative ways to stay active and engaged. Many free online resources are becoming available to offer support during this time. 

Listed in this blog are just a few of the resources available for caregivers and their loved ones with Alzheimer’s disease or memory concerns offered by the Alzheimer’s Foundation of America.

In addition to many resources already available through their website, the  Alzheimer’s Foundation of America has created a virtual platform to provide free public resources that can be done from the safety of your home.

These community activities are available online even after the live class is hosted and can be found using the links below.

Find their Facebook Page here.

Find their YouTube Channel here.  

Here is a recent video of a virtual chair yoga group! 

The AFA main website has added helpful resources pertaining to topics such as:

To view all of these resources please visit the AFA’s Coronavirus Information for Alzheimer’s Caregivers page.  

The Alzheimer’s Association  has also provided a resource with tips for caregivers during this time that can be found here. 

Tips for Caregivers

Long Term Care Setting Recommendations

The Alzheimer’s Association is also offering virtual support groups and a 24/7 helpline for those with questions during Covid-19.

Community Virtual Activities

Many local organizations that are remaining temporarily closed to the public are offering online experiences as well such as The Oregon Zoo. They are offering many videos on their website and YouTube channels such as this one.

More Oregon Zoo videos can be found here.

Videos accompanied by an activity can be found here.

The Oregon Coast Aquarium has live cameras that can provide a calming activity. Watch the Shark, Seabird, and otter cams here.

Many zoos, aquariums, and wildlife refuges across the country offer similar virtual visiting options. It may be fun to explore places in different parts of the country or even in other countries! 

We hope you are able to enjoy some of these activities while remaining home during this pandemic.

Remember to help combat the spread of misinformation by keeping up to date with Covid-19 information from reliable sources such as The Center for Disease Control and Prevention (CDC), The National Institutes of Health, and your state and local health departments.


New Sanitizing Procedures for Covid-19


We Have Re-Opened!

We are pleased to resume clinic and research operations at Center for Cognitive Health! Please take a moment to review our plans for sanitizing to ensure patient, subject, and staff safety during Covid-19. Please reach out to us with any questions or concerns. 

To protect patient and subject safety and support a sanitary, healthy, and safe workplace, the following practices have been implemented:  

  • Subjects and study partners will be masked and escorted directly into a clean room (see procedures below) for interviews and examinations upon entering the clinic.
  • Interaction with subjects and study partners will be conducted by masked employees.
  • Employees will wash their hands prior to seeing subjects, eating food, drink, or after going to the bathroom.
  • Proper and frequent hand washing is encouraged.
  • Employees have been encouraged to avoid touching eyes, nose, or mouth with unwashed hands.
  • Tissues and no-touch disposal receptacles with liners are provided at each workstation or in a common area. Gloves are required when removing garbage bags, handling, and disposing of trash followed by washing hands after handling or disposing of trash.
  • Soap has been provided at all bathroom and other sinks in the facility. If soap and water are not readily available, alcohol-based hand sanitizer that is at least 60% alcohol has also been provided. If hands are visibly dirty, soap and water should be chosen over hand sanitizer.
  • Hand sanitizers have been placed in multiple locations for easy access and to encourage hand hygiene.
  • Handshaking and other forms of personal contact will be avoided.
  • Employees are required to follow coughing and sneezing etiquette.
  • Employees are instructed to not use other workers’ phones, desks, offices, or other work tools and equipment, when possible. If necessary, clean and disinfect them before and after use.
  • Disposable wipes and/or cleaning rags with approved cleaners have been provided at key locations so that commonly used surfaces (e.g., doorknobs, keyboards, remote controls, desks, other work tools and equipment) can be wiped down by employees before each use and when necessary.
  • Sick workers are required stay at home or go home if they start to feel/look ill.

 Each employee will clean and disinfect or if clean, disinfect their workstation prior to beginning their shift with a focus on frequently touched surfaces. The frequently touched surfaces include worktables, tools, chairs, doorknobs, light switches, handles, desks, faucets, sinks, keyboards, printers, telephones, remote controls, copy machine parts, machine control stations, handrails, etc.

