Alisa G. Woods, PhD

People with Alzheimer disease and even mild cognitive impairment may be dangerous to themselves or others on the road. Assessments of driving ability could be useful for evaluating whether or not people with impaired cognition should in fact drive at all.

A new study out of Toronto provides more information about driving ability in the cognitively impaired and how it can be assessed. The recent report appeared in the Journal of Alzheimer’s Disease.

The investigators, led by Megan Hird of the Neuroscience Research Program, St. Michael’s Hospital, Toronto, Canada, wanted The scientists performed a systematic review of the literature and meta-analysis of driving assessment methods. These included actual on-road driving, cognitive tests, and driving simulations. They assessed the predictive ability of the tests as well as specific areas of driving impairment in these individuals.

The review and meta-analysis included a total of 32 articles, including 1,293 subjects with Alzheimer disease, 92 subjects with mild cognitive impairment, and 2,040 healthy controls. Researchers used several different outcome measurements to test for driving ability, including on-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior.

The study authors identified several statistically significant predictors of driving performance. These included global cognition, visuospatial function, attention, and executive function. Two tests were the most effective for predicting driving performance: the Trail Making Test part B and the Maze test. In the Trail Making Test part B, a subject is required to connect alternating encircled numbers and letters. The test measures visual attention and the ability to switch tasks. In the Maze test a subject draws through mazes of increasing complexity, without back-tracking. It is designed to measure planning and foresight.

The scientists further discovered that even people with very mild Alzheimer disease are more likely to fail a driving test compared to healthy control subjects.

Overall, Hird and colleagues concluded that, “The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients.”

Although the meta-analysis and systematic review provides some information about driving ability and cognition, more studies with greater specificity are still needed. For example, the effect of mild cognitive impairment on driving is not yet clear, possibly because studies of driving tend to focus more on Alzheimer disease-notable by the lower total subjects with mild cognitive impairment assessed in this meta-analysis compared to those with Alzheimer disease.

The authors also suggest that specific subject characteristics need to be assessed, namely “Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and [mild cognitive impairment] (amnestic, non-amnestic, single-domain, multiple-domain).”

Further prospective clinical trials may aid in the development of cognitive tests that can assess whether or not an impaired individual should drive. According to the American Academy of Neurology (AAN) 

, a mini mental State Exam of 24 or less can indicate risk for unsafe driving. AAN guidelines also note that caregivers may be best to assess whether or not an individual with Alzheimer should drive. Future studies may concentrate on the predictive ability of direct cognitive tests, along with caregiver assessments.

A systematic review and meta-analysis of on-road simulator and cognitive driving assessment in Alzheimer's disease and mild cognitive impairment

Articles

Investigators questioned whether cognitive tests could predict driving ability in people with Alzheimer disease and mild cognitive impairment.

Driving with Cognitive Impairment

A new study from researchers in Texas and Alabama suggests that a busy lifestyle in older adults could help improve and sustain memory. The research report appeared in the journal 

Prior research suggests that performing mentally challenging tasks can help older adults retain memory, but what about those individuals who are busy as part of their general lifestyle?

“We were surprised at how little research there was on busyness, given that being too busy seems to be a fact of modern life for so many,” noted Denise Park, one of the study authors.

Led by Sara B. Festini of the School of Behavioral and Brain Sciences, University of Texas at Dallas, the investigators wanted to test the effects of an engaged lifestyle on cognition. They studied 330 adults between the ages of 50 to 89 who were participants in the 

 The DLBS is a large research project that aims to study the healthy brain in adults, in the decades from age 20 to 90. More than 500 individuals enrolled in the study, and they are evaluated every four years.

In this particular sub-analysis of the DLBS, subjects completed several tests, including of working and long-term memory, reasoning, and crystallized knowledge (such as vocabulary). The cognitive tests were given over 2 days, in 2- to 3-hour sessions per day.

Martin and Park Environmental Demands Questionnaire (MPED)

. This is a self-report instrument designed to measure day-to-day events experienced by adults between the ages of 35 to 84. The busyness assessment included questions such as “How busy are you during an average day? How often do you have too many things to do each day to actually get them all done? How often do you have so many things to do that you go to bed later than your regular bedtime?” Participants rated each question on a scale of 1-5.

