Hero

Videos

Slideshows

Articles

Podcasts

Poll

The US Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Acadia Pharmaceuticals regarding their supplemental New Drug Application (sNDA) for pimavanserin for the treatment of hallucinations and delusions in patients with dementia-related psychosis (DRP). The FDA indicated the application cannot be approved in its current state.

The CRL cited the lack of substantial evidence of effectiveness needed for approval—specifically, lack of statistical significance in some of the subgroups of dementia and insufficient numbers of patients with less common forms of dementia.

“Acadia stands behind the robustly positive results from the pivotal Phase 3 HARMONY study and the prospectively agreed trial design and criteria for establishing efficacy in DRP. Over the entire course of the review, the Division did not raise any concerns regarding the agreed upon study design, including the issues raised in the CRL,” said Steve Davis, Chief Executive Officer of Acadia. “We will immediately request a Type A meeting to work with the FDA to address the CRL and determine an expeditious path forward for the approval of pimavanserin in DRP.”

Type A meetings are considered “immediately necessary for an otherwise stalled drug development program to proceed,” according to the 

Prior agreements with the FDA Division of Psychiatry regarding the pivotal phase 3 HARMONY study design concluded the intent was to target a broad DRP patient population analyzed as a single group. Prespecified requirements did not include statistical separation by dementia subgroups and minimum numbers of patients with specific subtypes.

The CRL also stated that the phase 2 Alzheimer disease psychosis study -019, a supportive study included in the sNDA filing, was inadequate and not well controlled.

 Reasoning for this belief included that it was a single center study, and there was no type I error control of secondary endpoints in which protocol deviations took place. Despite this, Acadia believes there is no impact on the positive results, nor on the study’s overall efficacy.

1. Acadia Pharmaceuticals. Acadia Pharmaceuticals receives Complete Response Letter from US FDA for supplemental New Drug Application for pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis. News release. April 5, 2021. 

https://www.businesswire.com/news/home/20210405005229/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Dementia-Related-Psychosis

2. US Food and Drug Administration. Type A Meetings. Accessed April 7, 2021. 

https://www.accessdata.fda.gov/cder/sb-navigate/topic3/topic3/da_01_03_0090.htm

3. Park B. FDA rejects pimavanserin sNDA for dementia-related psychosis. 

https://www.empr.com/home/news/drugs-in-the-pipeline/fda-rejects-pimavanserin-snda-for-dementia-related-psychosis/

CRL cites lack of substantial evidence of efficacy needed for approval. 

Dementia-Related Psychosis Treatment Receives Complete Response Letter

The medical science and research company Clarivate has named aducanumab, a potential Alzheimer disease (AD) treatment, as one of its top 5 “Drugs to Watch 2021.”

 Clarivate, which has published the “Drugs to Watch” list 

, included aducanumab on the list because it has a new mechanism of action and would be the first novel therapeutic for AD in more than 15 years. The company selects drugs in phase 2 or 3 trials that have the potential to bring in $1 billion in sales 

. Aducanumab is in phase 3 trials, and the US Food and Drug Administration (FDA) has promised to render its verdict in June.

, expects it will be a game changer. Lavretsky, professor in-residence in the Department of Psychiatry at the University of California, Los Angeles, told 

, “It will revolutionize Alzheimer disease treatment and care, and will have a profound impact on the lives of millions of family caregivers, who will be relieved from caring for their relatives, or the time of caregiving will be shortened, improving lives of millions of people around the world, and reducing the cost of the disease to the society.”

Aducanumab would be the first approved drug in the last 15 years that could slow down the cognitive decline associated with AD. 

, for cases across the spectrum from mild to severe, are 

The drug might address a root cause of AD. It builds on the amyloid cascade hypothesis, in which “production and accumulation of excessive amyloid-β (Aβ) may be the main cause in the onset and progression of Alzheimer's disease.”

 If so, removing or lowering of Aβ in patients with presymptomatic and early AD could be an effective therapy, and even used as a preventive, subunit vaccine.

, noted, “this drug will be the first antiamyloid therapy and disease modifying therapy for Alzheimer disease.” Tampi is professor and chairman of the Department of Psychiatry & Behavioral Sciences at the Cleveland Clinic. Lavretsky described aducanumab as a “breakthrough treatment with a novel mechanism as recombinant chimeric human IgG1 mAb targeting beta-amyloid.”

Excitement is especially strong for the drug since innovation in therapies for AD has been frustratingly slow. The problem, Tampi explained, is that AD is caused by neurological degeneration, and “it is very difficult to develop different therapies to reverse these neurobiological changes in the brain.”

Finding effective treatments has also been difficult due to “uncertainty about the underlying mechanisms of the disease, the reliance on postmortem diagnosis, and the lack of reliable biomarkers for disease early diagnosis and progression, despite almost 120-year history of research,” Lavretsky added. “Many potential therapies failed to document efficacy and did not achieve the FDA approvals.”

Sure enough, despite its promise, aducanumab has had its own set of struggles. Last November brought disappointment, when the FDA published a negative review of aducanumab, citing insufficient evidence of clinical efficacy.

The news was especially disappointing, given aducanumab’s success in previous trials. In 2015, aducanumab underwent two phase 3 efficacy trials.

 The 221AD301 ENGAGE study enrolled 1350 participants with mild cognitive impairment due to AD. It compared monthly infusions of 1 or 3 doses of aducanumab with placebo over an 18-month period, and their effects on cognitive decline. In 2017 and 2018, data from the trials showed that the treatment was slowing cognitive decline. Consequently, aducanumab became the first such DMT for AD to demonstrate clinical efficacy in a phase 3 trial.

However, in March 2019 Biogen and Eisai announced termination of ongoing aducanumab trials, due to missing primary endpoints.

 Despite the termination, further analysis of the data suggested that a subgroup of participants experienced slower cognitive decline.

Trials resumed on January 27, 2020, when Biogen announced a phase 3b study of 2400 participants who had previously used aducanumab.

 Participants were scheduled to receive monthly injections over the next 2 years. Based on this trial, Biogen requested priority review from the FDA for licensing. The FDA turned down the application in November 2020, citing the weakness of efficacy data.

After aducanumab’s developers, Biogen Inc and Eisai Co Ltd, submitted additional data, the FDA extended its decision date to June 7, 2021.

If approved, aducanumab would meet an enormous need.

“It will offer a new hope to patients and their families and therapeutic optimism to geriatric clinicians and researchers,” said Lavretsky.

https://clarivate.com/drugs-to-watch/drugs-to-watch-listing/aducanumab/

2. Yu YZ, Xu Q. Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. 

3. Talan J. FDA Panel Votes ‘No’ to Approving Audcanumab for Alzheimer’s, Citing Inconsistent Data. 

. December 3, 2020. Accessed March 9, 2021. 

https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_Votes__No__to_Approving_Aducanumab_for.1.aspx

4. Aducanumab. Therapeutics. Alzforum: networking for a cure. Accessed March 9, 2021. 

https://www.alzforum.org/therapeutics/aducanumab

5. Biogen/Eisai Halt Phase 3 Aducanumab Trials. Alzforum: networking for a cure. March 21, 2019. Accessed March 9, 2021. 

https://www.alzforum.org/news/research-news/biogeneisai-halt-phase-3-aducanumab-trials

6. Biogen and Eisai Announce FDA’s 3-Month Extension of Review Period for the Biologics License Application for Aducanumab. News release. GlobeNewswire. January 29, 2021. Accessed March 9, 2021. 

https://www.globenewswire.com/news-release/2021/01/29/2166560/0/en/Biogen-and-Eisai-Announce-FDA-s-3-Month-Extension-of-Review-Period-for-the-Biologics-License-Application-for-Aducanumab.html

Aducanumab is named 1 of the 5 “Drugs to Watch” for 2021.

Is the First Disease-Modifying Therapy for Alzheimer Disease on the Horizon?

Gary Small, MD, talks about dementia-related psychosis and the one of the tools he's utilizing to help: Acadia Pharmaceutical's 

is Chair of Psychiatry and Physician in Chief for Behavioral Health at Hackensack Meridian Health.

About 2.4 million people in the US experience dementia related psychosis, yet only half ever receive a diagnosis. 

Treating Symptoms of Dementia-Related Psychosis

In this conclusion of his miniseries on dementia, John J. Miller, MD, talks about keeping everyone safe when patients get violent, plus other nuances of care. 

is medical director, Brain Health, Exeter, NH; editor in chief,

; staff psychiatrist, Seacoast Mental Health Center, Exeter, NH; consulting psychiatrist, Exeter Hospital, Exeter, NH; consulting psychiatrist, Insight Meditation Society, Barre, MA.

Handling aggression in patients with dementia can be difficult...

Aggression in Patients With Dementia

John J. Miller, MD, talks about approved treatments for early, mild-to-moderate dementia, one of which makes an appearance in "The Odyssey." 

What dementia treatment makes an interesting appearance in classical literature? 

The Odyssey

John J. Miller, MD, goes over the specifics of dementia and its varied presentations. 

Cognitive disorders are varied and complicated, and require a close eye...

Looking Closely at the Types of Dementia

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 

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

Dementia