  • Cleaning personnel or designated employee will clean and disinfect or if clean, disinfect their workstation and cleaning supply cart prior to beginning their shift. They will also clean and sanitize frequently touched surfaces in common areas such as floors, walls, doors, doorknobs, push plates, and handles, worktables, tables, chairs, doorknobs, light switches, handles, desks, telephones, remote controls, faucets, sinks, toilets, bathrooms, soap dispensers, handrails, food preparation and storage equipment such as coffee makers, microwaves, refrigerators, garbage cans, etc. on a regular basis as determined by the need and it should be at least daily, but can be more frequent.
  • Shipping and receiving personnel will also either leave undisturbed for 24 hours or sanitize packages and mail in case they need to be opened immediately.

Sanitation Procedures for Routine Operations 

Wear disposable gloves when cleaning and disinfecting surfaces. Gloves should be discarded after each cleaning. Wash hands immediately for 20 seconds after gloves are removed.  Cleaning and/or disinfecting shall be accomplished by using household cleaners and EPA-registered disinfectants that are appropriate for the surface. All label instructions for safe and effective use of the cleaning product or disinfectant shall be followed including precautions to take when applying the product, such as wearing gloves and making sure there is good ventilation during use of the product. 

When cleaning and disinfecting surfaces and areas, the following procedures will be followed: 

  • If surfaces are dirty, they should be cleaned using a detergent or soap and water prior to disinfection.
  • If EPA-registered household disinfectants are not available, diluted household bleach solutions can be used if appropriate for the surface. Unexpired household bleach is effective against corona viruses when properly diluted. A bleach solution can be prepared by mixing: 5 tablespoons (1/3rd cup) bleach per gallon of water or 4 teaspoons bleach per quart of water.

Sanitation Procedures When an Employee Is Infected 

Wear disposable gloves and a gown when cleaning and disinfecting surfaces. Gloves and gown should be discarded after each cleaning. Wash hands for immediately 20 seconds after gloves are removed. When cleaning and disinfecting surfaces and areas, the following procedures will be followed: 

  • Close off areas used by the sick person.
  • Open outside doors and windows, if possible, or increase air circulation in the area by adjusting the Heating Ventilation and Air Conditioning system. Wait 24 hours before you clean or disinfect. Clean and disinfect all areas used by the sick person, such as offices, bathrooms, common areas, shared electronic equipment like tablets, touch screens, keyboards, remote controls, and equipment.
  • If surfaces are dirty, they will be cleaned using a detergent or soap and water prior to disinfection.

• For disinfection, most common EPA-registered household disinfectants should be effective or a diluted bleach solution can be used if appropriate for the surface


COVID-19: What Can You Do?


     The newest coronavirus strain, COVID-19, has reached pandemic status. Similar to SARS (severe acute respiratory syndrome) from 2013, COVD-19 induces respiratory complications. Those 65 years or older or immunocompromised are at highest risk for complications from the infection. Younger, healthy individuals, including infants, are often asymptomatic or result in minimal and mild symptoms. Due to the currently rapid rate of infection, our hospitals are suffering shortages of PPE (proper protective equipment), medical supplies, medicines, and even medical staff. It is highly likely that we will all be exposed to this virus at some point, but to ensure we have the capabilities to adequately treat and care for those that become ill we need to slow the current rate of infection. As such, this week’s blog will provide precautions that everyone should take in order to minimize the impact of this virus.

     Listed here are some basic steps that everyone should be taking to prevent the transmission of COVID-19. A group effort is needed to slow the transmission of the virus, so remember, we’re all in this together!

  • Stay home as much as possible (known as social distancing or self-isolating). Because symptoms may take several days to develop, unknowingly infected individuals may continue spreading the virus in the community unless they self-isolate. Limit unnecessary visitors in your home. When leaving is necessary, maintain a 6 foot distance (or about 2 arms lengths) from those around you.
  • Wash your hands often and especially after touching things such as doorknobs or sinks outside the home. Be sure you’re using the proper technique and scrubbing for no less than 20 seconds for it to be effective.
  • Clean and disinfect frequently touched surfaces, since the virus can live for several hours to days on surfaces like cardboard, plastic, and certain metals.
  • Avoid traveling in publicly confined spaces, including cruise travel, non-essential air travel, and even public transit such as buses and trains when possible.
  • Avoid touching your face, especially with regards to your eyes, nose, and mouth. It can prevent you from introducing the virus into your system.

