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In 2019, the software company Cloudflare made its initial public offering. Two of its 3 co-founders celebrated, while its third co-founder lived with a difficult diagnosis: frontotemporal dementia. A 

 chronicles his heart-wrenching decline, from a superstar programmer to a shell of his former self.

It is tragic to lose a brain with incredible aptitude. Countless others have suffered and will suffer the same fate: a brain robbed of its full potential.

Disruptions to brain health, such as mental health conditions and neurodegenerative diseases, are becoming increasingly prevalent. These disorders, many of which are preventable or at least treatable, carry heavy tolls on families and communities. Additionally, they cost the global economy trillions of dollars per year in lost productivity; in 2010, it was estimated that brain health disorders cost $2.5 to $8.5 trillion.

 This cost is expected to double by 2030.

The COVID-19 pandemic has accelerated the global decline in brain health. Not only does the COVID virus directly attack the brain (leading to symptoms ranging from brain fog to seizures), but the pandemic has also generated excessive fear, 

anxieties, sleep disturbances, and forced social isolation

 In addition to the personal toll, there is a concrete economic cost: McKinsey & Company suggest that roughly 90% of employers have noted declines in employee behavioral health during the pandemic (along with concomitant losses in productivity).

How will the rise of artificial intelligence (AI) and big data influence these trends? Will they pose new dangers to brain health and the current economic order? Or could they be beneficial too?

The use of data is a double-edged sword; while AI can help us tackle tough problems in areas like climate change and healthcare, it also presents a risk to millions of individuals’ livelihoods. McKinsey estimates that automation threatens to displace “as many as 375 million workers—or roughly 14% of the global workforce” by 2030.

To manage this transition, business, civil society, and government leaders must initiate large-scale reskilling efforts. In these programs, brain skills will take center stage. Meta-cognition—that is, self-awareness of your own learning process—is central to this. Since any individual’s work skills will have a limited shelf life in a fast-changing world, the ability to understand and learn new things throughout one’s life is crucial.

Employees of the 21st century must continuously acquire knowledge, creativity, and flexibility to race with, and not against, machines. Doing so means re-imagining our brains and their value.

Brain Capital is a form of capital relevant to a complex, interconnected, and fragile global economy that puts a premium on brain skills and brain health.

 Brain skills include self-control, emotional intelligence, creativity, mindfulness, compassion, altruism, systems thinking, metacognition, critical thinking and cognitive flexibility; these skills are all dependent on brain health. Optimized Brain Capital creates flourishing, a state when people find fulfillment in their lives, social connectedness, and accomplishing meaningful and worthwhile tasks.

The growing role of artificial intelligence in the global economy has inspired the saying that “data is the new oil.”

 While the importance of data is hard to overstate, we believe that the convergence of several factors makes Brain Capital a resource essential for understanding and assessing the success of our modern economy and society.

The Brain Capital concept applies at the individual, organizational, national, and global levels. The individual certainly receives a massive payback from investing in Brain Capital. Similarly, organizations who can nurture and support Brain Capital will find performance and results significantly improving. At a national level, we believe that policymakers will increasingly recognize the importance of optimizing Brain Capital for national progress. If the nation takes care of Brain Capital, many things will then take care of themselves. At the global level, many of the immense challenges that can only be solved collectively—climate change, biodiversity loss, for example—require co-operative problem solving and associated skills emphasized by Brain Capital.

Improving Mental Toughness and Resilience

A focus on Brain Capital can help nurture key higher-level brain skills, like resilience, mindfulness, grit, adaptability, and confidence. Resilience is essential to navigating shocks of constant change, and the shocks of the 21st century are set to be of unprecedented magnitude. Climate change, nuclear weapons, biotechnology, cyber-terrorism, and advanced machine learning systems might all pose existential risks to humanity, as well as increasing stress at the individual level. To respond to the inevitable crises of this century, we must show extraordinary resilience, both collectively and individually. COVID-19 has shaken the global psyche and socio-economic systems. Renewed commitment to inventing new methods and approaches will be essential to help our economy and societies recover from the COVID-19 crisis and to transform it, hence enhancing its resilience to future shocks and crises. 

In recent years, misinformation and science denialism have played a large role in global politics and public opinion. Misinformation in the era of COVID-19 is directly harmful, encouraging unsafe practices based on false but popular beliefs (eg, masks can lead to oxygen deprivation).

