Day: 02/25/2024

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk

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Abstract

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Discussion

Studies in humans indicate that the chronic reduction of calories 15–20% below the normal levels results in potent effects on risk factors for diabetes, cancer, and cardiovascular diseases. Studies in monkeys indicate that caloric restriction (CR) can prevent diabetes or insulin resistance in the great majority of the animals and cause major reductions in the incidence of both cancer and cardiovascular disease, whereas preliminary findings indicate that both CR and alternate-day fasting can lower insulin resistance and other risk factors for age related disease52,53. However, chronic CR is a severe intervention that would not be sustainable for the majority of the population but that also causes detrimental changes which might negate its beneficial effects- including a reduction in weight and lean body mass54. In fact, in one monkey study described above, decades of CR had strong effects on morbidity but causes a limited longevity extension, and in another it had no effects on longevity and minor effects on cancer prevention55. Thus, interventions that can match or surpass the beneficial effects of chronic CR on morbidity but associated with reduced burden, better compliance, and very low side effects are needed.

It is also necessary to develop methods that can allow the assessment of biological age, therefore avoiding the need to perform long clinical and epidemiological studies to determine healthspan and lifespan. The rate of aging is heterogeneous and thus chronological time (‘age’) is not a reliable proxy of the physiologically changes that are associated with the biological aging process45. Therefore, biological age measures, like the KDM biological age, which merge multi-system biomarkers into a single variable meant to capture the level and rate of organismal aging, are now validated in a number of studies18,19,20,33,34. Based on this measure, an individual’s biological age can be interpreted as the age in a representative population that his/her biological profile most closely corresponds to, given a set of clinical multi-system biomarkers. For instance, a person may have a chronological age of 50, but on a biological level, they may better resemble the average 55-year-old in the population, and thus have a mortality and morbidity risk more akin to that of a 55-year-old. Furthermore, because the markers which make-up the composite biological age are modifiable, this measure may facilitate evaluation of interventions, such as our FMD trial, aimed at slowing the aging process and delaying disability and disease.

In general, our cohort was made up of individuals who were healthier than the average person in the U.S. population, given that on average they were predicted to be 3.5 years younger biologically compared to their chronological ages at baseline. This likely represents an enrollment bias as education years and SES are higher in our sample compared to the average American population. This is a common phenomenon in clinical trials as volunteers are often motivated and more likely to be health conscious56. Regardless, even in this relatively healthy group, positive changes in the biomarkers used to estimate biological age led to a decrease in median biological age of 2.5 years following the completion of 3 FMD cycles. Even though at baseline the generally healthy volunteers in the FMD trial already had lower than average risks for heart-disease, diabetes and cerebrovascular disease, our simulations after 3 FMD cycles indicates biological age reductions associated with further decreases in the 20-year risk for all-cause and cause-specific mortality. It should be noted that these are estimated risk reductions and decreases in mortality were not directly observed in this study. It assumes that associations between biological age and mortality also reflect the effect of change in biological age—which has yet to be proven. However, these results provide preliminary evidence of the potential benefits of FMD even among healthy individuals.

Unhealthy dietary habits and the associated obesity pandemic have been linked to many diseases, including diabetes, CVD, certain cancers, and non-alcoholic fatty liver disease, and an accelerated rate of aging itself. In our first study on the FMD effects in a randomized cross-over trial, we reported that the efficacy of the FMD on clinically relevant risk factors was higher in at-risk participants than in those study participants with risk factor values within the normal range34. Here, we observed similar effects on biological age estimates: the volunteers who most benefitted from the FMD intervention where those who were most unhealthy at baseline. Estimates based off the effects of the FMD trial suggest that early deaths may be delayed whereas maximal life expectancy is probably not extended. For instance, estimated life expectancies in the highest ranges did not show much differences between pre- and post-intervention.

Here we begin to provide potential mechanisms that may explain the reduction of biological age by FMD cycles: in MRI volunteers the FMD cycles lowered total and visceral fat and lowered the hepatic fat fraction in study participants with overweight and in study participants with non-alcoholic fatty liver disease, and lower insulin resistance and HbA1c in a small subset of study participants which builds on our previous clinical and pre-clinical results to indicate that FMD cycles help prevent and can be considered as a therapy to prevent metabolic syndrome and diabetes2,57. When controlling for weight loss the effects persisted, implying that the improvements were probably affected by but were not a reflection of weight loss. Finally, the correlation between the changes in the individual biomarkers and the changes in biological age may suggest that a large proportion of these improvements resulted from shared mechanisms, such as general rejuvenating effects in cells and organs leading to reductions in systemic inflammation as indicated by the high correlations between changes in biological age and changes in both CRP and albumin. This possibility is also supported by the effect of the FMD cycles in reducing the age-associated shift in the lymphoid-to-myeloid ratio towards a younger phenotype, which matches well our previous results in model organisms33. A number of our mouse studies indicate that these effects of the FMD cycles are at least in part caused by multi-system effects involving a coordinated initial reduction in cell number and organ/system size, associated with an increase in stem cells number and proliferation as well as cellular reprogramming leading to a temporary embryonic-like gene expression profile followed by regeneration during the return to the normal size/cell number upon re-feeding30,31,32,33.

Based on the changes observed in the previous and current analyses of the data, our simulation suggests that prolonged practice of FMD or similar dietary interventions may lead to improvements in population health. For instance, we estimated that if individuals underwent 3 FMD cycles each year, they would decelerate their rate of aging, such that for every one chronological year, they would gain less than a year in biological age. A simulation of the effect of 3 FMD cycles for twenty years assuming continued efficacy of this dietary intervention suggests a potential decrease in biological age of about 11 years. Given that the risks for most major chronic diseases rise exponentially with biological age, the slowing of the aging process could lead to a prolonged disease-free life expectancy by delaying the onset of age-related chronic conditions or slowing the accumulation of multi-morbidities. For instance, it has been estimated that delaying the aging process by seven years could cut mortality from age-related diseases in half at nearly every age58. It was also recently estimated that a 20% slowing of the aging process could have an economic value of $7.1 trillion over the next 50 years59. Even under the assumption that the effect of FMD weakened each time it was performed, the results from our simulation suggest that prolonged practice of FMD may have the potential to slow the rate of aging, extend life expectancy, and cut the risks of disease specific mortality.

