Nicola Davies, PhD

Alzheimer disease (AD) is a leading cause of disability and the fifth leading cause of death in patients age 65 or older.

 As the aging population continues to grow, the incidence of AD also increases, spurring research into innovative ways of detecting, managing, and treating the condition. Digital biomarkers, in particular, have aroused interest from researchers and manufacturers, as they have the potential to provide precise, quantifiable physiological information that can be used as diagnostic and prognostic indicators.

Any medical data that are objectively collected through digital technology, such as wearable devices and smartphones, are referred to as “digital biomarkers.” Given that the wearable health care device market is predicted to grow by 20% in the next 5 years,

 digital biomarker are an attractive option within the medical community.

Digital biomarkers show definite promise in detecting AD in its early stages.

“Although the gold standard for diagnosis is an autopsy or positron emission tomography (PET) scan, clinically validated end points for digital biomarkers are on their way,” said Graham Jones, PhD, director of innovation at Novartis. Indeed, over the past few years, much research has focused on the utility of digitally acquired data in detecting AD and predicting cognitive decline.

Based on their method of acquisition, 2 major categories of digital biomarkers are currently being employed for neurologic conditions

Active biomarkers, as the name suggests, require users to be actively involved in recording the parameter being measured. These biomarkers generally assess cognitive function through digitally administered tests or quizzes.

Passively collected data, on the other hand, occurs without active user engagement and results in continuous, real-time data acquisition. For instance, data such as step count, gait symmetry, and clarity of speech can all be recorded during spontaneous activities, and without any engagement on the part of the user.

According to Mircea Balasa, MD, PhD, a neurologist at Hospital Clinic de Barcelona in Spain, innovative digital biomarkers based on cognitive testing are being devised to improve on existing neuropsychological symptom tests, making them more standardized and reliable. One such innovation is using gamified versions of standard memory tests to make it more attractive and increase patient engagement. For example, Balasa and his team have been working on validating the Altoida Neuro Motor Index device, which is based on augmented reality technology and consists of a 10-minute gamified assessment that tests a patient’s functional and cognitive aptitude.

 “At present, the Altoid device shows promise in distinguishing patients with mild cognitive impairment from controls,” Balasa told 

Research has shown that AD presents with a definitive decline in sensory and motor functioning, even before cognitive decline begins.

 These deficits include general visual parameters, such as visual acuity, color perception, contrast sensitivity, and visual integration, all of which are reduced in patients with mild AD.

 Investigators have suggested that passive tests can measure the amount of fixation time on certain graphics that are repeatedly viewed, to quantify visual parameters over time.

 Both peripheral and central auditory system dysfunction occur in the prodromal stages of AD,

 and passively monitoring conversations could be one way of screening for AD. For instance, a study showed that atypical repetitions in 2 conversations that occurred on different days was a strong indicator of AD.

 Reading comprehension can also be evaluated by tracking eye movements.

In addition, slow gait speed is a strong predictive factor for dementia and cognitive decline.

 Measurement of gait speed using an accelerometer or gyroscope sensors has the potential to improve the detection of AD. Also, touchscreen sensors can evaluate fine motor control capabilities such as typing skills, swiping, and other keystroke patterns.

Imaging studies have shown that neuropathological lesions can develop in the autonomic nervous system (ANS) in the earliest stages of AD. “The ANS is fertile ground for diagnosis,” Jones told 

. “The ANS impacts several factors that can be picked up by digital tools—heart rate, reflexes, and respiration, for instance.” Indeed, the earliest stages of AD have been associated with heart rate variability (HRV),

 and mobile devices with built-in electrocardiogram (ECG) capabilities, such as the Apple Watch, can be used to monitor HRV in at-risk patients.

 AD is also associated with disturbed circadian rhythms,

 so devices that have built-in ballistocardiography sensors can be used to monitor sleep patterns.

Determining the Most Accurate Digital Biomarkers

Although investigators have studied a variety of digital biomarkers, very few have dealt with real-world, home-based evaluations. In 2019, Evidation Health set the ball rolling when they partnered with Apple and Eli Lilly and Company for a real-world study that produced around 16 terabytes of digital biomarker data. The investigators were able to establish that specific motor skills, such as reading, typing, and keystroke tasks were performed more slowly in patients who had mild cognitive impairment and dementia.

In 2018, the United Kingdom (UK) Alzheimer’s Society and the University of Oxford’s Big Data Institute launched the GameChanger project, which employs a smartphone app called Mezurio.

 Volunteers across the UK are being recruited to complete activities each day using the app, from which the data collected will be used to study markers of healthy cognition and determine factors that would be affected by cognitive decline.

Another project in the European Union, RADAR-AD, is focused on exploring the potential of mobile technologies in measuring disability progression associated with AD,

 while the US-based Alzheimer’s Drug Discovery Foundation is supporting digital biomarker exploration through its Diagnostics Accelerator.

"There is a very real expectation that digital biomarkers can monitor progression from prodromal to diseased states...[and] some evidence that learned behaviors—such as performing specific functions on tablets—coupled with certain exercise regimens, can delay the onset and severity of diseases like AD."