 The President of the Red Cross even labeled the dissemination of fake news about vaccines a “second pandemic.”

 Strengthening brain skills can help people evaluate existing information, become better critical thinkers, and avoid the proliferation of dangerous fictions.

While we believe Brain Capital deserves to play a larger role in the global conversation and policy, the title of this piece does not intend to disparage the importance of data. On the contrary, we believe that the 2 resources are complementary and inextricably linked.

Data are needed to improve brain wellness: artificial intelligence is enabling automated mental health solutions and aiding in the early diagnosis of neurological diseases. Digitization of existing, proven techniques allows scaling of benefits (eg 

 with mindfulness meditation). The scaling of proven techniques is critical in low- and middle-income countries where there are not enough trained mental health care workers—hence e-health, m-health, and telemedicine are vital.

 More broadly, computational neuroscience is a burgeoning field. The 

 in the US, which seeks to map functional circuits in the brain, is leveraging the latest and greatest in computational techniques. In Europe, the 

 is using supercomputers to build a digital simulation of the brain. The 

 seeks to compile data on the connections between neurons in the brain. There is also growing interest in the development of brain-computer interfaces (such as Musk’s 

) which aim to further interweave minds with machines.

Similarly, Brain Capital is the key resource needed to improve the data ecosystem: investment in brain health and brain skills helps foster the growth of curious, intelligent, well-adjusted knowledge workers to extract and use data. Further, Brain Capital will help ensure that society can function at the intersection of intelligence and wisdom, instilling robust ethical frameworks into actions that ensure more equitable progress.

Despite the current planetary emergencies and challenges that await us, there are reasons to be hopeful. For instance, the economic importance of mental healthcare has inspired many business leaders to act. McKinsey & Company

 have both recently published reports on the importance of mental health in the workplace. The 

 (created in partnership between Thrive Global, SAP, Qualtrics, and Fortune) aims to quantify employee well-being and its impact on business goals. An article in the 

$4 is returned to the economy for every $1 spent caring for people with mental health issues

 As many have come to believe that mental healthcare is an important and underserved market, money has followed in suit. Venture capital funding for mental health startups has skyrocketed: a recent editorial in 

 notes that in 2019, VC firms “invested a record-breaking $637 million in more than 60 different mental health–oriented companies, which is more than 22.8 times the investment in 2013.”

All this initial evidence points to the immense benefits of optimizing Brain Capital at every level. We hypothesize that Brain Capital has enormous positive externalities and spillovers. If Brain Capital is optimized at the individual level, it has a strong positive effect on family, community, and co-workers. If my organization nurtures Brain Capital, it makes my work (and life) better, and contributes to the nation, including in reducing individual and economic losses from brain disorders. If the nation focuses on Brain Capital, individuals and organizations all benefit.

We also hypothesize that the constituent elements of Brain Health and Brain Skills are themselves highly synergistic. If my critical thinking improves, my creativity also goes up. If I emotional intelligence is strengthened, resilience, grit and confidence improve. If my mindfulness improves, the propensity for mental illness declines.

Overall, we believe that a focus on Brain Capital will set up a synergistic cycle resulting in a significantly better society and economy.

Based on these hypothesized benefits, a diverse group of global experts recently proposed a 

 aimed at building on the Brain Capital, and reorienting the global economy around optimizing for higher Brain Capital.6The group prescribes an in-all-policies approach, suggesting a role for Brain Capital in policy areas ranging from Foreign Affairs & Trade (where a “brain health diplomacy”

 approach is proposed) to Aerospace & Aviation (where, for instance, long-duration spaceflights may present unique mental health challenges).

 Additionally, they outline a Brain Capital Investment Plan, leveraging traditional (eg venture capital, government grants) and novel (eg new collaborations like the 

) sources of capital. Finally, the team of experts encourage the development of a Brain Capital Index to formalize and track Brain Capital over time.

Brain Capital is of the utmost importance. By focusing global efforts towards continually building brain skills, early detection of negative changes, and treating brain disorders, we can help meet the challenges of the 21st century. We must build a future that prioritizes people and gives individuals the resources necessary to develop their full potential and well-being.

is a machine learning researcher at Stanford University.

is an associate with the PRODEO Institute.

is the founding director of the Center for Brain Health at UT Dallas.

is SVP and Head of Technology Investing, GIC.

is a venture partner at Alsop Louie Partners.

is a partner and Chief Economist at PWC Nigeria

is a senior oil and gas executive and investor.

is head of the OECD New Approaches to Economic Challenges Unit.

is president of the Euro-Mediterranean Economists Association.

is a co-founder of the PRODEO Institute and adjunct associate professor with the Institute for Mental and Physical Health and Clinical Trials (IMPACT) at Deakin University.