Overall, Festini and colleagues found that greater busyness corresponded with better cognition.  They measured the greatest effects for episodic memory; including knowledge of events, times, and places. Busy individuals also had better processing speed for memory, and superior working memory, reasoning, and crystallized knowledge.

The correspondence of busyness and better cognition was consistent in adults of all ages, from 50-89. Other research studies have shown that new learning retains neurons in the hippocampus, which the authors suggested as one possible mechanism for the results observed. The hippocampus processes episodic memory in particular, as well as the transition of short-term to long-term memory.

The authors noted, however, that the results are a correlation, so it is not clear whether busyness improves cognitive or if people with better mental abilities tend to engage in more activities. In their published report they noted “Although correlational in nature, these results are in line with an engagement framework, and they have implications for the usefulness of engagement training programs. Additional experimental work should be conducted to determine if manipulations of busyness influence cognition in a similar manner.”

Future studies from this research group may focus on whether cognition improves in people who increase their activity and which types of activities are most useful.

Festini and colleagues emphasized the likely benefits of an active lifestyle, noting “Overall, our findings offer encouragement to maintain active, busy lifestyles throughout middle and late adulthood.”

The busier the better: greater busyness is associated with better cognition

Did an active schedule help or hinder cognitive skills such as memory, reasoning, and crystallized knowledge in a group of adults aged 50-89 years?

Does a Busy Lifestyle Improve Memory?

In a mouse model of stroke, Johns Hopkins researchers have found that intrinsic nervous system repair mechanisms could allow mice to recover more quickly. Specifically, mice partially lost the use of their front paws following an initial stroke, but were able to successfully grab food pellets after a second stroke.

The research appeared in the online journal 

The scientists first trained animals to perform a grasping task then gave them a stroke using photocoagulation. After 7 days, the animals were retrained in the reaching task, for a total of nineteen days. The animals did not fully recover, and were given a second stroke. The researchers then retrained the animals in the reaching task after only one day post-recovery, for a total of nine days. The animals fully recovered to normal performance following the second stroke.

The findings build upon the idea that neurons may have more plasticity, i.e., capacity for repair in adulthood, than previously believed.

The authors noted in their report that the findings in no way suggest that inducing a stroke is a viable treatment option. However, the findings do open up the intriguing possibility that the nervous system has intrinsic repair mechanisms that could be exploited. If the mechanisms mediating repair after a second stroke could be uncovered, this might open up new avenues for stroke treatments and for the prevention of neural damage following stroke.

“If we can better understand how to reopen or extend the optimal recovery period after a stroke, then we might indeed change how we treat patients for the better,” remarked Steven Zeiler, MD, PhD, in a press release. Zeiler is an assistant professor of neurology at the Johns Hopkins University School of Medicine. “Our study adds new strong and convincing evidence that there is a sensitive period following stroke where it’s easiest to relearn motor movements - a topic that is still debated among stroke researchers” he added.

The research is a follow-up to a prior Johns Hopkins study, which identified the first seven days as the optimal recovery time following induced stroke in mice.

 However, in this study the scientists were able to extend the stroke recovery window by giving animals the antidepressant fluoxetine right after the stroke. Because fluoxetine works as a serotonin reuptake inhibitor, the effects observed could be due to actions on the serotonergic system.

The antidepressant increased the animals’ ability to learn the same pellet-grabbing task. However, the study did not show that it could be possible to reopen the learning period. These new results suggest that learning can indeed occur again.

In their study report, the investigators concluded “New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.”

The research could have implications for recovery of function in individuals who have suffered more than one stroke. However, at present the results have only been observed in an animal model. Further investigations of recovery of function following stroke and the mechanisms underlying it need to be conducted in humans.

Paradoxical motor recovery from a first stroke after induction of a second stroke: reopening a postischemic sensitive period

. Neurorehabil Neural Repair. 2015 Dec 31.

Research in mice shows potential value of common antidepressant in stroke victims too sick for immediate rehab

New research in a mouse model could have implications for recovery of function in individuals who have suffered more than one stroke.