Digital biomarkers have the potential to advance several stages of the disease process:

 The current standard for diagnosis of AD is through PET molecular imaging, which is expensive and often only available at regional facilities. In contrast, when patients use mobile or wearable devices, there is continuous monitoring of passive biomarkers and data can be compared to the patient’s previous data. This makes it easier to detect any decline in nervous system parameters. “Any deviations from normal biomarker levels can be used as an indication to recommend more specific investigations, such as PET scans,” Jones said.

 Currently, neuropsychological testing is used to monitor cognitive function in high-risk individuals. However, these tests are not always reliable and may fail to detect the earliest stages of cognitive impairment. According to Balasa, active digital biomarkers could be used instead to create prognostic models that can help monitor patients who are at higher risk of developing cognitive decline. “Such individuals do not normally seek medical advice, as they don’t usually have clinically relevant cognitive decline,” he said.

 Digital biomarkers are a cost-effective solution to collect objective, continuous, quantifiable data in a longitudinal manner. The precision of this data can increase the statistical power of clinical trials.

 In the advanced stages of AD, neurons are destroyed and the opportunity to study disease pathology is limited. By identifying patients in the early stages of the disease via digital biomarkers, researchers can gain a deeper understanding of the pathophysiology of AD, which can help develop novel treatment strategies.

Wearable devices still have a long way to go before they can be reliably used for the diagnosis and management of AD. “The issue for most of these devices is clinical validation with appropriate double-blinded trials,” Jones said. For effective real-world usage, clinical validation needs to be followed by regulatory approval. The Altoida device is currently the only device-specific for AD that has FDA approval and CE marking. While the Apple Watch has FDA approval for fall detection and ECG rhythm monitoring, its AD-specific features still need validation and approval.

Actively measured biomarkers require dedicated engagement on the part of the patient, who must manually enter inputs into the recording device. Lack of interest or even beginning memory loss are some challenges that can prevent the effective use of this kind of biomarker. While passive biomarkers do not face these challenges, the large volumes of data that are acquired create the need for extensive storage systems. Analysis of this data may require complex tools and trained personnel.

In addition to these disadvantages, both kinds of data face another challenge: wearable devices record vast amounts of medical data that must remain confidential. “We need to navigate data privacy and Health Insurance Portability and Accountability Act regulations,” said Jones. Some applications such as Apple Health allow users to access their health care data directly through their own devices, which may increase the need for secure access to such data.

In Jones’ opinion, apart from timely diagnosis, there are 2 future directions that hold promise. The first is monitoring disease progression. “There is a very real expectation that digital biomarkers can monitor progression from prodromal to diseased states,” he said, adding that cognitive performance could also be tracked digitally. Secondly, and more promising, is the possibility of actual treatment using digital tools. “There is some evidence that learned behaviors—such as performing specific functions on tablets—coupled with certain exercise regimens, can delay the onset and severity of diseases like AD,” he said. Of course, these digital forms of treatment need sound exploration and validation before they become a reality.

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KDD ‘19: Proceedings of the 25th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining


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Articles

Digital biomarkers offer promise to revolutionize the diagnosis and treatment of Alzheimer disease via our increasing ability to gather active and passive data.

Data Evolution in Alzheimer Disease: Is the Future Digital?

Sleep-disordered breathing (SDB) refers to any disorder in which the patient has difficulty breathing while asleep, including obstructive sleep apnea (OSA) and central sleep apnea (CSA). OSA, which occurs because of upper airway obstruction during sleep, is far more common, with estimates of approximately 936 million people worldwide suffering from the condition.

“With OSA, snoring and breathing pauses and reduced airflow during the night leads to sleep fragmentation and unrefreshing sleep, which in turn impairs daytime functioning,” said Stuart MacKay, BSc(Med), MBBS(Hons), FRACS, associate professor at Illawarra ENT Head and Neck Clinic in Australia. 

“Patients can feel groggy, tired, [and] sleepy and have a higher rate of motor vehicle collisions and workplace accidents. In addition, via a variety of pathophysiological pathways, but especially due to repetitive oxygen desaturation, patients with more significant sleep apnea are at risk of hypertension, arrhythmias, ischemic events, and other cardiometabolic consequences.”

A small subset of patients may have CSA, when the brain fails to send signals to breathe. CSA is less common in the general population, but there are increased rates in people with specific conditions, such as heart failure and chronic opioid use.

Although OSA and CSA have different causes, both contribute to reduced quality of life and have been linked to decreased cognition, increased cardiovascular risk, and increased mortality.

Continuous positive airway pressure therapy: Not suitable for all

Most sleep experts recommend continuous positive airway pressure (CPAP) as the first-line treatment for SDB, regardless of the severity of apnea. The CPAP device continuously delivers pressurized air into the upper airway, which helps keep the air passages open. Results from studies have shown that using CPAP therapy can significantly reduce the severity and morbidity associated with sleep apnea.

The main limiting factor in the use of CPAP for OSA is the lack of compliance to therapy. The device delivers air under moderate to high pressure, which can cause a certain level of discomfort for patients. “Although it is minimally invasive, not everyone can tolerate CPAP,” said Peter M. Baptista, MD, PhD, a senior clinical consultant at the Otorhinolaryngology Unit at Clínica Universidad 

de Navarra in Spain. “In addition, CPAP can cause nasal obstruction and feelings of claustrophobia.”

One cohort study estimated that only 37% to 41% of patients adhered to CPAP therapy in the long term,

 which ultimately hinders the achievement of good treatment outcomes. A recent meta-analysis showed that the cardiovascular risk associated with OSA was reduced only when patients wore the device for longer than 4 hours per day.