     Other than age, risk factors for complications from COVID-19 include chronic lung disease, moderate to severe asthma, heart disease related complications, and compromised immunities. The most common symptoms are fever, shortness of breath, tightness in the chest, and coughing, and generally appear 2-14 days after exposure. Emergency warning signs that may require immediate medical attention include trouble breathing, persistent pain/pressure of the chest, confusion or inability to arouse, and a bluish tint to the lips or face (This list is not all inclusive). If you experience these symptoms, call your doctor immediately. It is important that you call first, as your doctor may request specific precautions prior to your arrival to avoid viral transmission from you to others, or vice versa. For active medical emergencies call 911 and be sure to notify the dispatch personnel that you or your loved one has a suspected case of COVID-19.

     If you are caring for or living with someone who may have coronavirus, there are further steps you should take to prevent the spread. These include;

  • Using separate bathrooms if possible.
  • Avoid sharing personal items, including dishes, towels, bedding, etc.
  • If facemasks are available, have those infected wear them while in the same room with others, including yourself. Note: Facemasks can prevent transmission of the virus by those already infected through the air but are not guaranteed to prevent contraction by an uninfected person, meaning do not buy/use them unless you likely have COVID-19. The excessive purchasing and use of facemasks has already led to shortages in healthcare facilities like hospitals.
  • Wash your hands, laundry, and household surfaces frequently and thoroughly.

     COVID-19 is a novel mutation of coronavirus. It can be transmitted through animal-to-human and human-to-human contact and spreads easily and sustainably within communities, making social distancing and other precautions all the more important. Coronaviruses are primarily spread through respiratory droplets, hence the necessary 6 foot distance from others. Unfortunately, you can also contract COVID-19 by touching a contaminated surface and then your own mouth, nose, or eyes. Although the virus can live on certain surfaces for days, our food products that are shipped over a period of days or weeks at ambient, refrigerated, or frozen temperatures should not contain any active virus.

     Patients confirmed positive for COVID-19 should be isolated either in the hospital or at home depending on the severity of symptoms. How long someone is sick or shedding the virus varies, meaning that releasing someone from isolation should occur on a case-by-case basis and in consultation with doctors, disease prevention experts, and other public health officials whenever possible. As a general rule, one should isolate themselves for at least 14 days after the last exposure to any possible COVID-19 case. Keep in mind, symptoms may not present within an infected individual for up to 14 days if at all. If asymptomatic after 14 days CDC guidelines suggest you can no longer spread the virus unless re exposed. Infected, yet asymptomatic individuals are known as carriers. While they appear unaffected they are still able to transmit or “carry” the virus to others.

     Although certain states have mandated specific stay-at-home restrictions, including Oregon and Washington, a national lockdown is currently not being enforced. It is recommended to remain in your home as much as possible, but you are still able to shop for essentials, like groceries, prescriptions, etc. There is no need to stockpile groceries, toilet paper, etc. The Federal Emergency Management Agency (FEMA) recommends buying only what your family needs for a week. Grocery stores will not be closing and therefore, over-purchasing food, water, and other necessities only leads to shortages for others in need. Deliveries are not being disrupted but stores do need extra time to restock due to staff shortages and increased demand, so most store hours have been reduced.

     While there has been discussion within the government of providing stimulus checks to citizens, this decision has not been finalized. As such, if you receive any correspondence, verbal or written, claiming to be able to get you that money now, it is a scam. Do not provide them with any personal information. The Federal Trade Commission has more information about these scams on their website.

     Non-essential places like theaters, salons, and gyms are closed until further notice. Schools around the country have closed for the remainder of the year or converted to online curriculum only. Many are being asked to work from home or can no longer work at all. Social gatherings with people from outside the household are no longer allowed and playgrounds, state parks, and campgrounds have all closed.