However, there are major limitations that need to be acknowledged in regards to our simulation: First, the models used to estimate the effects of 3 cycles of FMD on Biological age were based on results from two clinical trials and include only 86 participants. Moreover, trial participants generally shared advantageous social, economic, behavioral, and health characteristics and therefore their results may not generalize to the population as a whole. For instance, other characteristics that are not exemplified by our study participants may alter the effect of FMD on biological age, potentially leading to an overestimation of the long-term effects in our simulation. The simulation also does not take into account compliance, dropout, or the bias that may arise as a result of enthusiastic volunteers. For example, for a portion of the population it could be difficult to undergo 3 yearly FMD cycles for decades. Therefore, the effects are based on a compliance that may be feasible only for a portion of the population, although the clinical trials on normal, hypertensive, cancer, diabetes and Alzheimer patients indicate that even 6-12 consecutive monthly FMD cycles are feasible for the majority of the participants. Also, projections obtained by extrapolating the effects after 3–6 months of the FMD to a lifelong intervention should be cautiously interpreted, since they may be erased in study participants returning to their previous lifestyle in the absence of additional FMD cycles. Notably, although both trials included patients that were in the 60 s and reached 70 years of age and did not display age-dependent side effects, it has not been conclusively established whether the FMD may affect lean body mass and metabolic parameters in a harmful way or interfere with medications in the elderly, although both of the trials described in this study indicate no lean body mass loss after 3-4 consecutive monthly FMD cycles CITE 34 and 36. In fact, in the over 65-70 population, which begins to lose weight and lean body mass, 3 yearly FMD cycles may be as effective as suggested by our mouse study33 and our study on the effect of protein restriction in over 65 individuals16. However, results from an Alzheimer disease trial recently reported by our group with participants in the 55-80 age range indicated that the majority of subjects could complete an average of 6 FMD cycles without safety concerns, indicating that additional trials are necessary to determine whether FMDs may also be effective in the elderly https://doi.org/10.1016/j.celrep.2022.111417. We also did not account for the possibility of mortality in the simulation, and thus results are assuming all individuals remain alive.

It will be important to compare the FMD cycles with other dietary intervention studies in humans such as the CALERIE projects or the University of Illinois at Chicago’s alternate day modified fasting trial to estimate whether these interventions also affect biological age. Together our findings indicate that the FMD is a feasible periodic dietary intervention that reduces disease risk factors and biological age.

Source: Nature

Innovative Nanogel Shown Effective in Treating Spinal Cord Injuries

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A recent study has introduced an innovative nanogel capable of delivering anti-inflammatory drugs directly to glial cells, showing promise in treating spinal cord injuries that lead to paraplegia or quadriplegia.

Innovative nanogels developed by researchers have shown effectiveness in targeting glial cells for the treatment of spinal cord injuries, offering a new avenue for therapeutic intervention.

In a study published in Advanced Materials, researchers Pietro Veglianese, Valeria Veneruso, and Emilia Petillo from Istituto di Ricerche Farmacologiche Mario Negri IRCCS in collaboration with Filippo Rossi of the Politecnico di Milano have demonstrated that an innovative nanovector (nanogel), which they developed, is able to deliver anti-inflammatory drugs in a targeted manner into glial cells actively involved in the evolution of spinal cord injury, a condition that leads to paraplegia or quadriplegia.

Challenges in Current Treatment Approaches

Treatments currently available to modulate the inflammatory response mediated by the component that controls the brain’s internal environment after acute spinal cord injury showed limited efficacy. This is also due to the lack of a therapeutic approach that can selectively act on microglial and astrocytic cells.

Nanogel – Scheme of selective drug treatment in the central nervous system. Credit: Politecnico di Milano – Istituto Mario Negri

Nanogel Development and Efficacy

The nanovectors developed by Politecnico di Milano, called nanogels, consist of polymers that can bind to specific target molecules. In this case, the nanogels were designed to bind to glial cells, which are crucial in the inflammatory response following acute spinal cord injury.

The collaboration between Istituto di Ricerche Farmacologiche Mario Negri IRCCS and Politecnico di Milano showed that nanogels, loaded with a drug with anti-inflammatory action (rolipram), were able to convert glial cells from a damaging to a protective state, actively contributing to the recovery of injured tissue.

Nanogels were shown to have a selective effect on glial cells, releasing the drug in a targeted manner, maximizing its effect, and reducing possible side effects.

Insights and Future Directions

“The key to the research was understanding the functional groups that can selectively target nanogels within specific cell populations,” explains Filippo Rossi, professor at the Department of Chemistry, Materials and Chemical Engineering ‘Giulio Natta’ at Politecnico di Milano. “This makes it possible to optimize drug treatments by reducing unwanted effects.”

“The results of the study,” continues Pietro Veglianese, Head of the Acute Spinal Trauma and Regeneration Unit, Department of Neuroscience at Istituto Mario Negri, “show that nanogels reduced inflammation and improved recovery capacity in animal models with spinal cord injury, partially restoring motor function. These results open the way to new therapeutic possibilities for myelolysis patients. Moreover, this approach may also be beneficial for treating neurodegenerative diseases such as Alzheimer’s, in which inflammation and glial cells play a significant role.”

Can the Ketogenic Diet Treat Mental Illness?

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Reports are promising, but rigorous trials are needed, experts sayShare on LinkedIn. Opens in a new tab or window

A photo of foods associated with the ketogenic diet

The ketogenic diet has long been known for its use in treatment-resistant epilepsy, but attention is now turning to its potential benefits in mental illness as well.

Could something as simple as a diet actually improve notoriously difficult-to-treat conditions including major depressive disorder, bipolar disorder, and schizophrenia?

The evidence to date has been less rigorous than gold-standard randomized controlled trials. But new studies are underway, and more clinicians are keen to explore reports of patientsopens in a new tab or window whose psychiatric conditions improved when they adhered to a ketogenic diet.

Nonetheless, there are challenges inherent to dietary intervention trials that must be mitigated, and broader buy-in from the medical community at large remains to be seen.

“There have to be randomized trials before we can make enthusiastic and evidence-based treatment recommendations,” Drew Ramsey, MD, a nutritional psychiatrist and member of the American Psychiatric Association, told MedPage Today. “That said, I’m hopeful and optimistic that patients are going to have more tools to treat their mental health disorders.”

What Does the Evidence Say?

Ramsey noted that some randomized controlled trials have shown that dietary interventions — albeit not specifically the ketogenic diet — can help improve depression. For instance, the SMILES trialopens in a new tab or window showed better symptomatic improvement and remission rates with a dietary intervention compared with a control social support group, and the AMMEND studyopens in a new tab or window showed greater improvements in symptoms and quality of life for young men on the Mediterranean diet compared with controls.

As for the ketogenic diet specifically, Georgia Ede, MD, a nutritional psychiatrist based in Massachusetts, told MedPage Today that the body of research for its use in psychiatric conditions “is really starting to grow.”

Ede co-authored a French study published in Frontiers in Psychiatryopens in a new tab or window in 2022 entitled, “The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients.”