Can Stroke Initiate New Neurological Repair Mechanisms?

Researchers at Brigham and Women’s Hospital (BWH) and the National Institute of Neurological Disorders and Stroke (NINDS) have initiated a new project to identify those at risk for multiple sclerosis (MS).

“By focusing on first-degree family members of MS patients, the research team seeks to better understand the sequence of events that leads some people to develop the disease. Their work also sets the stage for developing and testing interventions with which to block the onset of MS.”

The scientists introduced the Genes and Environment in Multiple Sclerosis (GEMS) project via a new report published in the Annals of Neurology.

 The investigators will assess risk using both genetic and environmental assessments in 2632 first-degree relatives of people with MS residing in the United States.

“This first report from the GEMS study is important because it shows that we can recruit the large number of family members that is necessary to perform a well-powered study of MS risk factors,” noted first author Zongqi Xia, PhD, of BWH’s Ann Romney Center for Neurologic Diseases.

In the initial analysis, the researchers found a subset of family members that may be at higher risk for MS. The risk factor assessment could help identify those individuals who might be most likely to develop MS, although further work is needed to refine the MS risk algorithm.

“Early detection of MS means the possibility of earlier treatment, which could delay the accumulation of disability,” remarked author Phil De Jager, MD, PhD, Director of the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH. “Our long-term goal is to map out the sequence of events leading from health to disease, in order to be able to identify and intervene early in individuals at high-risk of MS,” he added.

Recruitment has been accomplished through both patient advocacy groups including the National Multiple Sclerosis Society, as well as through Facebook. A 

 has been set up as well, through which the public can gain information about the study. A total enrollment of 5000 first-degree relatives is planned, with the project continuing for the next 20 years.

Several measurements are being collected for the study, including a medical history questionnaire, family history, and exposures from the environment, as well as saliva collection for DNA analysis.

“Since the disease likely starts many years before the first symptom appears, we do not yet understand how genetic and environmental risk factors come together to trigger MS,” stated co-senior author Daniel Reich, MD, PhD, of the Division of Neuroimmunology and Neurovirology at the NINDS. “When a patient comes to see a neurologist for the first time, the process of brain inflammation is well underway, since many lesions have few or no symptoms.”

The initial report and overall project could greatly help in assessing risk and facilitating prevention of MS.

“This report is an important first step. We do not yet have a tool that we can use clinically to predict MS. To develop such tools further, and to develop a platform for testing strategies to prevent the disease altogether, we are expanding GEMS into a larger collaborative study that will accelerate the progress of discovery and bring together a community of investigators to overcome this important challenge,” says De Jager. “Overall, the risk of MS remains very small for most family members. The most effective therapies for MS will ultimately be those that prevent its onset, as halting inflammation and disease progression are much more difficult once the disease has become established.”

Genes and environment in multiple sclerosis project: a platform to investigate multiple sclerosis risk

2. EurekAlert. Predicting who will develop multiple sclerosis. 8 Feb 2016. 

http://www.eurekalert.org/pub_releases/2016-02/bawh-pww020816.php

By studying first-degree relatives of patients with MS, can researchers perfect a risk algorithm for the disease?

Predicting Multiple Sclerosis Risk: GEMS Project

Much recent news has focused on the Zika virus and the neurological problems it may cause. What are the risks, and what precautions should be taken by neurologists?

Zika virus spreads through mosquito bites, specifically 

 mosquitos, a variant typically found in the Americas, including portions of the USA. Symptoms of infection include fever, rash, pain in the joints, and conjunctivitis, rarely severe enough to require hospitalization. About 80% of those infected through mosquito bite experience no symptoms at all. However, some people infected with Zika may develop Guillian-BarrÃ© syndrome, an autoimmune disease that can cause weakness and even paralysis. The link between Zika and Guillian-BarrÃ© is not yet clear.

Although the symptoms of Zika-related illness are typically mild or non-existent, neurological consequences for unborn infants of mothers infected with Zika can be severe. Infants can develop birth defects including microcephaly. Transmission from mother to child is intrauterine; no transmission via the breast milk has been documented so far.