     Due to the drastic changes many of us are facing in our daily lives and routines, it is not abnormal to experience an increase in stress, anxiety, and fear, which is why it is integral that we remember to take care of ourselves and eachother. To prevent these feelings, we recommend the following;

  • Take breaks from watching, reading about, or listening to the news and social media. Hearing about the pandemic repeatedly can be upsetting, so limit your exposure.
  • Take care of your body. It is helpful to take deep breaths, stretch, or meditate when these feelings of anxiety come on. Eat healthy, exercise regularly, get plenty of sleep, and avoid drugs and alcohol.
  • Go outside! You are allowed to take walks, go for bike rides, and walk the dog, but restrict it to your own neighborhood while maintaining a 6 foot distance from others.
  • Make time to unwind. If you are stuck at home, utilize this time for activities you enjoy or even to find new ones!
  • Connect with others. Talking with others about your feelings and concerns can alleviate much of the stress associated with them. Although we must physically distance ourselves right now, we still have access to eachother via phone, video, email, letters, etc. and socializing is important in maintaining mental health.
  • Try to keep a somewhat regular schedule. Wake up at a normal time, eat your meals regularly, and go to bed at a reasonable time.
  • Call your healthcare provider if stress is preventing you from completing your daily activities for several days in a row. If you, or someone you love, are feeling overwhelmed to the degree that you want to harm yourself, please call 911, SAMHSA’s Disaster Distress Helpline (1-800-985-5990), or text TalkWithUs to 66746.

     For more information, please visit the resources listed below. The link to Oregon’s specific coronavirus webpage is included below, and contains information regarding what is and is not allowed in light of the recent executive order mandating a shelter-in-place policy in Oregon.

CDC COVID-19 News:
Alzheimer’s Foundation of America COVID-19 News for AD Patients and Caregivers:
FEMA COVID-19 Rumor Control:
Federal Government COVID-19 News:
Federal Trade Commission’s COVID-19 Scam Information:
Oregon State COVID-19 News:

Neurofeedback: Possibility for Alleviation of Cognitive Decline

    Our response to stimuli may be detrimental to our health and cognition, like being stressed while driving in traffic. Neurofeedback retrains our physiologic response to stressful situations, by measuring our brain waves and modifying them in a desirable manner. These waves have been classified into 4 types:

Delta: Delta waves are what we experience when we are sleeping.

Theta: Associated with a “daydream” like state in which cognitive efficiency is reduced.

Alpha: Correlates to a state of relaxation, essentially the brain is “idling” and not currently engaged but ready to respond if needed.

Beta: Associated with active mental/intellectual activity and outward concentration on the task(s) at hand.

    During normal aging, brain activity shifts with increasing delta and theta waves in patients with Alzheimer’s disease (AD) a larger increase in theta activity with reduced alpha/beta activity is seen. Neurofeedback trains  patients to consciously control their neural activity, increasing alpha/beta activity and decreasing delta/theta activity. Those practiced in neurofeedback can “activate” their own brain to be more engaged and capable of focusing on tasks requiring complex cognition, and possibly alleviating AD symptoms. 

    Neurofeedback training was assessed in individuals with probable AD also taking cholinesterase inhibitors. Half were also treated with neurofeedback training while the other half just received treatment as usual (TAU), with cognitive testing occurring pre- and post- treatment. Neurofeedback training sessions began within two weeks of pre-treatment testing. Sessions occurred twice a week for 15 weeks, during which participants watched a movie while receiving an electroencephalography (EEG). If the training worked (e.g. increased neural activity) the movie was shown in a higher contrast (visual cue) and the participant heard a beep (auditory cue) to notify/reward them. After completion of all training sessions, participants were re-tested and administered cognitive assessments.Patients receiving neurofeedback training had higher total cognitive testing scores, including improved orientation and memory compared to the untreated group. The neurofeedback group showed an improvement in memory and learning with no improvement or decline in other areas compared to their pretreatment scores. The TAU group declined in total cognitive scores in all areas except orientation in time.

    These results suggest that neurofeedback training is effective in preventing cognitive decline for AD patients. While these results are promising, previous studies show conflicting results. In one study, both neurofeedback training and placebo improved attention, executive function and memory suggesting that this may have been a ”placebo effect”. In another study that trained to increase alpha power,  participants experienced an improvement in memory and cognitive performance. Admittedly, each study had slightly different  treatment goals, which may have contributed to these differential results. In order to concretely confirm the efficacy of neurofeedback training in AD, further research is required. 

