Marco Meglio

Alzheimer disease (AD) is defined by the presence of amyloid plaques and tangles in the brain leading to progressive memory loss and an inability to carry out daily function. In 2020, as many as 5.8 million Americans were living with AD, with this number projected to nearly triple by 2060.

 As society continues to age, AD poses as a serious challenge for the medical community and neurologists specifically. 

What was once seen as a disease that began with old age, advances in research have shown that AD is a continuous process that starts in the brain several years prior to the onset of symptoms. Because of this, the approach to diagnosis has changed and will continue to change over time. Now, patients who show the earliest signs of cognitive decline are followed up for additional screening, with a combination of biomarkers and imaging techniques to confirm the presence of amyloid-ß (Aß) and tau, the 2 major hallmarks of the disease.

In 2011, the National Institute on Aging and Alzheimer’s Association (NIA-AA) proposed diagnostic guidelines for AD, including the pre-symptomatic and symptomatic stages of the disease.

 Years later, the group updated the framework to biologically define AD through validated biomarkers that include Aß and phosphorylated-tau (p-tau) PET; the cerebrospinal fluid (CSF) concentration of Aß42; the CSF Aß42/40 ratio; the CSF concentrations of total tau (t-tau) and p-tau181.

“The framework of how we diagnose Alzheimer disease has shifted. We’ve moved towards a framework of diagnosing it by its underlying biology instead of the signs and symptoms,” Michael Alosco, PhD, director of Boston University’s Alzheimer’s Disease Research Center Clinical Core, told 

®. “It places more emphasis on biomarkers to detect whether or not the disease is present in the brain. Using biomarkers plus signs and symptoms is the best way to get a specific, accurate diagnosis.”

Alosco, who also serves as an associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine, added, “we’re not at the place where we’re clinically taking blood samples and making diagnoses, but we’re very close. The first step is characterizing the person’s signs and symptoms, and then nailing down etiology using our biomarkers.”

A year after the 2011 NIA-AA guidelines, the US Food and Drug Administration (FDA) approved Eli Lilly’s florbetapir F18 (Amyvid) as the first diagnostic agent to image AD-related Aß neuritic plaques in the living brain.

 Prior to the approval, the only way to confirm diagnosis of these plaques was from post-mortem biopsies. Florbetapir is an 18F-labeled ligand that, in nonclinical studies, has shown to bind to Aß aggregates in postmortem sections of human brains and in brain homogenates.

“Blood-based biomarkers are very versatile, they can provide a lot of information, and they’re cheap and ready to use,” Martin Sadowski, MD, a professor of neurology, psychiatry, and pharmacology at the NYU Grossman School of Medicine, told 

. “They can tell us where the patient is, what stage they are in, and the level of complexity in the brain. They tell us whether the patient has beta-amyloid, tau, active neuroinflammation, active neural degeneration, etc.”

In 2020, the FDA approved Tauvid (flortaucipir F18) for intravenous injection, becoming the first approved drug used to help image tau in AD.

 Intended for those being evaluated for AD, the tool is indicated for PET imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles, a primary marker of AD. After Tauvid is administered intravenously, it binds to site in the brain associated with this tau protein misfolding. 

Over the past year, there have been a number of other notable approaches to enter the field. Roche’s CSF Elecsys assays, which include the beta-amyloid1-42 CSF II (Abeta42) and t-tau assay, received 510(k) clearance in June of this year.

 These assays are designed to detect AD pathology in earlier stages of the disease and are intended to be used with other clinical diagnostic evaluations. 

The approval of such assays came less than a year after the FDA cleared Roche’s Abeta42 and ptau181 assays. According to Roche, the assays “achieve 90% concordance” with amyloid PET scans.

“The blood tests are offering a prescreening tool for ruling out symptomatic individuals with a low likelihood of Aß pathology,” Lynn Bekris, MD said. “This approach makes it possible to avoid unnecessary CSF amyloid testing, therefore reducing costs and the burden associated with these more invasive and costly examinations.”

Bekris, an associate staff and associate professor at 

, believes that the most useful markers in clinics right now are CSF p-tau and Aß42, which she noted “are the most robust markers of the disease.”

AD-Detect, another diagnostic screening test that evaluates the ratio of Aß42 and Aß40 in plasma, became available to physicians in May 2022.

 Patients may supply a blood specimen at 1 of over 2000 Quest Diagnostic patient service centers nationwide for testing.

While specialists still debate whether mild cognitive impairment (MCI) is truly a diagnosis, what is acknowledged is that people with MCI have a risk state that could in the future develop into dementia or AD. Thus, the identification of patients at the earliest stages, otherwise known as the prodromal phase, is critical.

With the FDA’s approval of lecanemab (Leqembi; Eisai), an antiamyloid therapy, earlier this year, eligible individuals must be able to confirm a presence of Aß in the brain to recieve treatment. Going forward, many in the field believe this will be the standard for any approved medication.

For years, patients would pay out of pocket costs for PET imaging; however, earlier this year, the Centers for Medicare and Medicaid Services (CMS) announced they will cover the imaging tool in cases for patients for a follow-up of potential AD diagnosis.

 In its decision memo, the agency noted that appropriate patient selection is “key to ensuring benefits outweigh harms of newly developed drugs targeting amyloid.” This decision may prove to be critical in the coming years as society continues to age and more patients present to clinics with cognitive and executive issues. 

As the field enters a new era of novel treatments, there will be an increased emphasis on the efficiencies of the healthcare system, and how to provide these therapies to those in need. “We still don’t know the optimal way for a prescreening process that is going to work in the primary care setting,” Bekris said. “We won’t know how precise some of these blood-based biomarkers are, and the field is interested in pinning down the best correlated tau biomarkers. There’s a lot of work being done on tau in blood right now, but those have not been FDA-approved. They’re really in the research arena right now.”

Emerging Concepts and Approaches to Aid in the Diagnosis of AD

Several in the field expect a number of blood- and imaging-based techniques to emerge over the coming years. The use of artificial intelligence (AI), a hot topic across not just neurology but all medicine, has begun to gain ground in this field.

Pixyl.Neuro, an AI-generated medical technology designed to improve detection and accelerate MRI reading time, was FDA-cleared earlier this year.

 Using proprietary AI algorithms combined with Pixyl’s computing infrastructure, the software enables quick analysis in less than 5 minutes. 

Numerous types of machine learning, a branch of AI, have also begun to make headway in research settings. A published study using a machine learning model developed by researchers at Duke Health showed an ability to differentiate normal cognition from MCI using retinal images.

 Once considered a phenomenon, retinal imaging has shown to be an innovative and promising method to aid in the diagnosis of AD. RetiSpec, a medical imaging company, has developed a hyperspectral imaging technology that evaluates changes in the retina for early and accurate detection of AD markers.

RetiSpec is designed to look at the distinctive signs of AD, as well as Parkinson disease (PD), vascular dementia, and amyotrophic lateral sclerosis, which all share some overlapping pathologies. “We increasingly see how mixed pathologies are to blame for a lot of the symptoms,” Alosco said. “It’s not just 1 or 2 proteins. [We need] to get better techniques for evaluating some of these other pathologies where we don’t have good biomarkers. For example, looking at α-synuclein, looking at biomarkers for chronic traumatic encephalopathy. How can we develop these other biomarkers so that we can differentiate the diseases and hone in on the one or multiple [pathologies] that are present is where we’re going to see a lot of improvement.”

α-synuclein has been widely discussed as a prominent biomarker for not only AD, but other neurodegenerative disorders. Alterations in α-synuclein dosage have led to familial PD, and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies, and multiple system atrophy. Importantly, α-synuclein regulates the fibrilization of both Aß and tau, 2 of the most key proteins in AD pathophysiology.

Amprion’s SYNTap biomarker test, which became commercially available in 2021, represents the only seed amplification assay to help in the diagnosis of synucleinopathies such as PD, DLB, and AD.

 In clinical settings, the test has shown that approximately one-third of patients with AD have a second parallel disease that is driven by the misfolded α-synuclein. These patients, all of whom can now be more easily detected, tend to have more rapidly progressive symptoms, and may respond differently to treatment than patients with just AD, rather than a mixed dementia. 

“There are biomarkers of the immune response to amyloid and tau that some people are investigating, including my lab,” Bekris said. “The research community is also observing differences in amyloid and tau biomarkers by comorbidities, such as kidney disease, which can impact the levels observed in plasma or CSF. There are some differences in amyloid and tau measures in biofluids, by race and by sex—although more by sex—that still have to be better pinned down. We don’t really know why these differences are happening, so we need to characterize it and use more cohorts to try to understand that a little better.

In addition to blood-based biomarker approaches, several in the field are dedicating efforts towards improving and expanding the imaging techniques available in clinic. F-PI-2620 and MK6240, second-generation tau tracers designed to detect the neurofibrillary tangles of AD, have begun to emerge in research settings.

“These are designed to have a little bit better imaging properties and less off-target binding,” Alosco added. “Those are being shown to be increasingly useful for Alzheimer disease, but also for other forms of dementias.”

Alosco also believes there will be an increased effort towards understanding and diagnosing vascular dementia and the vascular aspects of AD. The vascular theory that AD is treatable based on the brain’s continuing need for cerebral blood flow (CBF) especially in the presence of advancing age.

 Previous research has shown that a decrease in CBF that can occur as a function of normal aging phenomena, less blood results in decreased mitochondria, decreased ATP, and a decrease in neuronal activity, which could potentially lead to AD. Arterial spin labeling, an MRI technique that enables the measurement of brain perfusion noninvasively at the tissue level, has been increasingly used to assess CBF in research settings.

“Exactly what comes first is unclear, but I think I some of these more vascular imaging techniques will have important value in this field,” Alosco continued. “Whether or not it’s going to specifically talk to you about the presence of Alzheimer disease is unclear, but at least in terms of getting a sense of other types of pathologies that might count for symptoms will be interesting.”

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4. FDA approves Amyvid (Florbetapir F18 injection) for use in patients being evaluated for Alzheimer’s disease and other causes of cognitive decline. News release. Eli Lilly. April 9, 2012. Accessed December 6, 2023. https://www.prnewswire.com/news-releases/fda-approves-amyvid-florbetapir-f-18-injection-for-use-in-patients-being-evaluated-for-alzheimers-disease-and-other-causes-of-cognitive-decline-146638165.html

5. FDA Approves first drug to image tau pathology in patients being evaluated for Alzheimer’s disease. News release. FDA. May 28, 2020. Accessed December 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-image-tau-pathology-patients-being-evaluated-alzheimers-disease

6. Roche receives FDA clearance for additional Alzheimer’s disease cerebrospinal fluid (CSF) assays, supporting timely diagnosis and treatment decision-making. News release. June 27, 2023. Accessed June 27, 2023. https://www.prnewswire.com/news-releases/roche-receives-fda-clearance-for-additional-alzheimers-disease-cerebrospinal-fluid-csf-assays-supporting-timely-diagnosis-and-treatment-decision-making-301863708.html

7. Roche Alzheimer’s disease Cerebrospinal Fluid (CSF) assays receive FDA clearance, supporting more accurate and timely diagnosis. News release. Roche. July 19, 2022. Accessed December 6, 2023. https://diagnostics.roche.com/us/en/news-listing/2022/roche-alzheimers-disease-cerebrospinal-fluid-assays-receive-fda-clearance.html

8. Quest introduces first-to-market consumer-initiated blood test for Alzheimer’s disease risk assessment on questhealth.com. News release. Quest Diagnostics. July 31, 2023. https://newsroom.questdiagnostics.com/2023-07-31-Quest-Introduces-First-To-Market-Consumer-Initiated-Blood-Test-for-Alzheimers-Disease-Risk-Assessment-on-questhealth-com

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Articles

While specialists still debate the diagnostics of impaired cognition, the identification of patients at the earliest stages is beginning to be met through new biomarkers and available assays.

Changes in the Diagnostic Process of Alzheimer Disease: A New Era of Blood-Based Approaches

 pandemic was formally declared by the Centers for Disease Control in March 2020, countless questions swirled around what sort of short- and long-term effects the virus could have on an individual and their brain.

Vaccines aside, the symptoms of the COVID-19 have been well documented, even in the early stages of the pandemic. Infected patients can experience a range of symptoms—from mild to severe—that include fever or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell, sort throat, congestion, nausea or vomiting, and diarrhea that can last from anywhere between 2-14 days.

As evidence began to pile up, it became clear that individuals who are immunocompromised may be more prone to a severe case of COVID-19, which could lead to hospitalization, intensive care, ventilator use, and death. Older adults have been proven to be at the highest risk for severe COVID-19. In fact, more than 81% of COVID-19 deaths occur in people over 65, and the number of deaths among people over that age is 97-times higher than the number of deaths in those between the ages of 18 and 29 years.

After closely following people who contracted the virus, the clinical community started to gain a better understand of potential post-acute sequelae (PASC). PASC of COVID-19 has had a wide prevalence range reported, mainly due the heterogenous definitions of the condition, differences in populations being assessed, and types of symptoms or signs included in rate estimates. Some patients have had ≥20 different symptoms, indicating that COVID-19 is a multisystem disease.

Men and women can both be affected by PASC. A recent meta-narrative review showed that men are at a greater risk for increased symptom severity and death; however, PASC is more common in women, and women are more likely to have persistent fatigue, anxiety, and depression and at a 6-month follow-up.

 Additionally, individuals with underlying pulmonary conditions, obesity, and older age are at increased risk for developing PASC.

For the management of PASC, clinicians have generally recommended controlling comorbid conditions, such as diabetes, hypertension, kidney disease, respiratory diseases, and ischemic heart disease, and treating specific complications when necessary. Anosmia and ageusia, otherwise known as the loss of sense of smell and taste, have been other PASC symptoms that had shown persistence even after recovery from COVID-19; although, it’s uncertain whether these symptoms are permanent or transient.

Over time, the FDA began to authorize certain medications for emergency use to treat COVID-19 and thus, the subsequent issues that follow. Nirmatrelvir (Paxlovid), an oral protease inhibitor that is active against MPRO, is packaged with ritonavir, a strong cytochrome P450 3A4 inhibitor that has been used to boost HIV protease inhibitors, was among those to receive authorization.

 A recently published large-scale trial included those treated with oral nirmatrelvir within 5 days after a positive test (n = 9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of their infection (n = 47,123).

The findings were a success, as nirmatrelvir-treated patients showed a reduced risk of PASC (HR, 0.74; 95% CI, 0.69-0.81) including a reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system, coagulation and hematologic disorders, fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Additionally, mirmatrlevir was associated with a decreased risk of post-acute death (HR, 0.52) and post-acute hospitalization (HR, 0.70). These associations remained true in unvaccinated, vaccinated, and boosted individuals, and in those with primary SARS-CoV-2 infection and reinfection.

Hyper Inflammation and Truths Behind Alzheimer Risk

At first, researchers believed that SARS-CoV-2 infection primarily affected the pulmonary system, but accumulating evidence suggested that it also affects the panvasculature in the extrapulmonary systems by directly or indirectly causing endothelial dysfunction and multi-organ injury. The consequential endotheliitis/endotheliopathy can incite multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition, mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy.

“It can also ramp up amyloid deposition or decrease breakdown of amyloid, and potentially also tau tangle formulation,” said Jennifer Frontera, MD. “That’s the whole kind of viral or inflammatory hypothesis of Alzheimer [disease]. It’s led to people doing studies with valacyclovir for patients with HSE (herpes simplex encephalitis) and mild cognitive impairment. Just to see if treating the chronic infection or the reactivation of that infection will ameliorate some of the pathological changes.”

Frontera, a neuro-critical care specialist at NYU Langone, has experience on all levels of the pandemic, serving both on the front lines during some of the earliest days, to being a leader in the research field, where she’s conducted multiple trials exploring the effects of the virus on the brain and body. She believes the general concept of increased microglial activation from inflammatory states could be “in-play” when it comes to post-COVID cognitive disorders.

“The more we understand about what’s happening in COVID-19, or hypoxia, for example, may help us understand other Alzheimer-type pathologies and what interventions might be useful in people with sporadic Alzheimer [disease], for example,” Frontera added. “Hopefully there will be more evolution in terms of our understanding of cognitive processes in general, even as they relate to post-ICU patients.”

The link between COVID-19 and Alzheimer disease is still being understood, with some studies signaling a connection and others pumping the breaks. A retrospective study published in September 2022 suggested that individuals at least 65 years infected with the virus are at an increased risk for the neurodegenerative disorder. That trial, which included 6,245,282 older adults, also showed an elevated risk when stratified by age groups (65-74, 75-84, ≥85 years), race or ethnicity (Black, White, Hispanic, with the highest risk in those above 85 years old (HR, 1.89; 95% CI, 1.73-2.07), and in women (HR, 1.82; 95% CI, 1.69-1.97).

Some of the fears of long-term development of Alzheimer disease stem from “brain fog,” a term commonly used to describe the sluggish, fuzzy feelings patients experience weeks, and sometimes months after infection. Headed by the National Institutes of Health, a mouse study showed that even a mild case of COVID-19 could cause long-term changes to the immune system and neurons. Weeks after being infected, the microglia in the mice stayed reactive. Investigators concluded that this reactivation caused trouble with completing tasks, such as making new neurons in the hippocampus, a region of the brain that plays an important role in learning and memory.

Although the pathological mechanisms of COVID-19 still remain a question, research has debunked, or at least cleared up, some of the initial thoughts, the biggest being the virus’s role in central nervous system (CNS) invasion, according to Frontera. “We really don’t think that’s a major player here, or a pathological driver. Encephalitis, meningitis, that are related to direct SARS-CoV-2 is really not a thing,” she said.

A 2021 paper by Conor McQuaid et al reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions, neurological COVID-19 manifestation, and the aging cerebrovascularture.

 After sifting through the literature, the authors concluded that there is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus.

The paper highlighted that although unknown, the normal route of infection and presence of SARS-CoV-2 in severely infected patients could be from the olfactory mucosa, an idea that has been brought up previously before. “It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure,” McQuaid et al wrote. “Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.”

Throughout the pandemic, it has been widely understood that the severity of COVID-19 is one of, if not the, greatest predictors of long-term prognosis. In December 2020, the FDA issued the first emergency use authorization for a vaccine for the prevention of COVID-19 in individuals aged 16 years and older, with the goal to lower hospitalization rates, ventilation rates, and ultimately, death.

In fact, it worked. A 2022 retrospective study of nearly 200,000 hospitalizations showed that COVID-19-associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. Among sampled cases, vaccinated hospitalized patients with the virus were older than those who were vaccinated (mean age, 70 years vs 58 years; 

<.001) were more likely to have 3 or more underlying medical conditions (77.8% vs 51.6; 

As more vaccines were authorized over time, some were curious whether they could have a positive impact on the symptoms of long COVID in those already infected. “Vaccines are lowering the severity of COVID-19 if you do get it, and therefore you’re less likely to have long COVID, but I don’t think that if you already had long COVID and get vaccinated that it’s necessarily improving anything,” Frontera added.

“Theoretically, it could still, but I think the interest in that area kind of fell off as people weren’t seeing an association between post COVID vaccination and long-term outcomes. I don’t know if it’s a myth, but we probably underestimate the impact of pandemic-related stressors on outcomes and how people are doing. Are there comorbidities like mood disorders, anxiety, depression, and so forth, that exacerbate symptoms or are even sometimes, the progenitor of symptoms. For example, untreated depression can present as brain fog. That doesn’t mean everyone with brain fog has depression, and that’s the reason there are comorbidities that should be looked at and addressed.”

While severe COVID-19 cases continued to cause concern, researchers started to uncover that even those with a mild case or no symptoms can develop long COVID. In a 2022 study that featured 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no evidence of infection, a total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks.

The trial, led by Anuradhaa Subramanian, MSc, a research fellow at the University of Birmingham, also showed that the risk of developing long COVID increased along a gradient of decreasing age. The largest adjusted HRs for symptoms of long COVID included anosmia (6.49; 95% CI, 5.02-8.39), hair loss (3.99; 95% CI, 3.63-4.39), sneezing (2.77; 95% CI, 1.40-5.50), ejaculation difficulty (2.63; 95% CI, 1.61-4.28) and reduced libido (2.36; 95% CI, 1.61-3.47). In a post-hoc subgroup analysis of patients infected during the first and second stages of the pandemic in the United Kingdom, the association between SARS-CoV-2 infection and the reported symptoms was more pronounced among those infected during the second wave of the pandemic.

There are several aspects of COVID-19 that are still not fully understood and will continue to be researched in the coming years. “There’s been a lot of press related to the neurological aspect, and at the end of the day, the shortness of breath and pulmonary recovery is probably the main issue people are facing,” Frontera added. “The neurological components are probably a factor for some percentage of people. How much of them are directly related to COVID? It’s hard to know.”

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Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. News release. FDA. December 22, 2021. Accessed December 14, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19#:~:text=Today%2C%20the%20U.S.%20Food%20and,of%20age%20and%20older%20weighin

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Wang L, Davis PB, Volkow ND, Berger NA, Kaelber DC, Rong X. Association of COVID-19 and new-onset Alzheimer disease. Journal of Alzheimer’s Disease. 2022;89(2):411-414. doi:10.3233/JAD-220717

A possible mechanism behind brain fog. News release. National Institutes of Health. Updated August 30, 2022. Accessed December 14, 2022. https://covid19.nih.gov/news-and-stories/a-possible-mechanism-behind-brain-fog

McQuiad C, Brady M, Deane R. SARS-CoV-2: is there neuroinvasion? Fluids and Barriers of the CNS. 2021;18:32. doi:10.1186/s12987-021-00267-y

FDA takes key action in fight against COVID-19 by issuing emergency use authorization for first COVID-19 vaccine. December 11, 2020. Accessed December 14, 2022. https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19

Havers FP, Pham H, Taylor CA, et al. COVID-19-associated hospitalizations among vaccinated and unvaccinated adults 18 years or older in 13 US states, January 2021 to April 2022. JAMA Intern Med. 2022;182(10):1071-1081. Doi:10.1001/jamainternmed.2022.4299.

Subramanian A, Nirantharakumar K, Hughes S, et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nature Medicine. 2022;28:1706-1714. doi:10.1038/s41591-022-01909-w.

Almost 4 years since the beginning of the pandemic, continuous research efforts have begun to paint a better picture of the impact the virus has on the brain and the central nervous system.

COVID-19 and the Brain: Understanding the Neurological Effects of the Virus as the Pandemic Evolves

For years, the conversations surrounding care for patients with 

 (MS) mainly centered around drug development and the optimization of disease-modifying therapies (DMTs). There are now more than a dozen DMTs approved for MS, administered in various forms such as tablets, injections, or infusions. Although, as clinicians have learned, the management of these patients extends past treating solely the relapses.

Integrative wellness is a practice based around the belief that treating patients involves much more than only disease and symptom management and has become an approach adopted by more clinicians in recent years. This all-purpose type of method encompasses aspects of diet and nutrition, exercise, sleep, and ongoing preventive care, among others.

 Although there are no set guidelines on how to conduct this care, there are several overlapping themes and ideas.

The conceptual idea of integrative wellness often also carries a stigma, with many assuming these practices are not backed by scientific evidence. Contrary to this belief, ongoing research and the COVID-19 pandemic have confirmed the need for alternative approaches, particularly for patients with MS, who may benefit from interventions tailored to their individual needs.

Kathy Zackowski, PhD, OTR, senior director of patient management, care, and rehabilitation research, National Multiple Sclerosis Society (NMSS), has been at the forefront of researching and advocating for this new style of care. Her organization funds work that ranges from better understanding the use of acupuncture and yoga, to the resilience of psychosocial approaches, to the relationship of dieting and changes in the gut microbiome.

“The whole idea with wellness is that this is something that everyone can do right now,” Zackowski told 

®. “You don’t need a lot of equipment, but you need to understand the important elements of a wellness strategy for you. For someone in pain, we might recommend some of these psychosocial strategies looking at resilience and pain management, but for someone who’s weak, they may need just exercise. Exercise is its own intervention. It's not simple to go out and say, ‘go exercise.’ We need to understand what elements of that intervention are important for that person.”

The variety and usage of these integrative wellness approaches differs from clinic to clinic, which has added to its natural phenomenon. At Cleveland Clinic,

 physicians recommend maintaining a low-salt Mediterranean diet, getting at least 150 minutes of moderate movement per week, maintaining vitamin D levels between 40-70 ng/mL, not smoking or using tobacco products, and undergoing routine mental health screening.

Although there is a migration towards a better understanding of the need for collaboration and comprehensive care, some specialties are not consistently included in the model. Registered dietitians, for example, have historically been excluded from the multidisciplinary care team, with information on nutrition coming instead from integrative or alternative practitioners.

Mona Bostick, RDN, LDN, a nutritionist living with MS with a dedicated passion for optimizing nutrition, commented on this exclusion, adding that while nutrition is often miscast as an “integrative” approach, diet and how patients eat is not an alternative treatment for MS, but it is rather a pivotal aspect of overall health. Bostick is the founder of her private practice, Food Matters 365, now called MSBites, a source for evidence-based nutrition and wellness advice to help patients with MS.

“I believe the shift toward the integrative exists precisely because dietitians have not been included in the care team. With MS being such a disease [that] steals control over the things you thought you had control over, when alternative practitioners are promising to heal, beat, reverse, or give you that control back, the vulnerability that MS presents is going to make someone take a risk on that,” she told 

®. “It’s important to know that nutrition and what you eat plays an important role in your overall health, but it doesn’t offset demyelination—nuance and context around what food can do is missing a lot of times in these integrative and alternative messages of this practitioners. I find that to be disconcerting because there is a vulnerability to the MS population, for sure.”

Zackowski echoed similar thoughts to Bostick, adding that even the general public should be exposed to nutritional dietitians. “With MS, it’s complicated. We don’t have the cure yet, and one of the ways the [National MS] Society talks about this is the pathway to cures. The idea that there’s not just one cure, there are multiple cures, and people define cure in a different way. One way of defining cure is taking away symptoms. If diet can provide some improvements in the symptoms people [with MS] have that’s one form of an MS cure,” she explained.

Sharing Best Practices for a Sense of Community

Amidst the ongoing COVID-19 pandemic, the shift to telemedicine challenged clinicians to provide care remotely, whether that be for symptom management or for integrative approaches. Interestingly, some clinicians say the use of telemedicine had a positive effect in increasing collaboration and information sharing within the MS field, as the unknowns associated with COVID-19 generated a need for experts to share timely data relating to the virus and overall best practices with one another.

Mitzi Joi Williams, MD, CEO, Joi Wellness Group Multiple Sclerosis Center, spoke on this increased sense of community within the MS field since the onset of the pandemic and over the course of 2021. Williams noted that her colleagues were not afraid to share findings and information from registries, whereas in the past, the scientific community had cultivated a sense of protectiveness in terms of clinical data that had yet to be published.

“The information sharing that has emerged from the COVID-19 pandemic has really been amazing, and to see the collaboration from people from different academic centers, from the academic centers in the community, to across the pond, across the world, across the globe, has really been astounding,” Williams told 

Social media has been crucial in establishing this sharing of information and collaborative attitude, allowing experts in the MS field to share information quickly and freely via online platforms like Twitter, Williams said. Monthly webinars and conferences also aided in the dissemination of updated data, with experts then able to implement practices in real time.

“I hope this collaborative approach amongst MS specialists, general neurologists, and my colleagues around the globe stays,” Williams said. “There has been this amazing unity amongst everyone to try to find the scientific answers we need to be able to adequately care for our patients. We've seen a lot of synergy with people creating registries fairly quickly—a lot of things that we thought couldn't get done are absolutely getting done, [and] a lot of things we thought couldn't be done remotely are absolutely being done remotely.”

Zackowski spoke on ongoing work of the NMSS to improve this collaboration and sharing of information as it pertains to wellness, which includes the development of the Wellness Research Group and 3 different subgroups: physical wellness, nutritional wellness, and psychosocial wellness.

 Information published online is tailored specifically to patients or clinicians, making it easier to access veritable, valuable sources, Zackowski said, noting that patients “do not need to be scientists” in order to understand findings from ongoing studies. This is not, however, a foolproof method for getting the word out about wellness, particularly due to the need for practices and information to be adjusted for individual patients.

“The idea of integrating just those 3 areas is challenging—and that's not really addressing everything—there's so many symptoms that people have with MS that I think can be addressed by different wellness approaches,” Zackowski said. “I think it's really hard to get the message out to people about what to do because there's no regulatory body on how to make sure the standards are the same everywhere, and that's something we as a society are trying to grapple with a little bit more.”

Although there is good reason to be excited about these integrative approaches, clinicians themselves also agree that there is a need for extended research that aims at understanding and optimizing these methods. As of now, clinicians use their better judgement, paired with what’s been observed in the literature and through the help of their multidisciplinary teams. There is no current law-abiding guideline that the community has developed or strictly follows.

“When you talk about exercise, diet, or even cognitive rehabilitation, no one knows exactly the right dose, Zackowski stressed. “How much do you need as a person with MS to address your particular issue? We do this automatically with medications because the FDA dictates that you have to put a particular dose and explain what that dose is. In the wellness area, we need to address those things, we need to understand the dose, the intensity, the setting that this is done in, and how that approach will be effective in people who have more than one symptom.”

Despite advances in research in recent years, the space is stilling being held back. Without backing from pharmaceutical companies or industry leaders, it has been difficult to conduct large scale trials that further help validate these methods. These groups have yet to formally recognize integrative wellness as something that has significant therapeutic benefit, especially since the data thus far has been hard to quantify.

That, ultimately, leaves supporters of integrative wellness practices like Bostick and Zackowski to fend for themselves in terms of powering research, or forces them to turn to organizations such as the NMSS in hopes of acquiring funding and materials.

“I’m thinking of getting pharmaceutical companies interested in this combined approach that uses a medication and a wellness strategy,” Zackowski said. “This might be another way to encourage greater funding for this, but it will take time and money to get this understood better. We are right on the forefront though—we’re at a place where this can be studied now, and I’m encouraged by that.”

In addition to the need for increased research, there remain complexities in the integration of dietitians into standard of care, according to Bostick. “Out in the community, there are dietitians everywhere. At this point, the obstacle is that continuing education hours are expensive and difficult to obtain. There’s not been a reason for a dietician to justify becoming educated and informed on this topic, because they’ve not yet been welcomed into the comprehensive care team,” she said.

Bostick added that once the talents of these specialists are more appreciated, they may go back to their communities and advocate for these roles as well as provide information for newcomers to feel more comfortable. While a dietitian may have a broad knowledge of nutrition, they may not be as equipped at that moment to treat the MS-specific component. “Broadly speaking, multiple sclerosis is not discussed in our education and training. That’s the obstacle,” she said.

Much like how the efficacy of drugs continues to be optimized in post hoc analyses, it will only be a matter of time before similar studies to further validate these wellness approaches. Overall, the commitment to these nontraditional, forward-thinking ideas represents the general trend within the medical system in recent years to treat the patient from a complete holistic perspective that addresses all downstream aspects of the disease, and not just the root cause.

This contribution to HCPLive’s 2021 This Year in Medicine series comes from sister publication 

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Clinicians have begun to incorporate more holistic ways to approach the treatment of multiple sclerosis symptoms by focusing on better overall health, exercising, and dieting.

The Expansion Toward Integrative Wellness Approaches in MS Care

This article was originally published in NeurologyLive.

The US Food and Drug Administration (FDA) has approved JZP-258 (Xywav) for the treatment of idiopathic 

, making it the first treatment cleared for this indication. The approval was granted to Jazz Pharmaceuticals. 

The combination agent of calcium, magnesium, potassium, and sodium oxybates will be available to patients in the fourth quarter of 2021 following Risk Evaluation and Mitigation Strategies (REMS) implementation.

The company announced the acceptance of its supplemental new drug application (sNDA) for JZP-258 in February, which included data from a positive phase 3 study (NCT03533114) that showed the investigational agent was effective and safe for adults with idiopathic hypersomnia. 

The oral solution received fast track designation from the FDA in September 2020 for this indication, and in December was granted a rolling submission, allowing for the submission of portions of the application as completed.

Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by chronic excessive daytime sleepiness (EDS). A majority of physicians in the space have turned to off-label use of wake-promoting therapies typically used in patients with narcolepsy to help address the sleepiness issues.

"We are excited that with today's approval Xywav will become the first and only medicine indicated to treat idiopathic hypersomnia, a unique medical condition that can have significant effects on the lives of those diagnosed with the condition," Bruce Cozadd, chairman and chief executive officer, Jazz Pharmaceuticals, said in a 

 "This milestone exemplifies our patient-focused R&D strategy and internal development capabilities, and underscores oxybate as a key growth opportunity for Jazz. With this launch we will have achieved our goal of five product launches in two years."

The double-blind, multicenter, randomized phase 3 trial featured patients who had EDS associated with idiopathic hypersomnia, and all of those treated with the agent experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores–the primary end point–during the open-label titration period.

A randomized withdrawal portion of the study included 115 patients who were assessed on primary and key secondary end points including Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS). 

Those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (

Xywav has a Boxed Warning as a central nervous system (CNS) depressant and for its potential for abuse and misuse. The most common adverse reactions, occurring in at least 5% of adults in the phase 3 study, were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

JZP-258 originally received approval for the treatment of cataplexy or EDS in patients 7 years of age or older with narcolepsy in July 2020. The basis of that approval was built on data from a phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study, for which the drug demonstrated statistically significant differences (

 <.0001) in the weekly number of cataplexy attacks and ESS scores compared with placebo.

"Idiopathic hypersomnia can have a significant impact on the social, educational and occupational functioning of people living with the condition. Today's FDA approval is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder," Dianne Powell, board chair and chief executive officer, Hypersomnia Foundation, said in a statement.

"Our mission and values have consistently centered around supporting patients and scientific discovery and this announcement truly provides a sense of hope for those living with idiopathic hypersomnia."

The combination agent breaks ground as the first treatment approved for this indication.