In Brazil, cases of microcephaly have roughly doubled in 2015, potentially due to Zika outbreak.

 The first report of Zika infection in Brazil occurred in March of 2015. Although it was initially unclear whether or not a link existed between Zika infection and birth defects, on February 1, 2016, the World Health Organization announced an International Public Health Emergency, based on the “spike in cases of microcephaly and Guillian-BarrÃ© syndrome in the Americas.” An emergency committee “agreed that a causal relationship between Zika infection during pregnancy and microcephaly is strongly suspected, though not scientifically proven.”

Countries in which active infection has been reported include Mexico, several countries in Central and South America, American Samoa, Samoa, Tonga, and Cape Verde, Africa. A full list of those countries with active Zika transmission can be found on the 

The Centers for Disease Control and Prevention (CDC) developed recent guidelines to aid US-based healthcare providers treating infants at risk for Zika virus infection.

 The CDC recommends Zika virus testing for those mothers at risk, which means anyone who has been in areas with ongoing Zika virus transmission during pregnancy, even if they never had symptoms of Zika infection. This includes reviewing fetal ultrasounds for microcephaly or intracranial calcifications and maternal testing for Zika virus infection. If maternal Zika infection is confirmed, the CDC recommends fetal ultrasounds every 3-4 weeks.

Infants with cranial abnormalities including microcephaly and intracranial calcifications should also be tested for Zika virus infection. Healthcare providers need to contact state or territorial health departments to record the infection. Testing for Zika virus infection is performed both through molecular and serologic testing, including “reverse transcription-polymerase chain reaction (RT-PCR) for viral RNA, and immunoglobulin (Ig) M ELISA and plaque reduction neutralization test (PRNT) for Zika virus antibodies” according to the CDC.

As of February 3, 2016, 35 Zika virus cases have been reported in the United States, and no locally-acquired cases. There is no vaccine or medicine that can prevent Zika infection.

People travelling to, or residing in, areas with active Zika infection should be advised to wear long pants, long-sleeved shirts, and permethrin-treated clothing, and use insect repellents to avoid mosquito bites.

1. Dyer O. Zika virus spreads across Americas as concerns mount over birth defects. BMJ 2015;351:h6983. 

2. World Health Organization. Latest Zika situation report. Feb 5, 2016. 

http://www.who.int/emergencies/zika-virus/situation-report/en/

3. Interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection - United States, 2016. Centers for Disease Control and Prevention. Jan 29, 2016. 

http://www.cdc.gov/mmwr/volumes/65/wr/mm6503e3.htm

4. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak - United States, 2016. Centers for Disease Control and Prevention. Jan 22, 2016. 

http://www.cdc.gov/mmwr/volumes/65/wr/mm6502e1.htm

Although not scientifically proven, there is a strong causal relationship between Zika infection and two severe neurological disorders.

Neurological Consequences of Zika

Consumption of legal marijuana and cannabis-containing products is on the rise in the United States, due to new laws allowing medical and recreational use in several states. Medicinal use of marijuana also appears to be increasing in Europe. With more marijuana and cannabis use, as well as better control of the active ingredients found in marijuana, people may want to have a greater understanding of how much cannabis they can safely use. Psychiatrists may also want to advise their patients who use recreational or medicinal cannabis about how much is too much, or whether any use is advisable.

Some researchers propose that the use of cannabis can cause psychosis.

 A research group based in Italy and the UK conducted a recent study looking at the association between high potency cannabis as well as frequency of use and possible damage to the corpus callosum.

 The corpus callosum is the large white matter tract connecting the two cerebral hemispheres. They also examined whether there is a relationship between white matter damage, cannabis use, and psychosis. The scientists used a brain-imaging technique called diffusion tensor imaging tractography to examine the corpus callosum in people with first episode psychosis who did or did not use cannabis compared to cannabis users with no history of psychosis.

The study subjects included a total of 56 people with first episode psychosis, of which 37 were cannabis users, and compared them to 43 cannabis users without any history of psychosis. All of the study subjects completed a survey that assessed whether or not they used cannabis, how often they used cannabis, and what kind of cannabis they used. This included questions about low-potency, defined as “hash-like,” and high potency, defined as “skunk-like.” According to the researchers, “skunk-like” cannabis is known to contain higher content of r Î9-tetrahydrocannabinol, the active ingredient found in marijuana.