1. Upson S. The devastating decline of a brilliant young coder. 

https://www.wired.com/story/lee-holloway-devastating-decline-brilliant-young-coder/

2. Harvard School of Public Health, World Economic Forum. The global economic burden of non-communicable diseases. September 2011. 

http://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf

3. Carson J, Eyre H, Lavretsky H. Dear mental health innovators: the COVID-19 honeymoon is almost over. 

https://www.psychiatrictimes.com/view/dear-mental-health-innovators-covid-19-honeymoon-almost-over

4. Coe E, Enomoto K, Gupta A, Lewis R. National employer survey reveals behavioral health in a COVID-19 era as a major concern. 

https://www.mckinsey.com/industries/healthcare-systems-and-services/our-insights/national-employer-survey-reveals-behavioral-health-in-a-covid-19-era-as-a-major-concern#

5. Illanes P, Lund S, Mourshed M, Rutherford S, et al. Retraining and reskilling workers in the age of automation. 

https://www.mckinsey.com/featured-insights/future-of-work/retraining-and-reskilling-workers-in-the-age-of-automation#

6. Smith E, Ali D, Wilkerson B, Dawson WD, et al. Brain Capital grand strategy: toward economic reimagination. 

https://www.nature.com/articles/s41380-020-00918-w

7. Seligman MEP. Happiness is not enough. 

University of Pennsylvania Authentic Happiness

https://www.authentichappiness.sas.upenn.edu/newsletters/flourishnewsletters/newtheory

8. Bhageshpur K. Data is the new oil—and that’s a good thing. 

https://www.forbes.com/sites/forbestechcouncil/2019/11/15/data-is-the-new-oil-and-thats-a-good-thing/?sh=74cab3bc7304

9. Goodman J, Carmichael F. Coronavirus: ‘deadly masks’ claims debunked. 

10. Kaur H, Thomas N. ‘Fake news’ about a Covid-19 vaccine has become a second pandemic, Red Cross chief says. 

https://www.cnn.com/2020/12/01/media/red-cross-chief-warns-vaccine-mistrust-trnd/index.html

11. Maulik PK, Thornicroft G, Saxena S. Roadmap to strengthen global mental health systems to tackle the impact of the COVID-19 pandemic. Int J Ment Health Syst. July 29, 2020. 

https://ijmhs.biomedcentral.com/articles/10.1186/s13033-020-00393-4

12. Shih JJ, Krusienski DJ, Wolpaw JR. Brain-computer interfaces in medicine. 

13. Eyre HA, Ellsworth W, Fu E, Manji HK, et al. Responsible innovation in technology for mental health care. 

14. Pfeffer J, Williams L. Mental health in the workplace: The coming revolution. 

https://www.mckinsey.com/industries/healthcare-systems-and-services/our-insights/mental-health-in-the-workplace-the-coming-revolution

15. Chapman S, Kangasniemi A, Maxwell L, Sereneo M. The ROI in workplace mental health programs: good for people, good for business. 

https://www2.deloitte.com/content/dam/Deloitte/ca/Documents/about-deloitte/ca-en-about-blueprint-for-workplace-mental-health-final-aoda.pdf

16. Aarons-Mele M. We need to talk more about mental health at work. 

https://hbr.org/2018/11/we-need-to-talk-more-about-mental-health-at-work

17. Shah RN, Berry OO. The rise of venture capital investing in mental health. 

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2770792

18. Dawson WD, Bobrow K, Ibanez A, Booi L, et al. The necessity of diplomacy in brain health. 

19. Chang DD, Storch EA, Black L, Berk M, et al. Promoting tech transfer between space and global mental health. 

What consequences will big data and artificial intelligence have on brain health and economics? 

Move Over Data, Brain Capital is the New Oil

BioXcel Therapeutics recently announced that its orally dissolving, thin-film formulation of dexmedetomidine, BXCL501, met the primary and secondary endpoints of the TRANQUILITY trial at the 60 mcg dose level.