Luijmes, R. E., Pouwels, S., & Boonman, J. The effectiveness of neurofeedback on cognitive functioning in patients with Alzheimer’s disease: Preliminary results [Internet]. Clinical Neurophysiology. 2016. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27374996
Frank, D. L., Khorsid, L., & McKee, G. M. Biofeedback in medicine: who, when, why and how? [Internet]. Mental Health in Family Medicine. 2010. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939454/

Temporal Memory: How Genetics Might Impact Memory Based on Time of Day

    The biology of how memories are made and retrieved is well studied. A new component possibly impacting our memory based upon the time of day was recently discovered in mice. A protein, BMAL1, may impact our ability (or inability) to recall memories as its levels fluctuate throughout the day. Although all mammals possess the protein, this effect has only been confirmed in mice.

    Melatonin release depends on our circadian rhythm (24 hour light and dark cycle), similarly BMAL1 released at different times of the day impacts memory retrieval. Normal mice, and mice genetically modified to produce BMAL1 with reduced functionality (dnBMAL1), were tested under different light conditions.  Zeitgeber time (ZT) refers to the earth’s 24 hour light/dark cycle, for example, ZT4 refers to the time 4 hours after lights are turned on. Mice explore novel objects longer than those previously seen. Adult mice exposed to novel juveniles for two minutes (training) at ZT4, and then re-exposed 24 hours later, show a marked reduction in the time exploring the juvenile implying recognition. In contrast, adult mice trained and tested at ZT10 showed no recognition due to either an encoding deficit, a retrieval deficit, or both. A third group trained at ZT10 and then tested at ZT4 showed recognition of the juvenile mouse, suggesting that memory encoding was not impaired when trained at ZT10. A fourth group trained at ZT4 and then tested at ZT10 showed impaired recognition similar to those trained and tested at ZT10, suggesting that mice with only two minutes of exposure (weak training) suffer memory retrieval deficits at ZT10. Exposure for three minutes (strong training) alleviated this time-of-day effect on memory retrieval. 

    BMAL1 experiences circadian transcriptional rhythms. BMAL1 mRNA levels in normal mice are lowest when measured at ZT10 (the timepoint with impaired retrieval) suggesting that BMAL1 may regulate memory retrieval. When strongly trained at ZT4, 8, 10, 12, 16, and 22 (and tested 24 hours later), dnBMAL1 mice show normal memory retrieval only at ZT4, 16, and 22, while normal mice show recognition at all timepoints. Although not all deficits can be corrected with strong training in dnBMAL1 mice, when endogenous BMAL1 is high at ZT4, 16, and 22, they are able to retrieve memories without noticeable impairment. This suggests that BMAL1 plays a role in memory retrieval.

    These same tests run in constant dark conditions showed similar results indicating that BMAL1 fluctuates due to an endogenous circadian rhythm, not external cues like light. Similar tests with object recognition and contextual fear conditioning resulted in similar outcomes. In both object recognition and fear conditioning, dnBMAL1 mice showed retrieval deficits compared to normal mice at ZT10 showing that even a particularly salient stimulus (like one paired with a foot shock in the fear conditioning test) can have impaired retrieval with reduced BMAL1 functionality.

     If these results are generalizable to humans then modifying BMAL1 production could have powerful effects on our ability to retrieve memories. Next time you have trouble remembering something wait until a different time of day when your BMAL1 levels might be higher and see if your memory improves.

Hasegawa, S., Fukushima, H., Hosada, H., Serita, T., Ishikawa, R., Rokukawa, T., Kawahara-Miki, R., et. al. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation [Internet]. Nature Communications. 2019. Available from: https://www.nature.com/articles/s41467-019-13554-y

Produce for Change: Can Fruits and Veggies Reduce Risk of AD?