For patients with CSA, it is more than just the discomfort of CPAP that can raise problems. “With central sleep apnea, there is an interruption in the neural drive to breathe,” Sanjaya K. Gupta, MD, assistant professor of medicine at the University of Missouri-Kansas City School of Medicine, told 

®. “There is no movement of the diaphragm, so using CPAP does not work unless the patient is making an effort to breathe.”

Clinicians have used a wide range of surgical procedures in OSA, including palatopharyngoplasty, tonsillectomy, and maxillomandibular advancement.

 However, each surgery targets only
1 anatomical area. Results from sonographic studies have shown that OSA presents with multilevel airway collapse, which means that a single surgery may fail to resolve the complete issue.

Surgery is not an option for patients with CSA. Apart from oxygen ventilation, the only other ways to manage CSA include treating the underlying heart condition that is present and cutting back
on opioid use.

Nerve stimulation for the management of sleep apnea

The search for newer, better alternatives to CPAP has resulted in 1 promising solution––nerve stimulation. By stimulating selected nerves, specific muscles that aid in airway relaxation or breathing can be made to contract. This addresses the problem of sleep apnea at a physiological level, which would reasonably be more effective and have fewer adverse effects.

For OSA, clinicians choose the hypoglossal nerve as a target for stimulation. “Hypoglossal nerve stimulation [HGNS] provides an opening of the airway at the level of both the tongue and palate,” said Baptista. Nerve stimulation causes the genioglossus muscle to contract, which moves the tongue forward. According to research by MacKay and colleagues, it is important to only stimulate the genioglossus. “Selective stimulation of the nerve fibers to the genioglossus, the main dilator of the airway, allows [the] avoidance of stimulating retrusor muscles that can compromise airway opening,” he said. “Results of such implantation are likely to improve patient and polysomnographic outcomes.”

Research results have shown that there is also palatoglossal coupling, which increases the airway space at the retropalatal level.

 This dilates and stabilizes the airway at multiple levels. In a recent systematic review, Baptista and colleagues reviewed 12 studies that used HGNS for OSA.

 They found the procedure reduced the number of apneic and hypopnea events per hour by 18 points, measured via the apnea-hypopnea index (AHI). There was also a reduction of 14.6 points in the number of oxygen desaturations measured via the oxygen desaturation index (ODI). According to MacKay, “The advantages of HGNS include the ability to avoid devices worn on the face and in the mouth, and avoidance of painful intra-oral/pharyngeal surgeries. Disadvantages include the requirement for commitment to titrations, follow-up, and ongoing device use.”

There are different types of HGNS, namely unilateral and bilateral. “Bilateral HGNS allows a higher likelihood of symmetrical tongue and, in cases of ‘coupling,’ palatal movement to improve airway patency in sleep,” MacKay told 

®. “Advantages over currently available unilateral stimulation include [fewer] components to implant, and external stimulation rather than an implanted ‘pacemaker.’ The incision is small and relatively painless.”

In CSA, stimulation of the phrenic nerve can be just as effective. This eliminates periodic respiration by causing consistent, regular diaphragmatic contractions, which generates negative intrathoracic pressure and restores a regular breathing pattern. Last year, investigators reported the results of using a phrenic nerve stimulator over a 3-year period.

 The result was sustained improvement across a wide range of sleep metrics, including the AHI, ODI, central apnea index, and arousal index. More recently, a pooled meta-analysis of 5 different studies showed that phrenic nerve stimulation could effectively reduce AHI scores by approximately 26.7 events per hour, as well as reduce the ODI scores by approximately 24.

The nerve stimulator needs to be implanted into the patient’s body to function. Several different devices are available to treat OSA through HGNS. In general, the device consists of a sensor electrode, a pulse generator, and a stimulation electrode.

 The sensor electrode is usually implanted into the intercostal muscles, or just below the ribs. During inspiration, it gives off an electric signal that is picked up by an implantable pulse generator (IPG). The IPG is usually placed in a pocket below the clavicle, medial to the delto-pectoral groove. After receiving an electric signal, it generates a pulse that is transmitted to the stimulation electrode, which is implanted around the medial branches of the hypoglossal nerve.

The device used in CSA has a slightly different design; a sensing lead is placed in the azygous vein, behind the heart, to the level of the diaphragm to detect breathing. A pacing electrode is placed in a vein adjacent to the phrenic nerve. “The device works 

automatically and in concert with patients’ normal respiratory cycle,” said Gupta. “The pacing and sensing leads are plugged
into a device that looks and functions similar to a cardiac pacemaker. Once connected, the device and leads are surgically placed under the skin in the right upper chest, just below the collarbone. The device is programmed to sense the patient’s breathing and the moment when the breathing stops, the device will deliver electricity through the pacing lead to the phrenic nerve, which will stimulate the diaphragm to contract.” All this happens automatically and seamlessly, in concert with the patient’s normal respiratory cycle. No intervention is necessary on behalf of the patient to initiate therapy, they don’t have to wear a CPAP mask, and the device turns off when they get up in the morning.

Can all patients with SDB receive nerve stimulation therapy? According to most experts, the answer is no. The type of patient selected can greatly influence treatment outcomes, and establishing which sleep apnea the patient has is a key priority. HGNS will not work if the patient has CSA. Conversely, phrenic nerve stimulation only benefits those with CSA; it is not indicated for those with primarily OSA. There is a third type of sleep apnea called “treatment emergent” CSA

 This is primarily OSA in which a central component emerges following the use of CPAP therapy. Uncertainty remains about whether nerve stimulation can benefit this subset of patients.

An obvious indication for HGNS is for patients who are unable to tolerate CPAP. However, before clinicians consider this procedure, the patient must be evaluated for other factors. “Patients should see credentialed sleep surgeons for a thorough assessment and discussion of treatment options if they cannot tolerate or adhere to CPAP or other devices long-term,” advised MacKay.

In a recent review study, Baptista highlighted 3 key factors that must be considered during patient selection.

 These include the severity of OSA, body mass index (BMI), and the severity of airway collapse at the palatal level. “If patients have [a] very high BMI (> 35) or concentric palatal collapse, HGNS is best avoided,” said Baptista. Obesity is a predictor for poor OSA treatment outcomes regardless of the type of treatment. In terms of severity of airway collapse at the palatal level, HGNS relaxes the palatal and retrolingual musculature, but if there is concomitant collapse in the posterior or lateral pharynx, this technique may not be effective. To ascertain the exact area of collapse, drug-induced sleep endoscopy can serve as a valuable diagnostic tool.

Nerve stimulation is a relatively expensive technique compared to CPAP and may not be financially feasible for patients with mild OSA. The FDA recommends using this technique for patients with moderate to severe apnea with an AHI score between 15 and 65.

For phrenic nerve stimulation, the severity of apnea and the proportion of central events are the main considerations. “We generally target patients with moderate to severe sleep apnea where at least 80% of the events are central in nature,” says Gupta.

Implantable nerve stimulation seems to be a reasonably safe method of treatment. In their meta-analysis, Baptista’s team analyzed the number of adverse events related to HGNS. Serious events were documented in 6% of all patients, for whom there was a requirement for surgical repositioning of the device or the replacement of electrodes.

 Minor adverse effects were reported by almost 60% of all patients, including discomfort from electrical stimulation and tongue abrasion due to constant movement. Although these effects were common during the first year of treatment, they reduced in subsequent years.

The meta-analysis for phrenic nerve stimulation showed serious adverse events in 3.9% of all patients. These included hematoma, migraine, and atypical chest pain, which necessitated the removal of the device. Minor adverse effects were reported in about 5.3% of all patients, including device discomfort, dislocation of leads, and lead failure.

 The more severe adverse effects may be avoided by refinements in surgical technique, whereas discomfort mostly resolves with time as the patient gets used to the device.

As the use of nerve stimulators continues to rise, the onus is now on making these devices more efficient and increasing their capabilities. Baptista believes that future research must focus on finding ways to circumvent lateral airway collapse at the palatal level. “We are just at the very beginning,” he said. “In a few years, there will be devices that are much smaller and perhaps capable of stimulating a specific group of fibers that allow airway opening.”

Research into nerve stimulation therapy still has a long way to go. Although prospective studies have illustrated the therapy’s standalone efficacy, there is no research comparing the use of this therapy to CPAP, which is still the gold standard for OSA. Longitudinal studies are also needed to assess secondary outcomes. “We still do not know if phrenic nerve stimulation can reduce morbidity and mortality rates,” Gupta pointed out.

According to Mackay, “Areas that represent the most exciting future investigation are patient preferences, combination therapies, further refinement of implantation and titration techniques, miniaturization of devices, and endophenotyping outcomes in low muscle hyporesponsive-type OSA patients.”

Most physicians are aiming for a more accurate diagnosis and evaluation, prior to wider acceptance of current treatment strategies. “For patients with an appropriate indication, the phrenic nerve pacing procedure can be life-changing,” stated Gupta. However, nerve stimulation has yet to gain wide acceptance. One main barrier, especially in the case of CSA, is the lack of a proper diagnosis. “CSA patients lack traditional symptoms such as snoring and daytime somnolence,” said Gupta, who feels that the only way to improve diagnostic accuracy is to maintain a high index of suspicion. “If you have a patient with heart failure, atrial fibrillation, or stroke who continues to complain of fatigue despite optimal medical therapy, consider the possibility of CSA,” he advised. A sleep study or polysomnogram is the best diagnostic test for sleep apnea and clinicians should recommend it to such patients.

Addressing sleep apnea at a physiological level may reasonably be more effective and have fewer adverse effects than more traditional treatment modalities that may only target one mechanism.

Stimulating the Future of Treating Sleep-Disordered Breathing

Although there have been relatively effective treatments for seizures since 1912, beginning with phenobarbital, the focus on the symptoms of epilepsy rather than the cause means that many patients with difficult to treat epilepsy still long for effective therapies. This is especially the case for autoimmune epilepsy, a under-recognized condition that is often unmanageable with conventional antiseizure medications.

 As a result, a truly “seizure-free” life has remained out of reach for many. This may be set to change as researchers continue to uncover the causes of different types of epilepsy and the mechanisms of action of different treatment modalities.

“Autoimmune epilepsy is essentially a seizure disorder where a neural-specific antibody is present, may be pathogenic, and may cause seizures,” said Lindsay Higdon, MD, a neurologist and epilepsy specialist at Jefferson University Hospital in Philadelphia, Pennsylvania. In one study, experts found that approximately 20% of unexplained epilepsy cases had evidence of circulating neural antibodies, suggesting an autoimmune cause.

 These antibodies can target antigens present on neural surfaces or within the neural cell.

Over the past decade, several neural surface antigens and intracellular antigens have been found and documented in patients presenting with epilepsy, and in 2017, autoimmune epilepsy was officially recognized as a distinct entity by the International League Against Epilepsy.

“There are several clues,” Sarosh Irani, BMBCh MA (Oxon), DPhil, head of the Oxford Autoimmune Neurology Group and associate professor at Oxford University in the United Kingdom, told 

. “These patients often present with an explosive onset, and a higher frequency of seizures than normal.” Most of these patients also present with other features of autoimmune encephalitis, such as memory disturbances, mood changes, and changes in personality. Some patients experience faciobrachial dystonic seizures, which are essentially diagnostic of an underlying antibody.

Patients with autoimmune epilepsy can also show characteristic MRI findings that are consistent with limbic encephalitis. A retrospective cohort study found that such patients usually demonstrated parenchymal atrophy that was disproportionate to age, or T2 hyperintensities in cortical or subcortical regions.

To help clinicians make an early and accurate clinical diagnosis, Divyanshu Dubey, MBBS, and a team of investigators at Mayo Clinic have developed and validated a predictive tool.

 The APE (Antibody Prevalence in Epilepsy of unknown etiology) score takes into consideration the onset and progression of the seizure disorder, clinical signs, and MRI and cerebrospinal fluid (CSF) findings. If the APE score is greater than 4, there is a high chance that the epilepsy is of autoimmune origin.

One of the main hallmarks of autoimmune epilepsy is that it is generally resistant to antiepileptic drugs. In a systematic review of 6 studies that included 169 patients with autoimmune epilepsy, antiepileptic drugs were effective in only 10.7% of cases.

 “Antiepileptic drugs may still be effective in a few cases, but they treat the symptom of the autoimmune condition, and not the cause,” Higdon said.

Once the cause is known, it makes sense to treat autoimmune epilepsy just like other autoimmune diseases—by modulating the immune system. “Along with antiepileptic drugs, we use either steroids, intravenous immunoglobulin (IVIG), or plasma exchange,” Higdon said. “All 3 treatments decrease immune-mediated inflammation in the central nervous system by suppressing or changing the immune system or removing anti- bodies.” Indeed, one study showed that immunomodulatory therapy led to a 19-fold increase in odds of a better seizure outcome, with plasmapheresis (odds ratio [OR], 32.5) proving to be more effective than intravenous steroids (OR, 8.25).

 In another study, about 75% of patients became seizure-free in the 2 months after starting immunotherapies.

Many researchers are exploring IVIG—a concentrate of human antibodies obtained from healthy donors&mdash;as an alternative to steroids and plasmapheresis. Its administration is a simpler procedure compared with plasmapheresis and can help avoid the adverse effects of steroid therapy.

This form of treatment—flooding the body with more antibodies&mdash;may seem counterintuitive. However, IVIG is believed to stabilize and strengthen the immune system. How does this happen? “Currently, no one can answer that accurately, but there are a few hypotheses,” said Irani. “The IVIG possibly saturates the immune system, preventing key causative antibodies like leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 immunoglobulin G (CASPR-2) from functioning. IVIG antibodies could also directly interfere with these antibodies, or with their targets.”

A recent randomized controlled trial conducted at Mayo Clinic provided further evidence that IVIG was effective in reducing seizures in a cohort who met criteria for autoimmune epilepsy.

 Patients who tested positive for LGI1 antibodies and CASPR-2 were enrolled in the study. Of 8 patients enrolled in the IVIG arm, 6 showed more than 50% improvement in seizure frequency compared with none in the placebo group. After 5 weeks, 6 patients in the placebo arm of the trial who had persistent seizures were switched to IVIG; 4 of these then reported more than 50% improvement in seizure frequency. IVIG is still a relatively new treatment strategy and needs more research before it is adopted as the main modality of treatment. “We don’t know how it accesses the central nervous system, and how it affects B cells that produce target antibodies,” Irani said. “Assessing these factors could help identify groups of patients who would respond better to treatment.” Indeed, not all studies have shown favorable results with IVIG. For instance, one study showed a poor response rate in patients who tested positive for antiglutamic acid decarboxylase 65 antibodies (GAD-65); only about 32% of these patients responded to treatment with IVIG.

Higdon clarified that the kind of antibody present could influence response to immunotherapy. “While antibodies to neural surface antigens (such as LGI1 and CASPR2) may respond well to immunotherapy, antibodies to intracellular antigens (like GAD-65) are less responsive,” she said. “This is because these antibodies may not be the cause of seizures, but more an epiphenomenon—a secondary symptom that occurs simultaneously with a condition but is not directly related to it.”

In a retrospective study of 50 patients, researchers showed that those who had antibodies to a neural surface antigen, the voltage gated potassium channel complex antigen, were more likely to become seizure-free compared with patients who had GAD-65 antibodies (

 Notably, those with antibodies to intracellular antigens may benefit from the addition of cytotoxic chemotherapy.

To predict which patients are more likely to respond to immunotherapy, Dubey and his team have also introduced and validated the RITE (Response to Immunotherapy in Epilepsy) score.

 This takes into account all the factors of the APE score, whether immunotherapy was started within 6 months of seizure onset, and, in addition, whether or not a neural antibody has been detected in plasma or CSF. Patients with a RITE score greater than 7 are more likely to respond to immunotherapy.

While IVIG may potentially be more convenient and safer compared with steroids and plasmapheresis, well-designed comparative studies are currently lacking. “Based on my current clinical experience, it is likely that steroids and plasma exchange will prove to be more effective,” Irani said. This opinion is partially shared by Higdon. Often, she said, “the response is transient and there needs to be repeated infusions or more aggressive immunotherapy with cyclophosphamide or rituximab.”

Many patients with autoimmune epilepsy can be successfully managed if a proper algorithm is followed, such as the one suggested by Higdon.

 “The first step, when you deal with a patient who has epilepsy of unknown origin, is to apply the APE score. If it is greater than 4, neural antibody testing should be carried out,” Higdon said. “Immunotherapy should ideally be initiated even before the antibody test results are received, either with steroids or IVIG.” She suggested that plasmapheresis be reserved for patients who fail to respond to previous treatments, or who have severe symptoms. If the antibody tests reveal the presence of an intracellular antigen, tumor screening must additionally be considered.

Of course, this fundamental algorithm does not cover all bases. “The ideal protocol for the duration of treatment and evaluation of response still needs to be developed,” Higdon said. It is also unclear if antiepileptic drugs can be tried again, if immunotherapy fails. In a retrospective study, a small proportion of patients did respond to antiepileptic drugs after immunotherapy had failed.

 The researchers stated that certain antiepileptics, like carbamazepine, also had immunomodulatory properties, and this dual effect could have been responsible for a seizure-free response in a small subset of patients.

Most experts feel that a better understanding of the pathophysiology of autoimmune epilepsy is the way forward. “We are currently focusing on how the B cells produce antibodies, and how these antibodies interfere with target antigens,” said Irani, whose most recent research has focused on exploring the characteristics and pathogenic potential of the LGI1 antibody. Understanding these key mechanisms could pave the way to establishing innovative methods of blocking the antibody effects.

1. Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol. 2017;74(4):397-402. doi:10.1001/jamaneurol.2016.5429

2. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. doi:10.1111/epi.13709

3. Fredriksen JR, Carr CM, Koeller KK, et al. MRI findings in glutamic acid decarboxylase associated autoim- mune epilepsy. Neuroradiology. 2018;60(3):239-245. doi:10.1007/s00234-018-1976-6

4. Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017;58(7):1181-1189. doi:10.1111/epi.13797

5. Cabezudo-Garci&#769;a P, Mena-Va&#769;zquez N, Villagra&#769;n-Garci&#769;a M, Serrano-Castro PJ. Efficacy of antiepi- leptic drugs in autoimmune epilepsy: a systematic review. Seizure. 2018;59:72-76. doi:10.1016/j. seizure.2018.05.004

6. Thompson J, Bi M, Murchison AG, et al; Faciobrachial Dystonic Seizures Study Group. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348-356. doi:10.1093/brain/awx323

7. Dubey D, Britton J, McKeon A, et al. Randomized placebo&#8208;controlled trial of intravenous immunoglob- ulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol. 2020;87(2):313-323. doi:10.1002/ana.25655

8. Li TR, Zhang YD, Wang Q, et al. Intravenous methylprednisolone or immunoglobulin for anti-glutamic acid decarboxylase 65 antibody autoimmune encephalitis: which is better? BMC Neurosci. 2020;21(1):13. doi:10.1186/s12868-020-00561-9

9. Feyissa AM, Lo&#769;pez Chiriboga AS, Britton JW. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e353. doi:10.1212/NXI.0000000000000353

10. Higdon LM. Autoimmune epilepsy. Practical Neurology. October 2018. https://practicalneurology. com/articles/2018-oct/autoimmune-epilepsy 

Could expanding insights into the pathophysiology of autoimmune epilepsy offer seizure-free hope for patients?

Unraveling Autoimmune Epilepsy

Four decades ago, a biological diagnosis of Alzheimer disease (AD) was possible only postmortem. Clinicians had to make a diagnosis on the basis of cognitive impairment and behavioral changes, typically when the patient had already progressed to late-stage dementia.

 However, advancements in the understanding of AD pathology have led investigators to believe that circulating biomarkers carry the potential to revolutionize early diagnosis of AD. It all began with the development of neuroimaging techniques in the early 2000s, which enabled the visualization of a diseased AD brain, revealing abnormal protein plaques and neurofibrillary tangles.

Interneuronal plaques contain an aggregation of amyloid-β (Aβ) peptides. These are formed by the sequential proteolytic processing of glycoproteins called amyloid precursor proteins. However, overproduction and/or reduced clearance may contribute to the aggregation of Aβ oligomers, resulting in the formation of plaques and trig- gering further Aβ overproduction.

 In contrast, tau tangles can form independent of Aβ pathology by the misfolding of microtubule- associated tau proteins, leading to their aggregation within neurons.

 Interestingly, Aβ and tau protein aggregation-mediated synaptic loss and cell death predate the development of cognitive symptoms by more than 2 decades, raising questions about the cause-effect relationship.

Currently, clinicians use a combination of MRI/ positron emission tomography (PET), psychological tests, and assessments to diagnose AD and track disease progression.6 However, the degree of pathologic change is not always the same in all subjects, and some uncertainty remains regarding how much change defines the disease.

 This complex and heterogenous pathology has hindered the elucidation of the onset, progression, and sequence of events in AD.

The detailed neurophysiological evaluations required for AD diagnosis place undue burden on resource-limited health care systems.

 Furthermore, cognitive examinations are subject to bias and may be incorrectly scored because of lack of training.

 Although PET and MRI scans can reveal AD neuropathology with high accuracy, their invasive nature and high costs place these diagnostics out of reach of many patients visiting primary care centers.

“Diagnosis earlier in the disease process means that a person may benefit more from new treatments once they become available,” said Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association in Chicago, Illinois. “Even in the absence of such treatments, dementia that is early and accurately diagnosed can be managed with current drug and nondrug interventions, whereas undiagnosed dementia cannot.” A growing consensus among experts is that biomarkers in the blood and cerebrospinal fluid (CSF) may facilitate early diagnosis, even before symptoms of dementia manifest.

Biomarkers Aβ1-42, phospho-tau (P-Tau), and total-tau (T-tau) in the CSF reflect 3 distinct pathologies associated with the AD brain: Aβ aggregation (A), neurofibrillary tangles (T), and neurodegeneration (N), respectively.15 The Aβ peptide Aβ1-42, which comprises

42 amino acids, aggregates in the AD brain, leading to their decrease in the CSF. In contrast, neurofibrillary tau tangles accumulated in neurons are released by neurodegeneration into the CSF, leading to increasing tau concentrations in patients with AD.16

CSF measurements of Aβ42, T-tau, and P-tau 181 accurately differentiate patients with AD from cognitively healthy individuals and those with some other neurodegenerative dementias.

“Biomarkers assessed in the CSF support the early detection, diagnosis, and classification of Alzheimer disease even at the prodromal stage, with a sensitivity and specificity of more than 85%,” Harald Hampel, MD, PhD, MSc, MA, chief medical officer at Eisai Inc in Woodcliff Lake, New Jersey, told 

®. “In addition, CSF biomarkers represent a reliable tool for the prediction of cognitve decline in cognitively healthy older adults and individuals with subjective cognitive decline, a known risk factor for Alzheimer disease.” Interestingly, a study of individuals carrying dominantly inherited AD mutations showed that CSF biomarkers were upregulated 10 to 15 years before the first symptoms of dementia.

 Furthermore, in a longitudinal study that analyzed aging participants without dementia, those with A+ T+ N+ (amyloid/ tau/neurodegeneration abnormality [+]) displayed the most rapid decline in cognitive memory.

Based on these findings, the National Institute on Aging and the Alzheimer’s Association have proposed a research framework for the diagnosis of AD using an AT(N) scale (

“Several studies have demonstrated that the plasma Aβ1-42 to Aβ1-40 ratio performs well in indicating the presence of brain amyloidosis [as assessed using PET scanning] in AD, even during prodromal/ preclinical stages,” Hampel said.

The Aβ1-42 to Aβ1-40 ratio has recently been suggested to further improve diagnostic accuracy and show a better concordance with amyloid-PET positivity. A potential explanation for this result is that Aβ1-40 serves as a proxy for “total” Aβ production, with the ratio normalizing for differences in basal Aβ production between individuals or normalizing for between-individual differences in CSF/ plasma dynamics or preanalytical confounders affecting both Aβ1-42 and Aβ1-40.

 Study results have shown that plasma Aβ42 and Aβ40 is nearly as accurate as PET imaging, with several patients who displayed abnormal ratios going on to develop AD symptoms within 5 years.

 Plasma T-tau protein concentrations detected using novel immunoassay techniques have also successfully differentiated between controls and patients with AD.

 More recently, plasma P-tau was found to be progressively increased in preclinical AD, mild cognitive impairment, and AD dementia. Furthermore, the values correlated with CSF P-tau measurements and tau PET.

Characterization of amyloid plaque aggregation in the AD brain has also led to the discovery of apolipoprotein in these peptide clusters. The discovery of apolipoprotein and associated dysregulation in lipid metabolism has elucidated associations among AD, cardiovascular disease, hypertension, insulin resistance, and diabetes.

Apolipoprotein aggregation results from a distinct mutation in the APOE gene; the &#603;4 allele of APOE is the most significantly associated mutation with AD, as verified in American, European, and Australian cohorts.

 A more recent study also confirmed that life-long exposure to APOE (resulting from APOE muta- tion) led to an increased risk of dementia.

 The Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) found that subjects carrying the &#603;4 allele of APOE who had mild cognitive impairment showed a greater decline in cognitive abilities.

 Therefore, sequencing of this allele could help identify high-risk cohorts, aiding early diagnosis.

“Other genetic polymorphisms can also interact with APOE, and others like brain-derived neurotrophic factor and Klotho may affect rates of decline,” said Colin Masters, MBBS, MD, of the University of Melbourne in Australia, who leads the Neuropathology and Neurodegeneration Laboratory at The Florey Institute of Neuroscience and Mental Health and who led the AIBL study. “We therefore look forward to the new generations of anti-Aβ therapy, which are looking promising.” Investigators are currently studying in clinical trials novel anti-Aβ monoclonal antibodies including BAN2401 (Eisai and Biogen), aducanumab (Biogen), and gantenerumab (Roche), which are designed to bind and remove Aβ aggregations.