Patients with severe and persistent mental illness (major depressive disorder, bipolar disorder, and schizoaffective disorder), with poorly controlled symptoms were admitted to a psychiatric hospital and placed on a ketogenic diet as an adjunct to conventional care.

Though 3 patients were unable to adhere to the diet for more than 14 days, the researchers concluded that following the ketogenic diet for treatment-refractory mental illness was “feasible, well-tolerated, and associated with significant and substantial improvements in depression and psychosis symptoms and multiple markers of metabolic health.”

More than 40% of patients experienced remission from their diagnosis, Ede said, and 64% left the hospital on less psychiatric medication than when they entered.

Among other recent research, a feasability pilot study of the ketogenic diet in bipolar disorder was recently completed in the U.K.

Findings of the study, published in BJPsych Openopens in a new tab or window last October, found that of 27 participants, 20 completed 6 to 8 weeks of the ketogenic diet. A majority of participants reached and maintained ketosis, indicating adherence to the diet, and adverse events were generally mild and modifiable, the researchers found.

What Studies Are Underway?

In an email, a spokesperson for the National Institute of Mental Health (NIMH) pointed MedPage Today to two trials that it is supporting in an investigation of the effects of the ketogenic diet on mental illness — one led by researchers based in Maryland, and another by a team in California.

Deanna Kelly, PharmD, of the Maryland Psychiatric Research Center — a joint program between the University of Maryland School of Medicine and state Department of Health — is leading an inpatient randomized controlled trial of a gluten-free diet in a subgroup of people with schizophrenia.

These patients were found to have high levels of IgG anti-gliadin antibodies. The goal of the trial is to determine whether participants benefit from a gluten-free diet, predicted to result in lower levels of schizophrenia symptoms and antibodies to gliadinopens in a new tab or window.

The inpatient setting enables complete control over what the participants eat, she said. Lending another layer of stringency to the trial is that individuals performing the psychiatric ratings are blinded.

Judith Ford, PhD, of the University of California San Francisco, who also received NIMH funding, and her team will look at whether neural network instability in schizophrenia can be improved by a ketogenic diet. Particularly, they are exploring whether deficient glucose metabolism — at least partially mediated by insulin resistance — contributes to network instability in the disorderopens in a new tab or window, a mechanism underlying accelerated aging and cognitive impairment in patients.

“So far, it’s helping people’s overall intellectual function,” Ford said.

As for current funding opportunities available through NIMH, the agency told MedPage Today that there are not any that “specifically focus on diet and mental health,” but that it would “consider relevant applications submitted under broader funding opportunity announcements.”

What Challenges Remain?

A number of researchers pursuing work pertaining to ketogenic diets and mental health have turned to a private organization funding work in this areaopens in a new tab or window.

Securing federal funding can be difficult, in part because of the need to show targets of engagement, Kelly said. Even if someone had a cure for depression, she explained, they would have to show, for instance, what links the outcome, improvement in depression, to the brain.

“People have to spend their lives [in order to] understand the target,” Kelly said. “Not everybody can afford that. Sometimes, it’s not really even that clear.”

“That’s why we need other funding agencies to step up and take risks,” she added.

Other hurdles for researchers include added costs for inpatient stays during clinical trials, and the lack of pharmaceutical funding for dietary interventions, Kelly said.

Mackenzie Cervenka, MD, medical director of the Adult Epilepsy Diet Center at Johns Hopkins Hospital in Baltimore and a member of the American Epilepsy Society, noted that potential interest in and promise of ketogenic diets for mental health is due in part to a more than 100-year history of the use of such diets for epilepsy patients.

However, Cervenka also noted that “awareness that there can be long-term side effects of the diet is important.”

If patients no longer see their doctor for prescription medications, they may not be monitored for potential areas of concern like kidney stones, hyperlipidemia, and bone health, she said.

Cervenka also noted that short-term studies “might not be sufficient to indicate what the benefits could be in real-world applications.” For instance, “in our experience about 50% [of individuals] will stop the diet within 6 months, whether they are responders or not,” she said.

This can be due to adherence difficulties, she said, or in the case of patients with epilepsy, not achieving sufficient seizure control, for instance, for the purpose of driving.

Ramsey also cautioned that it’s important to remember that “not everything works for everybody.”

Ultimately, regarding randomized controlled trials, “we need more,” Ede said. “Many clinicians will not feel comfortable until we have more.”

Do Organ Transplants Cause Personality Changes?

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Anecdotal evidence suggests a real possibility, but more research is needed

A photo of surgeons preparing a donor kidney for transplantation

Liester is a psychiatrist and a professor of psychiatry.

I have received some unusual phone calls in my nearly 40-year career as a psychiatrist, but Mary’s* call was unique.

“Dr. Liester,” she began, “I don’t need to see you as a patient. I just want you to tell me if I’m crazy. You see, I’m having memories of things that have never happened to me.”

That piqued my interest, so we agreed to meet for an appointment.

Mary was a pleasant, intelligent woman in her mid-40s who exhibited no signs of psychosis. In fact, she seemed quite rational and easy to engage in conversation. She began explaining why she had called: for the last year, Mary had been experiencing recurrent, intrusive memories of being hit by a car. In these “memories,” she was a pedestrian and she not only saw herself being struck by the car, but she felt the impact as the car struck her torso, sending her airborne. The problem was, Mary had never been hit by a car. When asked about any trauma, Mary recounted she had undergone heart transplant surgery just prior to the onset of these new memories. Her transplant surgery had gone well, but she was left wondering, “Could my new heart have anything to do with these new memories?”

Mary then divulged that she had recently learned the identity of her donor’s family. They lived in Seattle, and she was planning to visit them in the next week. We ended the appointment with me reassuring Mary that she was not crazy and asking her if she would meet once more after she returned from her trip. She agreed.

When Mary returned, she described what she had learned on her trip. Her donor was a pre-adolescent boy who was playing tag with friends when he ran between two houses, then into an alley where he did not see an approaching car. He was struck by the car in the torso in the same location where Mary had been experiencing the sensation of having been hit. The boy was declared brain dead, but his heart was not damaged, so his parents donated his heart. Mary’s reaction to learning this information was a sense of relief and closure. She now knew she was not “crazy.” But, I was left wondering, do organ transplants cause personality changes?

Relevant Research

One of the earliest patient accounts describing personality changes following organ transplantation is found in Claire Sylvia’s book, A Change of Heart, published in 1997, and it wasn’t until the 1990s that researchers began investigating this phenomenon.