    In our previous blogs we have touched upon a couple aspects of how diet can impact neurological function and risk for diseases like Alzheimer’s. As interdisciplinary studies are becoming increasingly more common, we are discovering even more ways that diet and exercise impact our overall health, genetics, and cognitive functioning. Today we will be focusing on a recent study suggesting that consumption of dietary flavonols, a class of molecules found in a variety of fruits and vegetables, might reduce risk for Alzheimer’s disease (AD) and improve cognitive functioning. In fact, if you read our blog regularly you may already know about one flavonoid (of which flavonols are a subclass), resveratrol, which is the predicted cause behind the “French Paradox”. If you aren’t familiar with the French Paradox you can read about it (and much more) on our blog at centerforcognitivehealth.com.

    Flavonols (and flavonoids) are a subclass of molecules called polyphenols, given their name for the many phenol rings that make up their chemical structure. Because of this shape, they act as antioxidants and many have powerful anti-inflammatory properties. In animal studies flavonols improve memory and learning and decrease the severity of AD pathology including decreased deposition of beta-amyloid plaques and neurofibrillary tangles with reduced microgliosis. Recent research by the Rush Memory and Aging Project (MAP) has attempted to determine if these effects are generalizable to human models, focusing on four common flavonols: kaempferol, quercetin, myricetin, and isorhamnetin.

    MAP began this study in 1997, taking a community of elderly volunteers with no known history of dementia, and began giving them yearly clinical neurological exams and comprehensive food frequency questionnaires (FFQ). They parsed apart the effect of diet on AD-induced dementia onset over the course of the next several years. As of 2018, 921 out of 1,920 participants were randomized in the study excluding individuals with possible AD diagnoses at screening and those with missing data. At each annual evaluation, the participants were given 19 cognitive tests later reviewed by a blinded neuropsychologist. A diagnostic classification for each individual was determined by a neurologist, geriatrician, and geriatric nurse practitioner. When analyzing these results, they took care to account for APOE genotyping, years of schooling, participation in cognitively stimulating activities, physical activity, depressive symptoms, and hypertension to control for any possible confounding variables causing cognitive dysfunction outside of dementia itself. Lastly, they analyzed the FFQ data based on the USDA’s Database for the Flavonoid Content of Selected Foods to determine each participant’s average flavonoid intake.

    Among the 921 participants who did not have dementia at the beginning of the study, 220 developed AD dementia during the follow-up period (average follow-up period was 6.2 years), with a mean age of 81.2 years at onset. Statistical analysis of all this data determined that dietary intake of flavonols were significantly predictive of a 48% decreased risk for AD. In terms of the specific flavonols, isorhamnetin and myricetin were associated with a 38% decreased risk and kaempferol was associated with a 50% decreased risk. Quercetin showed no significant effect on AD risk. Considering that these flavonols frequently co-occur in fruits and vegetables, they also modeled them all simultaneously to determine if one or more of the statistically significant effects were simply due to presence of another flavonol. As it turned out, only kaempferol had an independent association with AD risk. In essence this means that the protective effects of the other flavonols discussed in this study were only present when they co-occurred with the presence of kaempferol, suggesting that kaempferol was the most (and possibly the only) effective biomodulator.

    Kaempferol is abundant in leafy greens. As a general trend, it is clear that modifying one’s diet to include more fruits and vegetables of all kinds is likely to improve both general and cognitive health. However, with the rise of genomic testing, if you or someone you know becomes aware of an increased likelihood of AD it may be worth emphasizing intake of leafy greens and incorporating things like salad, broccoli, or peas into your culinary repertoire regularly. Additionally, while little research has been done on diet’s effect on symptomatic progression of those already suffering from AD, the antioxidant activity of flavonols like kaempferol may also be able to slow the disease progression. Hopefully, more research will be done on this particular topic in the future, but even if this is not the case, in this study those in the highest quintile of flavonol intake also had reduced risk of diabetes, hypertension, and stroke compared to the lowest quintile providing a serious possibility for increased quality of life overall.