To measure corpus callosum damage, they looked at a property known as mean diffusivity. This is a way to determine the extent of existing white matter lesions in the brain.

Overall, the investigators found that those individuals who used higher potency cannabis had more white matter lesions in their corpus callosum when compared to users of the less potent forms of cannabis. Daily use was also associated with a corresponding increase in white matter lesions, as measured by mean diffusivity. The most posterior part of the corpus callosum showed the greatest effects. Surprisingly, these changes were similar in cannabis users regardless of whether or not they had a psychotic disorder. The researchers did not find an association between cannabis potency and psychosis, or frequency of use and psychosis.

Overall, the study authors concluded that “Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.”

The study results suggest that cannabis use may have detrimental effects on the brain, and in particular the corpus callosum. It seems unlikely, however, that psychosis is related to corpus callosum damage in these individuals. Further studies will hopefully focus on possible effects of cannabis on causing psychosis, possibly due to an impact on different brain areas. In addition, it would be of interest to understand what physiological effects other than psychosis may be caused by damage to the corpus callosum in cannabis users.

Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users

. Schizophr Bull. 2014 Nov;40(6):1509-1517.

Effect of high-potency cannabis on corpus callosum microstructure

. Psychol Med. 2015 Nov 27:1-14. [Epub ahead of print]

Is there an association between high potency cannabis as well as frequency of use and damage to the corpus callosum?

Cannabis and the Corpus Callosum

A new study from the University of Wisconsin offers promising results for the eventual treatment of disorders characterized by serotonin deficits. Researchers were able to transform human stem cells into neurons that produce the neurotransmitter serotonin. The study appeared online in the journal 

Serotonin neurons are found in the raphe nucleus of the hindbrain. They are important for regulating many activities, including sleep, mood, aggression, cognition, satiety, and autonomic functions. These cells are also implicated in several psychiatric disorders, including depression, schizophrenia, bipolar disorder, anxiety disorders, and chronic pain. The generation of serotonin neurons in vitro could allow researchers to more easily study these cells, and also presents the enticing possibility that serotonin neurons might be generated for use as brain cell replacements in the future.

“Serotonin essentially modulates every aspect of brain function, including movement,” remarked principal investigator Su-Chun Zhang, in a press release.

Led by Jianfeng Lu of the Waisman Center, University of Wisconsin, Madison, the researchers who conducted the study were interested in differentiating human pluripotent stem cells (hPSCs) into neurons that specifically produce serotonin. To accomplish this, they exposed the cells in vitro to both WNT and sonic hedgehog.

WNTs aid in the development and placement of serotonin neurons in the brain. Sonic hedgehog is another molecule that controls the development of embryonic cells.

Zhang noted “Here, we had to instruct the stem cells to develop into one specific fate, using a custom-designed sequence of molecules at exact concentrations. That's especially difficult if you consider that the conditions needed to make serotonin neurons are scarce, existing in one small location in the brain during development.”

The investigators noted that the cells they induced using WNT and sonic hedgehog resembled serotonin neurons in several ways. They expressed tryptophan hydroxylase, which is crucial for the development of serotonin neurons and also had electrical characteristics identical to those typically measured for serotonin neurons. They released serotonin when treated with tramadol or escitalopram, drugs known to increase extracellular serotonin.

Although other studies have shown some induction of serotonin neurons from stem cells, the current report is by far the most robust and the most convincing.

Lead author Lu noted “Previously, labs were producing a few percent of serotonin neurons from pluripotent stem cells, and that made it very difficult to study their cells. If you detect 10 neurons, and only two are serotonin neurons, it's impossible to detect serotonin release; that was the stone in the road.”

Ultimately, the cells may be used for many purposes, including testing new medications. Zhang remarked “We think these can help develop new, more effective drugs, especially related to the higher neural functions that are so difficult to model in mice and rats, particularly because they are from humans, these cells may lead to benefits for patients with depression, bipolar disorder or anxiety. These are some of the most troublesome psychiatric conditions, and we really don't have great drugs for them now.”

Generation of serotonin neurons from human pluripotent stem cells

Other studies have shown some induction of serotonin neurons from stem cells, but a recent study presents by far the most promising results.

Generating Serotonin Neurons

Much research into brain repair processes focuses on neurons and ways to restore their function or prevent their loss. Glial cells, however, are the often neglected cousins that nevertheless make up most of the cells in the brain. A new study suggests that astroglia can actually be recruited to differentiate into neurons.

The groundbreaking discovery may ultimately be used to restore lost neurons in neurodegenerative diseases such as Alzheimer or Parkinson. It could present an alternative to conventional stem cell therapy, harnessing the body’s own cells to treat disease, but potentially without the need for invasive surgery.

Gong Chen, Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University, led the research effort. Five of Chen’s students, led by Lei Zhang, examined many different combinations of molecules before coming up with the solution that could transform astroglia into neurons.

"We have discovered a cocktail of small molecules that can reprogram human brain astroglial cells into neuron-like cells after eight-to-ten days of chemical treatment," Chen remarked in a press release issued by Penn State University. The researchers describe the contents of the complicated mixture in greater detail in the research report which appeared online in the journal 

The cells lived for up to five months in culture-far longer than the typical lifespan of neurons in a dish. The cells also formed neuronal synapses and circuits that were physiologically functional. The scientists transplanted the newly-formed neurons into mice, where they survived for up to a month.

Using molecular biology techniques, the researchers were able to determine that the astroglial reprogramming occurred due to dampening of glia-specific genes and via the activation of factors that are specific to neurons, called neuroD1 and neurogenin 2.

"These chemically generated neurons are comparable to normal brain neurons in terms of firing electric activity and release of neurotransmitters," Chen pointed out. "Importantly, the human astroglial-converted neurons survived longer than five months in cell culture and longer than one month in the living mouse brain after transplantation."

Chen imagines that ultimately the mixture might be used in a pill form. "The small molecules are not only easy to synthesize and package into drug pills, but also much more convenient for use by patients than other methods now being developed," Chen noted.

He acknowledges, however, that the drug cocktail does require extensive further study in humans. In particular, the components could have general systemic effects on other organs that need to be understood.

Chen and his collaborators have high hopes for the new technology. He remarked "Our dream is that, one day, patients with brain disorders can take drug pills at home to regenerate neurons inside their brains without any brain surgery and without any cell transplantation. Our invention of the small-molecule cocktail helps us to make a huge step closer to that dream."

Hopefully the research can advance beyond animal studies, to the long process of human trials, potentially providing a new avenue for much-needed new treatments of neurological conditions.

• Astrocytes can be converted into functional neurons.

• Factors responsible for neuronal differentiation of astrocytes block glia-specific genes and activate neuroD1 and neurogenin 2.

• Astrocyte differentiation into neurons may be used to treat neurological conditions in the future.

Small molecules efficiently reprogram human astroglial cells into functional neurons

. Cell Stem Cell. 2015 Oct 13 [Epub ahead of print]

A groundbreaking discovery may lead to repair of neurodegenerative diseases such as Alzheimer and Parkinson.

Transforming Glial Cells 

Danish and German scientists have identified impaired cytokine interferon-Î² (IFN-Î²) signaling as a possible molecular trigger for Parkinson disease dementia, as well as the related neurodegenerative disorder, Lewy body dementia. Correcting deficits in IFN-Î² via gene therapy may one day provide a treatment for these neurodegenerative diseases.

Parkinson disease is characterized by tremor and rigidity, caused by loss of basal ganglia dopaminergic neurons and marked by the presence of Lewy bodies-aggregated protein deposits containing alpha-synuclein. Dementia is another characteristic of later stages of the disease. Lewy body dementia shares overlapping characteristics with Parkinson disease. The two disorders are more distinct in earlier stages, since Parkinson is characterized by movement symptoms initially, while dementia occurs earlier in Lewy body disease.

The research report appeared in the prestigious journal 

. According to the study, IFN-Î² is responsible for neuronal homeostasis and cellular clean-up, and the absence of the cytokine could trigger neurodegenerative disease.

Led by Patrick Ejlerskov of the University of Copenhagen, the researchers studied mice that lacked IFN- Î², known as 

 mutant mice. The animals had impairments in both cognitive function and in movement, as measured by a water maze and RotaRod test, both standard behavioral tasks. The scientists used immunostaining of the mouse brain to identify the presence of Lewy bodies in the brain containing the characteristic protein alpha-synuclein. Surprisingly, they also found a reduction in dopamine neurons in the substantia nigra as well as impaired dopamine neuronal signaling-hallmark signs of Parkinson disease.

According to the study authors, the alpha-synuclein and Lewy body accumulation are the consequence of “late-stage autophagy.” Autophagy is a mechanism for cleaning up the cell. The process degrades proteins, organelles, lipids, and aggregates of protein and is a critical homeostatic process for the neuron.

“We found that IFN-Î² is essential for neurons’ ability to recycle waste proteins. Without this, the waste proteins accumulate in disease-associated structures called Lewy bodies and with time the neurons die,” noted Ejlerskov in a press release.

As a final stage of the study, the scientists tested the effects of corrective gene therapy in a rat model of Parkinson disease induced by injecting human alpha-synuclein into the rat substantia nigra. They used a lentivirus to over-express IFN-Î² in one group of the Parkinsonian  rats while another control group received the lentivirus only, as a sham treatment. The animals without the corrective gene therapy developed problems with autophagy and accumulation of several proteins in the brain, including alpha-synuclein. The animals with IFN-Î² overexpression did not have these problems. The gene therapy also protected dopamine neurons in the substantia nigra and improved movement problems in the animals. The scientists concluded in their manuscript “We showed that Ifnb gene therapy reversed pathology in a familial PD model, by promoting autophagy and a-syn clearance, which preserved DA neurons and associated neurologic deficit.”

Not only did this research study identify a possible new animal model for Parkinson disease and Lewy body dementia, but it the results also suggest a potential new avenue for gene therapy in these neurological conditions.

In a press release, principal investgator Shohreh Issazadeh-Navikas remarked, “This is one of the first genes found to cause pathology and clinical features of non-familial PD and DLB, through accumulation of disease-causing proteins. It is independent of gene mutations known from familial PD and when we introduced IFNÎ²-gene therapy, we could prevent neuronal death and disease development. Our hope is that this knowledge will enable development of more effective treatment of PD.”

Lack of neuronal IFN-Î²-IFNAR causes Lewy body- and Parkinson’s disease-like dementia

The discovery of a possible trigger for PD and Lewy body dementia could provide a new avenue for gene therapy in these neurological conditions.

Parkinson and Lewy Body-like Dementia Triggers

Marcel was 25 years old, living and working in Manhattan. The son of Algerian immigrants, Marcel had grown up in a suburb of Boston. Three years after his graduation from a small, private college in New England he was employed by a major communications firm. The company hosted a retreat at a hotel, consisting of structured group activities during the day and impromptu partying at night. A co-worker offered Marcel ecstasy, and he figured “why not?” He had taken psilocybin, also called “magic mushrooms” twice in the past. Three hours later Marcel found himself in the emergency room, unable to see. The ER physician was at a loss of what to do and simply had Marcel stay in the hospital for observation. Fortunately, the blindness resolved in a few hours, and Marcel was sent home. In the 20 years following the incident, however, some of the symptoms have persisted.

Now age 45, Marcel currently suffers from near constant anxiety. He dislikes going out, preferring to stay at home with dim lighting since visual stimuli are simply far too intense. A visit to an optometrist could not confirm any physical reason for his problems. When asked about his symptoms Marcel remarked, “I see what appear to be floaters in my vision which follow a predictable pattern when I move my eyes. It's like semi-translucent dark swirls, almost like seeing heat coming off a car hood in summer. Afterimages of light linger longer than they should. It seems as though the left side is worse than my right side. There is also a link to stress when seeing this phenomenon, which seems to increase visual, which feeds into the anxiety portion of this condition.”

Drinking makes symptoms worse, so Marcel refrains from alcohol. Although the visual symptoms are the most troubling, he also suffers from tinnitus. Visits to a variety of physicians, ranging from primary care to neurologists, resulted only in more confusion. Marcel noted that the doctors seemed frustrated. Ultimately, Marcel began to do his own research, finding one of the few specialists in hallucinogen persisting perception disorder (HPPD), a condition that is recognized in the DSM-5. According to a survey study, about 4% of recreational drug users experience HPPD-like symptoms.

The physician confirmed that Marcel’s symptoms are characteristic of HPPD, which can be caused by a variety of drugs, including LSD, ecstasy, psilocybin, and cannabis. He prescribed Sinemet (carbidopa-levodopa) and then later tried Wellbutrin (bupropion). Although some individuals with HPPD benefit from these medications, they had no effect on Marcel. There is no approved treatment for HPPD, so all prescribed drugs are used off-label. He also received Prozac (fluoxetine) at one point, which according to Marcel, “didn’t make a dent.”

Dr. Henry Abraham of the Department of Psychiatry, Tufts Medical School, has researched and treated the condition for many years.

 He is considered an expert in this field. He discussed HPPD and its treatment in an interview with 

. Dr. Abraham noted “there’s a tremendous lack of understanding of this condition and a tremendous lack of awareness.” He and colleagues have discovered several things about the little-studied disorder, including that it indeed has a specific neurobiological basis, characterized by occipital disinhibition and increased coherence when the eyes are closed.

 Coherence refers to hypersynchrony of brain waves.

Abraham has also found that medications that increase dopamine activity can help. He recently noted that about a third of 20 patients treated with Sinemet and tolcapone showed improvement in HPPD symptoms. Each patient served as his own control, but the study was not blinded or randomized, limiting the certainty of the finding.

 He speculates that these agents, which increase dopamine activity, “facilitate the focusing, increase pre-pulse inhibition, and filter out visual noise.”

Unfortunately, the condition can be misdiagnosed as schizophrenia, with negative consequences for patients. According to Abraham, “HPPD patients often have been given dopamine blockers which makes the condition worse…it anything they’re traumatized by the healthcare system rather than helped by it.”

Greater recognition and ruling out other conditions is criticalas a first step, according to Abraham. This includes first considering tumors, multiple sclerosis, temporal lobe epilepsy, Lyme disease, and other chronic central nervous system infections. Barriers to treatment include a lack of recognition of the condition, and stigma against those who have inflicted neurological damage to themselves, even if unwillingly. There is also a feeling of helplessness among some physicians that HPPD is untreatable and irreversible.

According to Abraham about half of those with HPPD will fully recover over five years. In addition, treating the comorbidities can actually help alleviate the core HPPD symptoms, since anxiety and depression appear to trigger the hallucinations. Benzodiazepines “can be helpful by reducing anxiety, which then decreases reactivity to environmental stimuli,” he noted. Clonazepam seems to be the most effective.

He also advises non-medication approaches for those suffering from HPPD, specifically 1) incorporation of an activity that requires intense focus in one’s life and 2) psychotherapy. “HPPD is largely a peripheral visual system problem, so it helps to maintain a fovealized life,” advises Abraham. “Cultivate something that requires focus and attention.” He gave the example of a patient who became a martial arts expert, which greatly reduced, though did not eliminate, her HPPD symptoms. Although it has not yet been empirically studied for this use, cognitive behavioral therapy (CBT) may also help.

When asked whether or not his symptoms have gotten better over time, Marcel replied “it changes…better in some ways but worse in others. My images in the left eye have gotten worse. Tinnitus started years later.” Overall Marcel feels that his life would have been quite different if he hadn’t developed HPPD, and wishes more professionals would take an interest in HPPD, noting “the future is lacking any concrete hope without research. That feeling is universal among those who have it.”

Hopefully, greater awareness of HPPD can lead both to prevention and effective treatment of this greatly unrecognized medical problem.

Names and details regarding Marcel have been changed to protect anonymity.

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Explore a case study and discussion with an expert on hallucinogen persisting perception disorder, a rare persisting visual condition.