In one early studyopens in a new tab or window in this area, neuropsychologist Paul Pearsall, PhD, investigated changes in the personality of 10 heart transplant recipients to see if they paralleled the personality of their donors. In each case he interviewed the heart transplant recipient, a member of their donor’s family, and a member of the recipient’s family. He found two to five similarities in each case between changes in the recipient’s personality post-transplant and the donor’s personality. These included changes in preference for food, music, art, sex, recreation, and career.

He also found specific instances in which the recipients were able to identify the names of their donors or had sensory experiences related to their donors. In another studyopens in a new tab or window, detailed in his 1998 book, The Heart’s Code, Pearsall reported that recipients of kidney, liver, and other organs also described changes post-transplant including their sense of smell, food preferences, and emotions, but these changes were usually transitory and not as robust as the changes found in heart transplant recipients.

More recently, we conducted a studyopens in a new tab or window on this topic at the University of Colorado School of Medicine, and found 89% of organ recipients (of any organ) reported changes in their personality following their transplant surgery.

These findings raise the question, what causes these personality changes? Numerous hypotheses have been proposed, including the effects of immunosuppressive drugs, the trauma of undergoing transplant surgery, and surreptitious acquisition of information about the donor from outside sources. Pearsall suggested another possibility: he hypothesized cellular memory might be responsible.

Where Are Memories Stored?

In 1894, Spanish neuroscientist Santiago Ramón y Cajal suggestedopens in a new tab or window memories are stored in the brain. He believed this storage occurs by restructuring synapses, the connections between neurons. More than half a century later, researchopens in a new tab or window by neurosurgeon Wilder Penfield, MD, found evidence to back this upopens in a new tab or window. The theory that memories are stored in the synapses of the brain persists to this day.

But memories stored in the brain would not likely account for the personality changes observed following organ transplants. Could a different type of memory explain these changes?

Several types of non-neurologic cellular memory exist. For example, the immune system remembers exposure to infectious pathogens and responds quicker if re-exposure occurs. This is known as immunological memory.

Another form of cellular memory involves DNA. The DNA in our cells is capable of storing enormous amounts of informationopens in a new tab or window. Almost all cells of the body are known to secrete DNA-containing packages known as exosomes that circulate throughout the body and deliver their contents to other cells where they are then incorporated into the recipient cell’s DNA. Is it possible that donor organs secrete exosomes that deliver DNA to the organ recipient’s cells, thus transferring DNA-encoded memory about the donor?

Epigenetic memory is another type of cellular memory. Epigenetics is the study of factors that turn genes on or off without altering the DNA sequence. Numerous types of epigenetic changes occur in human cells, and these changes create an epigenetic code that is stored and retrieved over time.

The totality of an individual’s epigenetic changes at any point in time is referred to as the epigenome. The epigenome, which can be viewed as a record of the interactions between an individual and the environment, persists as a form of cellular memory known as epigenetic memory. Just as DNA memory can be transferred between cells via exosomes, epigenetic changes associated with DNA can also be exchanged between cells, suggesting a possible means of transferring information between organ donor and recipient cells.

RNA memory could also be at play. Researchers at UCLA used the sea slug Aplysia to demonstrate the transfer of memoryopens in a new tab or window between individuals. These animals were exposed to repeated electrical shocks to their tails, which established a memory of the shock. RNA was then removed from the trained animals and injected into naïve animals, who responded as if they had been trained to respond to the electrical shock. This demonstrated that memory can be transferred via RNA, raising the possibility that organ donors’ memories might be transferred to recipients via RNA-containing exosomes.

Another potential method for transferring memory involves proteins. Over two decades ago, Sandra Peña de Ortiz and Yuri Arshavsky hypothesizedopens in a new tab or window that novel proteins could encode long-term memories. Exosomes are known to transfer proteins between cells, suggesting memories stored in such proteins could be exchanged between a donated organ and a recipient.

Ramifications

For now, the jury is out on these theories, and much more research is needed. But if memories and personality traits can be exchanged via organ transplantation, this suggests multiple potential consequences of organ transplant surgery. Not only could the transfer of an organ affect the recipient’s identity and personality, but relationships and surgical outcomes might be influenced as well. For example, my patient Mary wanted to stop taking her immunosuppressive medications because she believed she had “integrated” her new heart and therefore would not reject it if she stopped taking her medicines. Such a decision could have dire consequences, including rejection of the donated organ and death.

Future Directions

Further studies exploring personality changes following organ transplants may teach us not only about the types of personality changes that can occur, but also increase our understand of different aspects of personality and various processes involved in the storage and retrieval of memories. Although anecdotes do not prove personality changes occur as a result of organ transplantation, they do suggest the possibility of such changes, and provide a starting point for further explorations into this fascinating area of medical science.

Source: Madscape

How are pure honey and raw honey different?

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Pure honey and raw honey are two terms often used interchangeably, but they have distinct differences. Both types of honey are derived from the nectar of flowers and have numerous health benefits. However, the processing methods and characteristics of pure honey and raw honey vary significantly. To understand the differences, let’s delve deeper into each type.

Pure honey refers to honey that has been processed and filtered to remove impurities such as wax, pollen grains, and other substances. The processing of pure honey typically involves heating and straining to achieve a clearer and more consistent appearance. This process also helps to delay crystallization, allowing the honey to remain in a liquid state for longer.

On the other hand, raw honey is minimally processed and undergoes little to no filtration or heating. It is extracted directly from the honeycombs and may contain particles of beeswax, pollen, propolis, and even bee remains. Raw honey is often considered to be more natural and unprocessed compared to pure honey.

One of the significant differences between pure honey and raw honey lies in their nutritional content. Raw honey contains a higher concentration of vitamins, minerals, enzymes, and antioxidants compared to pure honey. The filtration and heating processes applied to pure honey can strip away some of these beneficial components, making it slightly less nutritious than raw honey.

Raw honey is known to contain small amounts of bee pollen, which can provide immune-boosting properties. Bee pollen is rich in vitamins, minerals, and amino acids, making it a valuable addition to raw honey. However, due to the filtration process, pure honey does not contain bee pollen.

Another difference between the two types of honey is their taste and texture. Pure honey often has a milder and more consistent flavor, as the heating process can remove some of the floral nuances found in raw honey. On the other hand, raw honey has a more distinct and robust flavor profile, often reflecting the specific flowers from which the nectar was collected. The texture of raw honey is also typically thicker and grainier compared to the smoother consistency of pure honey.

In terms of color, both pure honey and raw honey can vary depending on the flowers visited by bees. However, raw honey tends to have a more diverse range of colors, including variations of amber, gold, and even dark brown. Pure honey, on the other hand, is often lighter in color and may appear more transparent due to the filtration process.

When it comes to the potential health benefits, both pure honey and raw honey offer various advantages. Honey, in general, is known for its antimicrobial, anti-inflammatory, and antioxidant properties. It can be used as a natural remedy for coughs, sore throats, and wound healing. However, due to the higher concentration of beneficial compounds, raw honey may provide slightly more health benefits compared to pure honey.

It is worth mentioning that while raw honey is often preferred for its natural and unprocessed qualities, there are some concerns regarding its safety. Raw honey may contain spores of the bacteria Clostridium botulinum, which can cause botulism in infants under one year old. Therefore, it is generally recommended that infants avoid consuming raw honey.

In conclusion, both pure honey and raw honey have their own unique characteristics and benefits. Pure honey undergoes processing and filtration, resulting in a clearer and more consistent appearance, but with a potential reduction in nutritional content. On the other hand, raw honey is minimally processed, retaining more of its natural components, but may contain particles such as pollen and beeswax. The choice between pure honey and raw honey ultimately depends on personal preference and the desired taste, texture, and potential health benefits.

What are the health benefits of consuming probiotic-rich foods?

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Probiotic-rich food sources stand out enough to be noticed lately because of their potential medical advantages. These food sources, overflowing with valuable microbes, assume a urgent part in supporting different parts of our prosperity.

One essential advantage lies in gut health. The human stomach related framework is home to a tremendous local area of microorganisms, by and large known as the stomach microbiota. Probiotics, which incorporate strains like Lactobacillus and Bifidobacterium, add to keeping a fair microbiota. This equilibrium is critical for effective processing, as it helps with separating complex sugars and strands, forestalling obstruction and supporting a sound stomach lining.

Past processing, probiotics apply a significant effect on the critical piece of resistant cells lives in the stomach, and probiotics assist with directing safe reactions. By advancing the creation of antibodies and upgrading insusceptible cell movement, probiotic-rich food varieties might possibly decrease the gamble of diseases and backing by and large invulnerable capability.

The complex association between the stomach and the mind, known as the gut-cerebrum axis, is another region where probiotics exhibit their effect. Arising research recommends that the microbiota may impact state of mind and mental capability. Probiotics might assume a part in this communication, possibly offering benefits in overseeing conditions like tension and sadness.

Probiotics likewise add to nutrient absorption. By separating complex mixtures, they work with the retention of fundamental supplements, including minerals and nutrients, in the digestive organs. This wholesome help is pivotal for keeping up with by and large wellbeing and imperativeness.

For people with lactose intolerance, probiotics, especially Lactobacillus strains, aid the processing of lactose. This can be especially useful, permitting people to appreciate dairy items without uneasiness.

The job of probiotics reaches out to inflammation management. Persistent aggravation is embroiled in different ailments, including provocative entrail illnesses. Probiotics might assist with tweaking irritation, giving a likely road to overseeing such circumstances.

In the domain of gastrointestinal wellbeing, probiotics show viability in overseeing conditions, for example, diarrhea. Studies have shown that specific probiotic strains can diminish the length and seriousness of irresistible looseness of the bowels, offering a characteristic and steady methodology.

With regards to irritable entrail condition (IBS), probiotics have shown guarantee in giving alleviation. While the components are not completely perceived, the capacity of probiotics to impact stomach motility and regulate aggravation might add to mitigating side effects in certain people.

Integrating an assortment of probiotic-rich food varieties into one’s eating routine is vital to receiving the full range of rewards. Yogurt, kefir, sauerkraut, kimchi, and fermented tea are only a couple of instances of these wellbeing advancing food varieties. Notwithstanding, it’s vital for note that singular reactions can shift, and counseling a medical services proficient is prudent, particularly for those with existing ailments.

All in all, the utilization of probiotic-rich food sources offers a complex way to deal with wellbeing. From supporting processing and resistant capability to impacting mental prosperity, the advantages highlight the significance of sustaining a different and adjusted stomach microbiota. As how we might interpret the many-sided exchange between the microbiome and human wellbeing extends, probiotics stand apart as a promising road for advancing generally speaking health.

Intravascular Imaging-Guided PCI Reaches a Turning Point With Survival, MI Benefits

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A computer rendered view from within a stented artery.

For the first time, intravascular imaging-guided coronary stenting was associated with better survival and reduced myocardial infarction (MI) in a meta-analysis powered to detect these benefits against angiography, researchers reported.

Randomized to optical coherence tomography (OCT) or intravascular ultrasound (IVUS) guidance, patients who underwent percutaneous coronary intervention (PCI) with contemporary stents showed a decrease in target lesion failure (RR 0.71, 95% CI 0.63-0.80) and its individual endpoint components of:

  • Cardiac death: RR 0.55 (95% CI 0.41-0.75)
  • Target vessel MI: RR 0.82 (95% CI 0.68-0.98)
  • Target lesion revascularization: RR 0.72 (95% CI 0.60-0.86)

Additionally, the two intravascular imaging modalities were tied to decreases in stent thrombosis (RR 0.52, 95% CI 0.34-0.81), all MI (RR 0.83, 95% CI 0.71-0.99), and all-cause death (RR 0.75, 95% CI 0.60-0.93) when participants were followed for a weighted average of 24.7 months, reported a group led by Gregg Stone, MD, of Icahn School of Medicine at Mount Sinai in New York City.

“Compared with angiography guidance, intravascular imaging guidance of coronary stent implantation with OCT or intravascular ultrasound enhances both the safety and effectiveness of PCI,” the authors concluded in The Lancetopens in a new tab or window.

“To place these results in perspective, drug-eluting stents [DES] do not reduce death, myocardial infarction, or stent thrombosis compared with bare metal stents, yet are recommended with class I evidence in societal guidelines for their reduction in repeat revascularization alone,” they wrote.

Meanwhile, IVUS and OCT imaging are still stuck with a weak class IIa endorsement from societal guidelines on coronary revascularization despite older evidence that they reduce composite cardiac events and repeat revascularization compared with angiographic guidance alone.

“In contrast to the plateau in clinical outcomes that has been reached with drug-eluting stent technology, event-free survival might still be substantially improved by implanting drug-eluting stents with intravascular imaging guidance,” Stone and colleagues stressed.

The study authors suggested greater adoption of IVUS and OCT in mainstream clinical practice based on the meta-analysis. “These data warrant efforts to overcome remaining impediments to the routine use of intravascular imaging, including training and reimbursement issues,” Stone’s group urged.

Zhong Shiun Lee, MBBS, and Nicola Ryan, MBBCh, MPH, both of Aberdeen Royal Infirmary in Scotland, agreed.

“To date, the question among clinical interventional cardiologists often revolves around when intravascular imaging should be used to guide PCI,” they wrote in an accompanying editorialopens in a new tab or window. “[F]ollowing this meta-analysis the question surely becomes why are we not using intravascular imaging to guide PCI?”

“Substantial consideration to upgrading the use of intravascular imaging to a class I recommendation in future guidelines should occur as a result of the increased procedural safety and efficacy with the use of intravascular imaging demonstrated by this meta-analysis,” according to the editorialists.

Stone and colleagues had been motivated to perform their meta-analysis following the wave of positive IVUS/OCT trials released last summer, namely GUIDE-DESopens in a new tab or window, ILUMIEN IVopens in a new tab or window, OCTOBERopens in a new tab or window, and OCTIVUSopens in a new tab or window.

Ultimately, the researchers pooled 22 randomized trials published from 2010 to 2023. Included were nearly 16,000 patients undergoing PCI with DES randomized either to IVUS/OCT or to angiography alone to guide the intervention. Patients represented a range of clinical presentations and coronary anatomy complexity.

No differences in outcomes between IVUS and OCT groups could be detected by the sample.

Stone’s group reported that their results comparing intravascular imaging against angiography were generally supported by a separate network meta-analysis relying on indirect data and overall treatment effects.

“Between-study heterogeneity was minimal or absent for all endpoints examined in each pairwise comparison, publication bias was not detected, no areas of inconsistency were noted within the network, and the direct and indirect data were consistent for each comparison within the network. Analysis with Bayesian and frequentist methods also provided similar treatment effect estimates,” the authors added.

Nevertheless, the meta-analysis was limited by differences in individual trial designs and protocols that could not be adjusted for with individual patient-level data. The report was also not designed to determine how mechanistically IVUS and OCT could produce benefits in hard clinical outcomes, nor to assess complications attributed to intravascular imaging catheters.

“Finally, optimal imaging criteria differed between trials, making it impossible to draw conclusions with regard to which criteria should be used in clinical practice,” Lee and Ryan commented.

“Additional investigation is required to determine which patient and lesion types benefit most from intravascular imaging guidance and to establish the optimal techniques and procedural objectives for OCT-guided and [IVUS]-guided stent implantation,” study authors acknowledged.

Small study adds to growing hope CAR-T cell therapy could revolutionize autoimmune disease treatment.

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Antibodies flying towards nerve cells — in the lab coverage from STAT

People with autoimmune disorders don’t usually get to talk about a cure. There’s symptom management, hopeful periods of remission often followed by relapses, but rarely a lasting fix for the way their immune system attacks healthy cells. If the immune system is an army, then those with conditions like lupus, multiple sclerosis, or rheumatoid arthritis are often fighting a never-ending war of friendly fire.

But over the last few years, researchers in Germany have begun testing the potential of CAR-T therapy — a cutting-edge cancer treatment in which a patient’s immune T cells are genetically modified in a lab to better attack disease targets — to help those with autoimmune disorders. Their latest findings, published Wednesday in the New England Journal of Medicine, provide evidence that has led experts to consider, tentatively, using the c-word.

In a study of 15 patients — eight with lupus, four with systemic sclerosis (scleroderma), and three with idiopathic inflammatory myositis, a rare muscle disease — researchers eliminated or reduced symptoms and disease biomarkers with a single infusion of CAR-T cells designed to target B cells, immune cells that play a key role in driving autoimmunity. There were no relapses among lupus patients, who were monitored for up to two years after treatment. The myositis and sclerosis patients, who had shorter-term follow-up (usually about three to six months but up to a year) saw their symptoms significantly lessen.

“It’s wonderful. I mean, some people would think that this might be too good to be true, but it actually does look true,” said Carola Vinuesa, an immunologist and geneticist at the Francis Crick Institute in London, who was not involved with the research.

Patients included in the case study were experiencing severe forms of these diseases that affected at least two organs, with “not many treatment options left,” according to Fabian Müller, a hematologist-oncologist at University Hospital Erlangen and first author on the paper.

For patients with myositis, muscles are damaged by elevated levels of an enzyme called creatine kinase. Extreme disease can leave a person bedridden, struggling to breathe. One of the team’s patients with myositis, a 42-year old man, could barely stand before treatment and was only able to walk about 30 feet. Two or three months later, he was walking so much that he reported foot pain at a follow-up appointment, because his bones hadn’t yet gotten used to his stronger muscles, Müller said. Now, that patient walks 6 miles to work each day, just because he can, he said.

A patient with lupus, which can affect joints, skin, kidneys, lungs, and more, was experiencing heart failure before treatment. But afterward, her fatigue and other symptoms disappeared and she’s back to life as normal. A patient with scleroderma, which makes someone’s skin tight, hard, or stiff, is walking confidently again now that he feels like he is standing on steady ground once more.

The findings build on results the researchers presented at the annual American Society of Hematology meeting late last year. When the team first began publishing their research, experts were cautiously intrigued. Before the infusion of CAR-T cells, patients receive chemotherapy to prepare and clear their immune system. It was possible that early positive results were simply due to the proven benefits of chemo. But now, with positive results lasting for as long as two years, it’s becoming more clear that the therapy is driving the improvements.

But it’s still unclear exactly why the CAR-T therapy seems to work so much better than previous treatments that target B cells using monoclonal antibodies. Perhaps an antibody “doesn’t have the ability to actively traffic into tight spaces and can only see what’s in the blood or what’s getting a lot of blood, whereas the CAR-T cells have access to other tissues,” said Mark Leick, a physician at the Hematopoietic Cell Transplant and Cell Therapy Program at Massachusetts General Hospital.

Previous monoclonal antibody therapies target B cells via a protein they carry known as CD20. Müller and his team made CAR-T cells that would target B cells carrying a different protein, CD19. This difference could be part of the “deeper depletion” of B cells seen in CAR-T therapy, said John Isaacs, a rheumatologist and professor at Newcastle University who wrote a commentary on the study also published Wednesday in NEJM. Alternatively, CAR-T cells could simply be more lethal than antibodies, he said.

Critically, patients did not appear to lose immunity to diseases they’d previously been vaccinated against, “which is like a dream,” said Vinuesa. The team did observe a decrease in the level of SARS-CoV-2 antibodies in patients’ bodies after treatment, but two patients who received vaccines afterward saw those levels rise.

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Experts say it’s still too early to label CAR-T therapy as a real cure for the autoimmune disorders. Still, “it does look like probably the best treatment there’s been,” Vinuesa said. Patients who took handfuls of pills every day before are now treatment-free. “It definitely gives [the patients] an incredible break from disease.”

Longer term follow-up on bigger groups of patients is needed, which researchers across the globe are now racing to perform, said PJ Utz, a physician who runs a research lab at Stanford University studying autoimmunity. He knows of three companies pursuing CAR-T therapy for autoimmune disorders, including Kyverna Therapeutics, which filed for its initial public offering last month.

“I’ve been working on these diseases for 30 years now. And we always say, ‘We want to cure them, we want to cure them.’ We’ve never had anything like this where a disease completely disappears,” said Utz, who was not involved in the study.

As for the team of researchers pioneering the research, they aren’t legally able to form any company, Müller said, because they are using technology from German biotech Miltenyi to build the chimeric antigen receptors (CAR) and produce them in patient T cells. Still, they’re working on a Phase 1/2 expansion trial with another two dozen patients and longer follow-up periods, Müller said.

“There will be relapses coming. We’re sure it can’t be that good,” he said of the treatment. Part of the team’s continuing research will be figuring out how to address those relapses.

In cancer treatment, patients are considered cured if their disease hasn’t returned after five years off all therapy. And since CAR-T is a treatment borrowed from cancer, perhaps rheumatologists should consider adopting that same definition for a cure, Utz said. Müller noted that he would consider lupus patients cured three to five years after stem cell transplants. By either definition, most of the patients in this study may be on their way.

8 Things No One Tells You About Being a Caregiver for Someone With Alzheimer’s Disease

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Advice from people who have been there.

a young woman hugging her grandmother

Providing care for a loved one with Alzheimer’s disease immediately inducts you into an unfortunate club of people whose relatives have this condition. No one wants to be a member, but given that around 5.5 million people in the United States have Alzheimer’s, many, many people are.

Although there’s no roadmap for dealing with life when someone you love has Alzheimer’s, if you’re in this position, it can help to hear from other people in the same unbelievably tough spot. Here, we spoke with some Alzheimer’s caregivers to find out a few things they wish they’d known at the start of their journeys.

1. “You have to learn how to grieve losing someone while they’re still alive.”

Amy L. became one of her father, Art’s, caregivers after he was diagnosed with Alzheimer’s disease in 2012. Amy says she was ill-prepared for how much grief she experienced before her father passed away in 2015.

“You have to learn how to grieve losing someone while they’re still alive,” she tells SELF. “You always think about grief as something that happens once someone passes away, but this illness really changes who they are.”

Alzheimer’s disease is a progressive brain disorder, meaning someone has more (and more intense) symptoms as time passes. These symptoms include cognitive issues like confusion, difficulty doing normally minor tasks such as getting dressed, and memory loss that eventually becomes so severe your loved one may not recognize you, according to the National Institute on Aging (NIA). It would be crushing if these changes happened all at once, but the progression of Alzheimer’s stages is its own kind of awful.

“Each little change was devastating,” Amy says, describing difficult times like realizing that Art could no longer go to the bathroom alone, or his moments of clarity that something was wrong with his health. “You have to learn to cope with the new reality, and then another change comes,” Amy says. “When he passed, it was a whole different onslaught of grief.”

Amy wishes she had seen a grief counselor or therapist while she was going through this. “It would have been so helpful,” she says.

2. “I wish I had known from the beginning to just listen to and trust myself, because I am the only one who knows what it feels like to be in my own circumstance.”

Emmy G.’s mom, Linda, was diagnosed with Alzheimer’s disease five years ago and is now in a later stage of the disease. Emmy tells SELF that helping to care for her mother is “difficult and emotionally depleting.”

It’s not only that Emmy has had to adjust to her mom’s condition—it’s also changed how Emmy relates to other people besides her mom. “Being in my early 20s, it is hard to explain what I am feeling to those my own age, and for a while I felt distant from friends,” Emmy says. “In addition, older friends/family who have gone through similar experiences feel the need to judge or criticize how I treat my mom and offer up ‘suggestions’ for [how] I should act.

However, as Emmy gets more confident in her ability to care for her mom, people have commented less, and it affects her less when they do say something. “I wish I had known from the beginning to just listen to and trust myself, because I am the only one who knows what it feels like to be in my own circumstance,” she says.

3. “Alzheimer’s affects everyone differently.”

There’s a long list of potential symptoms people may exhibit as their Alzheimer’s evolves, but not everyone will experience each symptom. For instance, some people with Alzheimer’s disease undergo personality changes, but Cecelia N. tells SELF that her grandmother didn’t experience this before passing away in 2012. “However, some families aren’t that lucky,” she says. “Alzheimer’s affects everyone differently.”

4. “The most comforting feeling I found was talking to someone who could relate.”

Having a loved one with Alzheimer’s disease can be incredibly isolating, Amy says. After her father was diagnosed, she read everything she could online about the disease and tried to find others to talk to who had been through the same thing. “The most comforting feeling I found was talking to someone who could relate,” she says. “It made me feel not so alone.”

Amy says she even got in touch with two famous people who had been through a similar experience. “I reached out not because they were famous but because they had been where I was,” she says. “They both wrote me back, and it meant so much.”

Emmy also emphasizes the importance of this kind of support. She found help and resources through the Alzheimer’s Foundation of America, which has a national helpline staffed by licensed social workers from 9 A.M. to 9 P.M. Eastern Monday through Friday. You can reach the hotline at 866-232-8484.

The extent of resources out there for those dealing with Alzheimer’s and their loved ones might surprise you. Peggy M.’s husband, Tom, was diagnosed with early-onset Alzheimer’s in 2012 at the age of 57. (Early-onset Alzheimer’s means a person shows symptoms before they’re 65.)

“Our local Alzheimer’s Association offers some wonderful programs,” Peggy tells SELF. “We attend support groups and a memory café weekly.” (A memory café is a supportive gathering for those with memory loss and their loved ones to socialize and connect with each other.) Tom even sings in something known as the Forgetful Friends Chorus which is a choir based in Manassas, Virginia, made up of people living with early-stage Alzheimer’s. “We have made lifelong friends through these activities,” Peggy says. “Connecting with others who know what [we’re] going through and who can offer support and suggestions for dealing with the disease’s various challenges has been very helpful.”

5. “I should have said, ‘Can you come over on a Wednesday without me having to ask so I can go to the gym for an hour or get my nails done?’”

Amy says people regularly told her she should keep living her life while Art was sick, but she couldn’t bear to take much time for herself due to guilt. This contributed to her becoming completely overwhelmed, she says. Looking back, she wishes she would have told those who offered to help that she basically needed to be forced into self-care.

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“I should have said, ‘Can you come over on a Wednesday without me having to ask so I can go to the gym for an hour or get my nails done?’ If someone came over and just said, ‘Go!’ I would have,” she says.

On a related note, Cecelia says her family had “no idea of the community resources that were available,” including respite care, which provides short-term and time-limited breaks for families and unpaid caregivers. “These programs help out families so much,” she says. “It would have been great to know of those.”

6. “Alzheimer’s hits you hard financially.”

“Financially, we had no idea,” Cecelia says. “My grandmother passed away in 2012, and just last year we paid the nursing home off. It takes a financial toll on the whole family.”

Kim B., whose husband, Jeff, was diagnosed with early-onset Alzheimer’s disease in 2016 at the age of 51, agrees. “Alzheimer’s hits you hard financially,” she tells SELF. “Jeff was the main breadwinner in our family. He qualified for social security disability, but it pays only a small fraction of what he was earning.” The couple currently has three kids in college, and Jeff’s parents live with them. “I am currently working two full-time jobs in addition to being a caregiver, wife, and mom,” Kim says. “My days start at 6:30 A.M. and do not end until 10 P.M. It gets pretty exhausting.”

7. “There will be good days and bad.”

“Initially, it scared me when Jeff was having an ‘off’ day—short-tempered and reserved—but I have learned those days come and go,” Kim says. “I, too, have good days and bad days, and that is OK! On my bad days, I acknowledge it and tell myself tomorrow will be better,” Kim says. “There will be good days and bad. I always tell my kids, it is OK to have a bad day, but then you have to get up and keep going.”

Kim has also learned what contributes to Jeff’s bad days, like traveling, which can be helpful when it comes to reducing the challenges Alzheimer’s can cause.

8. “Appreciate your loved one every single day. Be grateful for how much they can do in that day, in that moment.”

Emmy recommends trying to find joy in your current relationship with your loved one, as impossible as that may feel sometimes. “[I] wasted an entire year crying about the future rather than appreciating what my mom was still capable of,” Emmy says.

Now Emmy tries to savor the experiences she and her mom can still share. She does this by taking Linda out to a meal for just the two of them, traveling to nearby towns where Linda used to spend a lot of time, and dancing together to music that Linda’s loved for years. “Appreciate your loved one every single day,” Emmy says. “Be grateful for how much they can do in that day, in that moment.”

Are There Early Signs of Alzheimer’s Disease to Watch For?

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Yes, but they’re not always easy to detect.

Early Signs of Alzheimers Disease What Should You Watch For

If your mom suddenly keeps misplacing her keys or your grandfather persistently calls you by your sister’s name, your mind might automatically jump to Alzheimer’s disease. But are these kinds of symptoms actually early signs of Alzheimer’s disease, or does it present differently in the beginning stages?

In the earliest stage of Alzheimer’s disease, people actually don’t exhibit any symptoms at all.

Alzheimer’s is a progressive brain disorder that happens in phases, slowly destroying a person’s memory, cognitive functions, and eventually many physical abilities as well. The condition happens in five different stages, starting with what’s known as preclinical Alzheimer’s disease. This is when a person isn’t showing any signs of the condition, but their brain is undergoing changes that will eventually cause symptoms.

During this time, protein deposits in the brain form abnormal clumps that interrupt the way brain cells communicate, the Mayo Clinic explains. The brain also begins to create tangled bundles of the fibers necessary for transporting materials essential for proper brain function, like nutrients. These changes mean that neurons that used to be healthy stop functioning, lose connections with other neurons, and die, according to the National Institute on Aging (NIA).

There’s a lot scientists still don’t know about Alzheimer’s disease, but it’s believed that this damage to a person’s brain can start 10 years or more before symptoms appear, according to the Mayo Clinic.

It may seem like memory issues would be the earliest sign of Alzheimer’s. They can be, but many people with the condition actually experience problems with other cognitive functions first.

The second stage of Alzheimer’s—but the first where people show symptoms—is known as mild cognitive impairment due to Alzheimer’s disease, the Mayo Clinic explains.

Signs of this often include problems finding the right words, issues accurately processing visual or spatial information, and impaired reasoning or judgment, the NIA says. However, in this stage it is also possible to have memory lapses and be unable to recall things like recent chats or upcoming appointments that were made recently, the Mayo Clinic says.

“These [symptoms] can be easy to miss or write off,” Scott Kaiser, M.D., a family physician and geriatrician at Providence Saint John’s Health Center in Santa Monica, California, tells SELF, because at this point they aren’t severe enough to affect a person’s daily life.

As the disease progresses to “mild dementia due to Alzheimer’s disease,” which is when people are usually diagnosed, symptoms become more varied and intense.

“We look for more consistent trends in terms of things getting worse over a somewhat shorter period of time,” Ian M. Grant, M.D., a behavioral neurologist at the Mesulam Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University Feinberg School of Medicine, tells SELF.

For instance, someone might begin asking the same questions about something they recently learned because they keep forgetting the answer, the Mayo Clinic says. More severe issues with problem-solving and decision-making can lead to a tougher time with important tasks like balancing a checkbook or sticking to a budget. People may also begin to feel increasingly unfamiliar in their surroundings and wander in search of a place that feels more recognizable, possibly getting lost

This is also the time when personality changes may begin to appear, the Mayo Clinic says. A person with Alzheimer’s might experience more anxiety or anger, for instance.

Again, there’s a lot that experts still don’t understand about Alzheimer’s disease, but the reason for these different symptoms likely depends on where the damage has taken place in a person’s brain, Dr. Kaiser says. For example, if someone has damage to their frontal lobe, which controls personality among other things, they may experience irritability, mood changes, and difficulty regulating their behavior, he says. Visual and spatial problems may be due to the disease building up in the occipital lobe, which is important for vision processing, Dr. Grant says.

If you suspect that a loved one is exhibiting early signs of Alzheimer’s disease, it’s important to see a doctor as soon as possible.

Getting checked out can alleviate a lot of stress and identify any underlying, non-Alzheimer’s issues that might be causing the symptoms. It could be that the symptoms are due to something potentially reversible. For instance, elderly people are at higher risk of subdural hematoma, which is brain bleeding that can happen after a fall, the Mayo Clinic says.

If the symptoms are actually due to Alzheimer’s, getting a proper diagnosis can help someone start treatment as quickly as possible, which is really essential when it comes to this illness.

Several medications have been approved by the Food and Drug Administration (FDA) to treat symptoms of Alzheimer’s, and they may even help slow the disease’s progression, the NIA says. The drugs work by impacting neurotransmitters, the chemicals that transmit messages between neurons, and may help reduce symptoms, the NIA says. However, they can’t offer a cure.

There are also many active clinical trials that are taking place in the search for promising Alzheimer’s treatments, the NIA explains. Many focus on the early stages of the disease, so that is the ideal time to start expressing interest in participating.

Finally, getting an Alzheimer’s diagnosis as early as possible is of the essence because it allows a person to get their affairs in order and line up help they may need, Dr. Grant says. This will generally help them plan how they can make the most of the time they have left. It might be tough to even think about this for a loved one, let alone help them get it done—but it only becomes harder the longer you wait.