Holland, T. M., Agarwal, P., Wang, Y., Leurgans, S. E., Bennett, D. A., Booth, S. L., & Clare Morris, M. Dietary flavonols and risk of Alzheimer dementia [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981
Bakalar, N. Why Fruits and Vegetables May Lower Alzheimer’s Risk [Internet]. New York Times. 2020. Available from: https://www.nytimes.com/2020/02/04/well/mind/why-fruits-and-vegetables-may-lower-alzheimers-risk.html

Neuroprotective Tap Water: Correlations in Lithium Concentration and Dementia


    Within the last few years, an interesting correlation has been discovered between the concentration of lithium in municipal water sources and the incidents of dementia in areas with varying amounts of lithium. In fact, it seems that lithium might provide some form of neuroprotection such that the higher concentration present in tap water predicts a decreased risk of dementia onset later in life. 

    Lithium has been used therapeutically since the mid-19th century but due to lack of scientific publications on its efficacy at the time, it was forgotten and while still used occasionally, administration of lithium was not a widely accepted medical practice. The first accepted use of lithium was promoted by Alfred Baring Garrod, a London internist, for treatment of gout resulting in an increased prevalence of lithium-containing products. In 1870, a Philadelphia neurologist recommended lithium bromide as an anticonvulsant and a hypnotic, followed a year later by Dr. William Hammond being the first physician to prescribe it for mania with relative effectiveness. After this, there are no significant historical references to the use of lithium in a medical setting for many years. 

    After lithium’s brief break from the medical limelight an Australian doctor by the name of John Cade, having read about lithium’s history as a treatment for gout, hypothesized that some condition involving uric acid (the underlying cause of gout) might also play a role in his manic patients’ “psychotic excitement”. In 1949, Cade decided to use lithium for a case study on its efficacy and gave 10 patients lithium citrate and lithium carbonate. Some responded remarkably well, even becoming “normal” enough to be released from in-patient treatment. Cade’s report of this small case study was noticed by others and soon the University of Melbourne began a trial with over 100 patients, discovering that lithium did indeed have very beneficial effects on mania.

    Lithium’s exact mechanism of action in the nervous system is complex. One widely agreed upon finding, however, is that lithium does not have direct or immediate action in the brain, but rather operates through the “second messenger” cyclic-AMP (cAMP). Lithium requires chronic administration over a long period of time to have significant effects.  Are areas with higher lithium concentrations in the groundwater providing an accidental neuroprotective treatment and if so, would it be possible to intentionally implement this on a wider scale, like with fluoride in drinking water and dental health?

    So far, the answer to this seems promising, particularly when it comes to Alzheimer’s disease (AD). The first study to suggest this found that people who live in areas with higher concentrations of lithium in the water were 17% less likely to develop dementia. This led to a growing library of research into lithium as a preventative measure for dementia. A study in rat models genetically modified to express amyloid plaques, like those in AD, found that low concentrations of lithium improved early learning deficits and reduced the number of amyloid plaques in the hippocampus. Regions with higher concentrations of lithium in the water have also been correlated to lower violent crime rates, fewer arrests associated with drug use/addiction, and lower suicide rates suggesting that this small level of lithium intake is capable of impacting behavior and cognition.

    Dr. Cuello, who oversaw the rat-model studies above, supports future lithium trials in AD patients. Microdosing lithium is an especially practical treatment as small amounts are more prone to pass the blood-brain barrier, while minimizing the amount of lithium in the blood, and therefore decreasing the likelihood of adverse effects. Lithium’s use in AD is just beginning but if you are interested in finding your area’s lithium concentration it is available from the United States Geological Survey (USGS).

Kessing, L. V., Gerds, T. A., & Ersboll, A. K. Association of Lithium in Drinking Water With the Incidence of Dementia [Internet]. JAMA Psychiatry. 2017. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710473/#!po=40.9091
Shorter, E. The history of lithium [Internet]. Bipolar Disorders. 2009. Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712976/
Sandoiu, A. Lithium microdose could stop Alzheimer’s from advancing [Internet]. Medical News Today. 2020. Available from:  https://www.medicalnewstoday.com/articles/can-lithium-halt-progression-of-alzheimers-disease
Brunello, N., & Tascedda, F. Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders [Internet]. 2003. Available from: https://academic.oup.com/ijnp/article/6/2/181/719874
Schrauzer, G. N., & Shrestha, K. P. Lithium in drinking water and incidences of crimes, suicides, and arrests related to drug addictions [Internet]. 1990. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1699579

Reflections: How an Interactive Art Exhibit is Building Community


    Art and music therapy are by no means new ideas, with the term art therapy first being coined in 1942 by British artist Adrian Hill and music therapy being implemented on a large scale around the same time to help soldiers during WWII. The fields of art and music therapy have continued to grow and, while not the most common forms of therapy, are still used today for a variety of conditions, primarily in the case of neurological disorders. One such disorder in which art and music therapies provide benefits is dementia. Combining art and music therapy with community outreach has great potential for therapeutic relief and providing a sense of connection with both art and those you experience it with.