Another exciting biomarker on the horizon is neurofilament light (NfL), a protein building block of axons that accumulate in the CSF following neurodegeneration in the AD brain.

 Furthermore, serum concentrations of NfL correlate with CSF levels, suggesting blood measurements could be used to detect brain pathologies.

 Study results have shown NfL levels to be upregulated even in those patients with dominant AD mutations presenting without symptoms of dementia, indicating that NfL could be an early biomarker of neurodegeneration.

Notably, however, NfL is a general indicator of neurodegeneration, not specific to AD. Still, in primary care settings, NfL could help identify in a noninvasive and cost-effective manner those patients who need further assessment.

From Clinical Trials to Market: What Lies Ahead?

Although these biomarkers look promising, their commercialization and wide adoption hinge on further research. “Accurate blood biomarkers would be a real boon to researchers, clinicians, and the public because of the ease, simplicity, accessibility, and lower cost of administering and evaluating them,” said Edelmayer. “Improvements in sensitivity of the assays have changed the ability to measure some of these markers, even in blood. That said, biofluids are still in a stage of validation. Comparing biofluid data with the gold-standard imaging biomarkers, and correlating them to cognitive and functional abilities, helps to build confidence, standards, and validation of biofluid technologies.”

In this respect, the Alzheimer’s Association is engaged in several efforts, including the Global Biomarker Standardization Consortium, which seeks consensus on the best ways to standardize and validate biomarker tests for use in global clinical practices. Also, the Accelerating Medicines Partnership - Alzheimer’s Disease project—a precompetitive partnership among government, industry, and nonprofit organizations&mdash;is focused on discovering novel, clinically relevant therapeutic targets and developing biomarkers to help vali- date existing therapeutic targets.

Furthermore, assay reliability, replication, and validation by independent studies in diverse cohorts are critical.

 “Among the various recommendations and solutions going forward, the recent development of fully automated assays provides the basis for the development of globally replicable and accepted cutoff points,” Hampel said. “Compared with traditional protocols, fully automated assays significantly minimize critical factors that influence the accuracy and replicability of the test. Eisai, in collaboration with its partners, is currently developing a fully automated assay for measuring Aβ in plasma.”

Investigators may also need to analyze individual variability in biomarker concentrations. “Validating the technologies in diverse populations will be key to driving accuracy and predictability of these technologies,” Edelmayer added.

“One such avenue that has not been sufficiently explored is [sex] differences,” Michelle M. Mielke, PhD, professor of epidemiology and neurology at Mayo Clinic in Rochester, Minnesota, told 

®. “Sex differences can lead to marked effects on the measurement and interpretation of AD biomarkers. For example, the effect of menopause and subsequent use of menopausal hormone therapy on blood and CSF AD biomarkers have not been adequately assessed.”

The modulation of the blood-brain barrier does demonstrate differences in sex.

 “However, the overwhelming majority of studies that examined fluid biomarkers have adjusted for sex,” Mielke said. “This is problematic because adjusting for sex treats it as a nuisance variable,

an unwanted variable that influences the relationship between the independent and dependent variable.” Therefore, landmark studies may have ignored marked differences in sex that influence the interpretation of biomarker levels.

In contrast with the use of single biomarkers, in the future, a panel-based assay that uses a combination of biomarkers may also prove more sensitive in detecting AD. However, inclusion of multiple biomarkers could complicate commercial development, validation, standardization, and FDA approval of these tools and diagnostics. The increased costs of such an assay may also limit widespread adoption.

Hampel suggested a different strategy. “Because the complete clinical development and standardization of blood-based biomarkers will probably take some more years, it is key to leverage the currently available mature validated CSF biomarkers based on lumbar puncture and laboratory analysis for the early detection of AD,” he said. “The main challenge related to CSF biomarkers is a reluctance by many physicians to adopt and perform lumbar puncture procedures because of its perceived invasiveness. However, several large-scale studies have demonstrated a very low incidence of any significant adverse events, particularly in an aging population. The physicians’ perception largely impacts the patient’s willingness to undergo the procedure. We must increase awareness and acceptance of this very practical and useful diagnostic approach on a global level.”

Biomarker discovery is a rapidly growing interest in AD research. Apart from the core markers currently in research (Aβ42, P-tau, and T-tau), a recent meta-analysis found more than 15 validated biomarkers of neurodegeneration, amyloid, and tau pathologies that demonstrate impressive diagnostic performance. Subsequently, the AlzBiomarker database has been developed with clinical data and results from studies of potential biomarkers, with the intention to consistently add new data when they are published.

 With the consolidated efforts of experts from around the world, the neurology community is 1 step closer to the reality of developing a novel blood test for AD diagnosis.

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2. Ferreira LK, Busatto GF. Neuroimaging in Alzheimer’s disease: current role in clinical practice and potential future applications. Clinics (Sao Paulo). 2011;66(suppl 1):19-24. doi:10.1590/S1807-59322011001300003 

3. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25&#8239;years. EMBO Mol Med. 2016;8(6):595-608. doi:10.15252/emmm.201606210 

4. van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020;21(1):21-35. doi:10.1038/s41583-019-0240-3 

Biomarkers in the cerebrospinal fluid and blood could hold the key to early diagnosis of Alzheimer disease.

Nicola Davies, PhD

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