“We are very encouraged by the promising topline results from the TRANQUILITY study, which was designed to identify a recommended dose of BXCL501 for a potential pivotal study in dementia patients suffering from agitation. Following decades of research, there are still no effective treatments that directly target agitation commonly seen with dementia patients, and we are thrilled by the potential of being the first to develop a therapy designed to address this significant patient and caregiver need,” Vimal Mehta, Chief Executive Officer of BioXcel, said to the press. “Based on the results observed, we believe BXCL501 has broad potential in treating the full spectrum of agitation in patients with dementia. We look forward to advancing BXCL501 into a late-stage study this year following dialogue with the FDA.”

BXCL501 is a selective alpha-2a receptor agonist for the treatment of agitation and opioid withdrawal symptoms. BioXcel believes that BXCL501 directly targets an agitation mechanism and has observed anti-agitation results in a number of clinical studies across several neuropsychiatric disorders.

The US Food and Drug Administration (FDA) granted BXCL501 Fast Track Designation for the acute treatment of agitation in patients with schizophrenia, bipolar disorders, and dementia. Two different phase 3 trials (SERENITY I and II) studied BXCL501 for the acute treatment of agitation associated with schizophrenia and bipolar disorders.

The TRANQUILITY study consisted of 54 participants in assisted living facilities with agitation related to dementia, 87% of whom had Alzheimer disease. Participants received BXCL501 at either 30 mcg, 60 mcg, 90 mcg, or a placebo. Participants reported no severe or serious adverse events, and the primary safety and tolerability endpoints were met. Adverse events in the trial included hypotension, orthostatic hypotension, and dizziness, with the most common adverse event being mild or moderate somnolence.

BioXcel also shared plans for a phase 2 trial studying hospitalized patients who have agitation symptoms associated with delirium, intended to begin within the next several months.

1. BioXcel Therapeutics. BioXcel Therapeutics announces BXCL501 met the primary and all secondary endpoints in the TRANQUILITY phase 1b/2 study for the acute treatment of agitation in dementia, including Alzheimer disease. News release. 

https://www.globenewswire.com/news-release/2021/01/05/2153316/0/en/BioXcel-Therapeutics-Announces-BXCL501-Met-the-Primary-and-All-Secondary-Endpoints-in-the-TRANQUILITY-Phase-1b-2-Study-for-the-Acute-Treatment-of-Agitation-in-Dementia-including-Al.html

A new formulation of dexmedetomidine meets primary and secondary endpoints in recently completed study. 

Medication for Agitation in Dementia and Alzheimer Disease Patients Moves Forward

 led by The Jackson Laboratory and University of Maine has discovered that the gene Dlgap2 is associated with Alzheimer disease, dementia, and cognitive decline. Researchers found post-mortem human brain tissues of individuals experiencing “poorer cognitive health” and “faster cognitive decline” had low levels of Dlgap2.

“The reason why this is so important is because a lot of research around cognitive aging and Alzheimer’s has been hyper-focused on well-known risk genes like APOE and brain pathologies,” Catherine Kaczorowski, associate professor and Evnin family chair in Alzheimer disease research at The Jackson Laboratory (JAX), and adjunct professor with the University of Maine Graduate School of Biomedical Science and Engineering (GSBSE), said to the press. “We wanted to give ourselves the option of looking at new things people keep ignoring because they've never heard about a gene before.”

Located in the synapses of neurons, Dlgap2 anchors critical receptors for signals between learning and memory neurons. The research team examined the memory and brain tissue from a large group of genetically diverse mice, relying on diversity outbred mice. The population came from 8 parents created by JAX, as they thought a diversified group would better reflect genetic diversity in humans. About 437 mice, each either 6, 12, or 18 months old were used.

“It’s great because you can harness the best parts of a mouse study and human society,” Andrew Ouellette, a PhD student at JAX and a GSBSE NIH T32 predoctoral awardee, said to the press. “Historically, research has been done with inbred mice with similar genetic makeups; same, similar genetic models. But clinically, humans don't work like that because they're not genetically identical.”

Quantitative trait loci mapping was performed on the mouse population. Study of entire genome sequences allowed for identification of the genes responsible for varying cognitive function and where they occurred. Researchers pinpointed the connection between Dlgap2 and memory decline in mice, and were then able to evaluate its significance to humans.

They found Dlgap2 is associated with the degree of memory loss in mice and risk for Alzheimer dementia in humans. Further research will be needed to determine how the gene influences dementia and brain functioning.

1. Ouellette AR, Neuner SM, Dumitrescu L, Hadad N, et al. Cross-species analyses identify Dlgap2 as a regulator of age-related cognitive decline and alzheimer’s dementia. 

2. University of Maine. New connection between Alzheimer's dementia and Dlgap2. News release. 

https://www.sciencedaily.com/releases/2020/11/201123161040.htm

A new study associates a gene that facilitates neuron communication in the nervous system with memory loss. 

Dlgap2: The Gene Associated With Memory Loss

I am looking forward to seeing “Mr Walker,” a gregarious man with an engaging smile, whose cognitive functioning has gradually declined over the past 4 years. I click his name in our telehealth waiting room. The screen lights up and through a fuzzy computer connection I see him.

He looks around, bewildered. He hears my voice but cannot determine from where it is coming. He cannot focus on the computer screen in front of him and does not know what is required of him. A voice from the side says, “Dad there’s the doctor. Didn’t you want to ask him something?” The patient stares blankly and asks, “Where? I don't see him.” To that, I say cheerfully, “Hello Mr Walker,” and I get a glimpse of his familiar smile before he falls back into the chair in silence.

Early claims that telehealth is “virtually perfect”

 do not fit well with our experience with dementia patients. It has been more than 5 months since our team saw our dementia patients in-person. Some we will never see again, as they have succumbed to the coronavirus. Others survived the battle with the virus, but their brains were injured on the battlefield, and their dementia progressed to a more severe stage of deterioration. We have muddled through using telehealth—usually with video but sometimes by phone—but it is not the same as pre-COVID-19 care.

Our patients and their caregivers (mostly indigent, minorities, and immigrants) often do not have the bandwidth connections to achieve optimal video images. This is not an ideal situation for patients with disorders that impair their intellectual and social functioning. They cannot see or hear us very well, and they may become more confused by the video interface or retreat into the background. We cannot be sure if they are getting clinically worse or whether the technology is creating surplus deficits.

We have adjusted how we treat patients, and the jury is still out as to the impact of these changes. For example, during the peak of the pandemic, we weighed the infection risks of obtaining blood work or neuroimaging in labs or radiology centers. These risks seemed to outweigh the benefits. On the other hand, because COVID-19 can present atypically in dementia patients,

 we were more vigilant concerning changes in their behavior, function, or cognitive status, and encouraged patients to obtain in-person medical evaluations, perhaps sooner than under normal circumstances. Sometimes with telehealth we must forgo smaller things, even if they are important for good geriatric care. Thus, checking blood pressure sitting and standing, checking pulse rate and rhythm, measuring weight—none of it is done if family members do not have the equipment.

, telehealth is better than nothing. Indeed, the parallels with schoolchildren are striking. It is estimated that 10% of individuals 65 years or older (about 5.6 million people) have dementia.

 Roughly two-thirds of individuals with dementia live in noninstitutional residences, and adult daughters and, to lesser extent sons, are the primary caregivers for nearly 7 of 10 people.

 One-quarter of these people receive some paid care, and this number rises to half in individuals with severe dementia.

 Increasingly more patients are participating in day programs that specialize in the care of individuals with dementia. Those with mild dementia can still benefit from senior centers.

The COVID-19 pandemic eviscerated the patients’ community support programs. Keeping people active in the day translates to calmer and more restful nights, and research suggests that 

 and mental stimulation may slow the course of these disorders.

 Two vulnerable populations have had to make difficult choices about interacting. Many home health aides come from communities especially hard hit by COVID-19. Most aides use public transportation that amplifies their risk, and at the beginning of the crisis, they did not have adequate personal protective equipment. Some decided not to go to work. Additionally, in-home nursing and physical therapy services were often discontinued. On the patient side, dementia patients with COVID-19 have twice the mortality rate of non-demented people.

 Families must often play a form of Russian Roulette: “Will the aide who comes today give our parent a fatal case of COVID-19?” Consequently, some family members voluntarily stay home to care for their loved ones. Others that had been forced to work from home or were laid-off opted to temporarily discontinue home care services. Much as COVID-19 taught parents that it is not easy to replicate the school experience, family caregivers learned that it is difficult to replace a home aide or day program, especially if they are facing the additional demands of telecommuting and school-age children learning at home.

What does this mean clinically? Early in the crises, close-knit family structures unwittingly spread the contagion. To protect their loved ones, caregivers faced the challenge of limiting personal contacts with children, grandchildren, friends, or other relatives. Outdoor activities had to be restricted as well. Thus, they do not go to parks, houses of worship, supermarkets, or restaurants. Commonly, patients complain of 

 or too much time spent staring out the window or simply lying in bed. The lack of daytime activity results in disordered sleep cycles, and they become increasingly confused and agitated. Diminished stimulation also increases depression, psychotic symptoms, physical decline, and possibly cognitive decline. Others try to leave the house and must be forcibly restrained by caregivers. Adult children that brought their demented parent into their own homes found that the latter often exhibited increased turmoil in unfamiliar surroundings. Rules about confinement and masks, incomprehensible to the individual with dementia, induce anxiety and fear. A vicious cycle ensued in which overwhelmed caregivers become less tolerant of the behavioral symptoms of their loved ones; this, in turn, aggravates these symptoms. We have prescribed more medications for these psychiatric symptoms, not only to relieve the patient’s distress but also to relieve the caregiver’s burden.

Increased reliance on medications, however, even when used judiciously, generates concerns in caregivers and physicians. 

The US Food and Drug Administration’s black box warnings

 for most of these drugs (eg, antipsychotic agents) link them with higher mortality risks. In the pre-COVID-19 era, we utilized alternative behavioral approaches such as day programs, senior centers, or various recreational facilities; given those options, caregivers were often more receptive to non-pharmacological strategies. Lately, I find myself encouraging a modest return to public spaces—a walk to the park or around the block—but many caregivers resist, fearful that such excursions could risk exposure to contagion, especially when their loved ones refuse to wear masks.

The good news is that we have been sending fewer condolence cards. We hope that a second wave will not arise, and we await the reemergence of the support network so vital for our patients and caregivers. Before the pandemic, such networks were underappreciated and underfunded by legislators; now, we fear curtailment from prior levels of services as states and cities struggle to balance their budgets. Taking care of persons with dementia and their caregivers is 1 of the most socially interactive specialties in medicine, and we are eager to see them in-person again. But because our patients are high-risk, they are first out and last in for office visits.

So we plod on, honing our telehealth skills and maximizing its benefits. For instance, we have found that telehealth can unobtrusively bring together clinicians and students from various disciplines into the patient’s room, as well as provide “home visits” for trainees who rarely see where patients live.

For now, I turn my swivel chair toward the luminous high-pixilated LED screen, put on my wireless, noise-canceling headphones, and like an internet-age version of the bemused Dr Bernard Rieux in 

: “I have no idea what’s awaiting me, or what will happen when this all ends. For the moment I know this: there are sick people and they need curing.”

 And expectantly, I ask, “Hello, Mr Walker, how are you?”

is State University of New York Distinguished Service Professor & Director of the Division of Geriatric Psychiatry at SUNY Downstate Medical Center. He is also the founding director of the Center of Excellence for Alzheimer’s Disease at SUNY Downstate Medical Center and the Geriatric Psychiatry Fellowship Program. The author receives support from the Health Services Research Administration Geriatrics Workforce Enhancement Program-COVID; Grant no. T1MHP39042.

This article was originally posted on September 18, 2020, and has since been updated. Scroll down for the 

1. George, J. Telehealth boom misses older adults. 

https://www.medpagetoday.com/practicemanagement/telehealth/87901

2. Naarding P, Oude Vashar RC, Marijnissen RM. COVID-19: Clinical challenges in Dutch geriatric psychiatry. 

The Demography of Dementia and Dementia Caregiving. Program and Policy Implications

. Population Reference Bureau working paper 40. May 2020.

4. Jia RX, Liang JH, Xu Y, Wang YQ. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: a meta-analysis. 

5. Azarpazhooh MR, Amiri A, Morovatdar N, et al. Correlations between COVID-19 and burden of dementia: An ecological study and review of literature. 

Telehealth poses challenges for patients, clinicians, families, and caregivers.

Treating Dementia Patients in the Time of COVID

 (FTD) describes a group of neurodegenerative disorders that are characterized by the clinical syndrome of progressive dysfunction in executive functioning, behaviors, and language.

 FTD is thought to be the third most common type of dementia after Alzheimer disease (AD) and dementia with Lewy bodies.FTD is also a common type of early-onset dementia (occurring among individuals 65 years or younger).

FTD was noted in 1892 by Arnold Pick, MD, when he described an individual who presented with aphasia, temporal lobar atrophy, and presenile dementia.

 In 1911 the association between Pick bodies and FTD was described by Alois Alzheimer, MD, PhD, who named the disorder “Pick’s disease.” The term Pick’s disease became synonymous with FTD, referring to both the clinical syndrome and the pathological diagnosis. Currently, “Pick’s disease” is used only to describe the pathological diagnosis. In 1982, M. Marsel Mesulam, MD, identified the language subtype of FTD: primary progressive aphasia (PPA).

Available evidence indicates that FTD is the second most common cause of dementia among individuals 65 years or younger.

 The prevalence of FTD among individuals with early-onset dementia is between 3% and 26%. The population prevalence of FTD varies between 1 to 26 per 100,000.

 These numbers probably underestimate the true prevalence, as the disorder is often missed or misdiagnosed.

FTD has 2 main subtypes, based on their predominating presentations: the behavioral variant of FTD (bvFTD), and the language variant, ie, PPA.

 Based on the localizations and underlying cerebral dysfunction, the language variant can be further subdivided into the nonfluent variant of PPA (nfvPPA) and the semantic variant of PPA (svPPA). Male predominance has been noted in the bvFTD and svPPA variants and female predominance in the nfvPPA variant. 

 details the diagnostic criteria of FTD’s 3 variants.

A third variant of PPA has been described as logopenic PPA (lvPPA),in which individuals exhibit specific impairment with confrontation naming or word-finding difficulties and impaired sentence repetition.

 Neuroimaging studies among these individuals demonstrate predominant left posterior perisylvian or parietal atrophy/hypoperfusion/hypometabolism. Definite histopathologic evidence or the presence of a known pathogenic mutation allow for a definite diagnosis of FTD. 

Evidence indicates that approximately 12.5% of individuals with bvFTD have concomitant motor neuron disease.

 In addition, 27.3% of individuals have features of minor motor system dysfunction, including occasional fasciculations and mild muscle wasting or weakness. As the disease evolves, the clinical presentation of the 3 variants overlap with each other and with syndromes of atypical parkinsonism, including progressive supranuclear palsy (PSP) and corticobasal degeneration syndrome (CBS).

Compared with AD, patients with FTD tend to have a shorter duration of survival from diagnosis and more rapid decline of cognition and function.

 The average survival time with FTD depends on the subtype; the average survival time is approximately 3 years for bvFTD and motor neuron disease and 12 years for with svPPA.

Current evidence indicates that FTD is a highly heritable disorder, with familial FTD accounting for approximately one-third to half of cases.

 Most cases of familial FTD present as the bvFTD variant. A family history of dementia is found in 25% to 50% of FTD cases, and about 10% have a clear autosomal-dominant inheritance.

 Mutations in the microtubule-associated protein tau (τ), progranulin, and chromosome 9 open reading frame 72 expansion are the most common causes of familial FTD. These mutations result in the variable clinical presentations of FTD.

The major variants of FTD are classified based on their respective protein-based inclusions and underlying molecular pathologies.

 The current neuropathological classification allows most cases of FTD to be placed into 1 of 3 broad molecular subgroups: frontotemporal lobar degeneration (FTLD)-τ subtype; the FTLD-TDP subtype associated with TDP-43; or FET protein accumulation.

 The FTLD-τ variant accounts for approximately 40% of all FTD cases. Approximately half the postmortem cases of FTD have abnormal deposition of transactive response DNA-binding protein 43 (TDP-43).

FTD may be misdiagnosed as other psychiatric disorders, including schizophrenia, bipolar disorder, depression, or obsessive-compulsive disorder.

 The bvFTD variant is most likely to be misdiagnosed as another psychiatric disorder; FTD may be misdiagnosed as AD or another type of dementia. 

 describes the differentiating clinical features of the dementias.

Given the high risk for misdiagnosis, suspected cases of FTD should be carefully evaluated. A thorough history from the individual and a reliable collateral source that tracks the progression of behavioral and cognitive symptoms are essential. A focused physical examination that identifies parkinsonian and/or upper motor neuron signs will assist in the diagnosis. Laboratory testing (including complete metabolic panel, complete blood count, thyroid function tests, liver function tests, vitamin B12 levels, and urine drug screen) should be done to rule out reversible causes of cognitive and behavioral impairments. Among atypical cases, toxicology for heavy metals, inflammatory biomarkers for autoimmune and paraneoplastic syndromes, and testing for infectious etiologies including syphilis and HIV should be considered.

Neuroimaging studies including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and single photon emission computed tomography (SPECT) scans can also assist in diagnosing FTD. 

describes the neuroimaging findings in FTD.

 Cerebrospinal fluid (CSF) assessment will help rule out AD when the patient has low β-amyloid concentrations and high τ protein concentration. Neuropsychological testing will help rule out other causes of cognitive and functional changes. 

 provides neuropsychological profiles of various types of dementias.

 Among individuals with a family history of dementia, movement disorders, and/or psychotic disorders, genetic counseling and a search for genes that cause FTD are both recommended.

Currently there are no US Food and Drug Administration (FDA) approved disease-modifying drugs for the treatment of FTD.

 found a total of 9 randomized, controlled, double-blinded clinical trials that evaluated various drugs for the treatment of FTD.

 These included 2 trials of the selective serotonin reuptake inhibitor paroxetine, 1 trial of trazodone, 2 trials of stimulants (methylphenidate and dextroamphetamine), 1 trial of the acetylcholinesterase inhibitor galantamine, 2 trials of the N-methyl-d-aspartate (NMDA) antagonist memantine, and 1 trial of the neuropeptide oxytocin. The investigators concluded that SSRIs, trazodone, and the amphetamines may be effective in reducing some behavioral symptoms. None of these medications, however, improved cognition among individuals with FTD. Available data also indicated that these medications were well tolerated.

The evidence for the use of antipsychotics for the treatment of behavioral symptoms in FTD comes mainly from case reports and uncontrolled studies.

 In addition, the use of antipsychotics can worsen the risk of extrapyramidal adverse effects, to which individuals with FTD are especially vulnerable. Furthermore, the boxed warning for the risk for death with the use of antipsychotics among individuals with dementia holds true also for individuals with FTD. For the treatment of behavioral symptoms in FTD, the evidence for the use of anticonvulsants—including valproic acid, topiramate, and carbamazepine—is limited to case reports. Evidence indicates that individuals with FTD and parkinsonism often do not respond to dopaminergic drugs, including levodopa/carbidopa, although some case reports indicate some benefits with these agents. 

Trials of τ aggregation inhibitors, τ acetylation inhibitors, anti-τ active vaccine, anti-τ monoclonal antibodies, anti-human sortilin monoclonal antibody, microtubule-stabilizing drugs, and progranulin expression activators have been completed or are currently in various phases of trials.

 Unfortunately, available results indicate that none of these drugs have yet been found to be beneficial.

Available evidence indicates that nonpharmacological management techniques are helpful among individuals with FTD.

 These interventions include environmental approaches that assist individuals who struggle to accurately interpret, understand, and react to their environment. In addition, behavioral modification techniques and providing familiar activities appear to reduce different types of behaviors. Evidence indicates that educational services and coping strategies that are focused on problem-solving are effective in managing behavioral symptoms and reduce caregiver burden. The development of individualized regimens incorporating environmental and behavioral strategies have been proven to be highly beneficial in assisting individuals with FTD. The family caregivers who use these strategies become more competent in managing patients’ challenging behaviors. Speech therapy has been 

to be beneficial among individuals with PPA.

The clinical syndrome of FTD is characterized by executive dysfunction, behavioral disturbances, and language impairment. FTD is often misdiagnosed or underdiagnosed due to the heterogeneity of its clinical presentation and the overlap of its clinical symptoms with those of other common neuropsychiatric disorders. Although there are no FDA-approved medications for the treating FTD, some agents have shown modest efficacy in improving behavioral but not cognitive symptoms. Nonpharmacological techniques can be beneficial in managing behavioral symptoms. Many newer therapies are currently under trial, although their benefits are not yet certain.

is chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Cleveland, OH; and professor of medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH. 

is executive vice president, Diamond Healthcare, Richmond, VA. 

is with the Behavioral Advisory Group, Strongsville, OH. The authors report no conflicts of interest concerning the subject matter of this article.

1. Young JJ, Lavakumar M, Tampi D, Balachandran S, Tampi RR. 

Often misdiagnosed as other psychiatric disorders, FTD is the third most common type of dementia and the second most common among patients 65 years or younger. How to spot the signs.

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