    The Nasher Museum of Art at Duke University is implementing this combination with great benefits for all involved. A recent program, called “Reflections”, allows for a private viewing of the museum by a very special group of 26 people. Half of those present suffer from a dementia-causing illness, primarily Alzheimer’s, and the other half are their caregivers. While being shown around the exhibit each person is encouraged to take part in a discussion about how the art they’re admiring makes them feel. Throughout the experience the tour guide asks progressively deeper questions about what feelings, and even memories, the art triggers. Through this process, those suffering from Alzheimer’s and other dementing illnesses are stimulated in a low stress environment and in a way that, in some cases, allows for access of memories that might not be retrievable otherwise.

    After viewing the art, participants in the “Reflections” program are brought to an exhibit focusing on music. It starts as an activity in which guests are given song lyrics and asked to find a visual art piece which, in their mind, encompasses that lyric. Then they are shown art pieces that use aspects of music, for example, a piece called “Cats and Dogs” that features vinyls such as “Purple Rain” by Prince, “November Rain” by Guns N’ Roses, and “Rain” by the Beatles. When asked if this piece brought about any specific memories one woman reminisced about receiving one of these albums from her sister at age 16, showcasing the power that music can have on memory and cognition. Finally, they are brought to a part of the museum in which music is played, changing from live music performed by Duke’s orchestra to a DJ who plays and remixes songs from the 1950s all the way up to releases within the last decade. After one guest asked for a song to dance to, the DJ played “Good Golly Miss Molly” which was met with tapping feet, air pianos, and general enjoyment. 

    Unlike the art, however, the real benefit of this experience is not even on display in the museum. The impact on the lives of those involved is something much more awe-inspiring, in the form of community. One caregiver mentioned that the program gives him and his wife an outing that they look forward to but also provides a sense of security in that “the more you can be with other people that have the same type of issues that you do, you find you’re not alone”. This is crucial because support groups on their own may provide community, and art or music therapy may provide an outlet for emotions and a sense of relief, but no other program combines both of these to allow for the unique relief that one feels when their everyday problems are shared within a community and are then released through engaging and enjoyable activities.

    This program became possible through private donors, the Duke Dementia Family Support Program, and a grant from the Alzheimer’s Foundation of America. Now, thanks to these generous contributions, the Nasher Museum hosts six to eight group tours through “Reflections” one day a month. For those who have taken part in the “Reflections” program this is not just an event or an outing but a rare instance in which they are not alone and are allowed to experience the world around them however they so choose. This provides a sense of freedom either from the symptoms of dementia or from the stress that caring for a loved one with dementia can bring. As such, if you feel called to make a difference like this and are financially capable, I encourage you do consider donating to the Oregon chapter of the Alzheimer’s Association here: https://act.alz.org/site/Donation2?df_id=32112&32112.donation=form1&_ga=2.28875576.527622574.1582139779-1009136760.1572449350

Bitonte, R. A., & De Santo, M. Art Therapy: An Underutilized, yet Effective Tool [Internet]. Mental Illness. 2014. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253394/
Davis, W., & Hadley, S. A History of Music Therapy [Book]. Music Therapy Handbook. 2015. Available from: https://books.google.com/books?hl=en&lr=&id=mfnhBQAAQBAJ&oi=fnd&pg=PA17&dq=music+therapy+history&ots=0jdkyj5043&sig=2dYYWtE_xJhB4s1r9DffyMPrm1w#v=onepage&q=music%20therapy%20history&f=false
Brown, T. How one NC museum is using art and music to unlock memories in people with dementia [Article]. The News & Observer. 2020. Available from: