Alzheimer's disease

Cannabinoids: pre-clinical studies on anti-inflammatory and neuroprotective effects in Alzheimer’s disease

 

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

https://neurologybuzz.com/

June 25, 2018

Introduction

Alzheimer’s disease is not a natural progression of senescence. It is a neurological disorder involving deposition of beta amyloid peptides in senile plaques and accumulation of amyloid precursor proteins within the cerebrum particularly in areas affecting memory and cognition. Current pharmaceutic agents at best can only slow the progression of this disorder. There is no cure. Because it not a devastating illness in that it does not decrease the longevity per se, nonetheless, it is devastating to the patient and family members around him or her.

With the advent of cannabinoids into the pharmaceutic fold, attention is turning towards medical value outside its well-known repertory including anti-inflammatory and neuroprotective properties. Can cannabinoids slow the inflammatory process that is involved in this neurodegenerative condition? This seeks to explore mechanisms by which cannabinoids may play a role in ameliorating the clinical effects seen in Alzheimer’s disease.

Endocannabinoid system

As an overview, the endocannabinoids system is found naturally within the body consisting of endocannabinoids, enzymes and receptors. There are 2 receptors the CB1 receptor which is concentrated in the nervous system and found to a lesser extent in other organ systems and the CB2 receptor which is found mostly in the immune system and in other systems.  Anandamide is an endocannabinoid that exerts its actions on the CB1 receptor, while di-arachidonoylglycerol has a low affinity for the CB1 receptor and interacts with the TPRV or transient receptor potential channels of the vanilloid subtype and the G-coupled receptor family.

Within the cannabis sativa plant are 2 most well-studied phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The CB1 receptor is where delta-9-tetrahydrocannabinol (THC), a mimetic of Anandamide, interacts and can cause psychoactive effects. Cannabidiol is a mimetic of di-arachidonoylglyerol with a lower affinity to the CB1 receptor where 100 times the amount of CBD is required to achieve the same psychoactivity as THC. When CBD and THC are combined there are less side effects since the CBD acts as a non-competitive allosteric modulator at the  CB1 receptor. When the 2 are combined there is an effect that is increased together compared to when each cannabinoid is taken alone, where the effect is significantly much different. The presence of CBD offsets side effects of THC. Common side effects include agitation, hyperactivity and paranoia.

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Mechanisms

Senile plaques are found to express CB1 and CB2 receptors within the brain in addition to microglial activation markers. The neurons are rich in CB1 receptors but seem to be greatly reduced in microglial activated areas. CB1 receptor expression and G-related coupled protein are reduced in brains with Alzheimer’s disease. Nitration of proteins are enhanced especially in CB1 and CB2 proteins in Alzheimer’s diseased brains. Adding synthetic cannabinoid WIN55-212-2 to rats caused an inhibition of microglial activation and neuron marker loss. Cannabinoids were found to ameliorate neurotoxicity caused by microglial activation (1).

Another study demonstrates the role of cannabinoids on inflammation in the mouse model using synthetic cannabinoids JWH-133 and WIN55.212-2. Cognition and inflammation were studied. FDG uptake on PET scan  was used to assess areas of metabolic uptake. The amyloid precursor protein mice showed poor object recognition. After administration of the JWH compound, cognitive impairments were reversed. There was reduced FDG uptake in the hippocampal areas. No changes were seen using WIN55.212-2. Beta amyloid proteins were significantly reduced in the mice models when cannabinoids were applied. Microglia was elevated in the APP mice which was reduced after cannabinoid administration (2).

In another mouse study, CB2 receptors were at a low level found in the neurons of unmanipulated mice whereas there was a noted increase in the CB2 receptors in mice that underwent chronic inflammation in the microglia surrounding plaques. This suggests that there is an upregulation of CB2 receptors in the presence of pathological inflammation. This may be a potential target in therapeutic agents in the future (3).

In summary

These pre-clinical studies demonstrate a neuroprotective and anti-inflammatory role of cannabinoids on Alzheimer’s disease. The CB2 appears to be upregulated around activated microglial cells around plaques implying a possible therapeutic target for future treatments. While pre-clinical studies are not human trials, elucidating these mechanisms may play a role in the future therapeutic benefits of cannabinoids on Alzheimer’s disease.

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References

  1. Ramirez, B.G., Blazquez, C., del Pulgar, T.G., Guzman, M., de Ceballos, M.L. Prevention of Alzheimer’s disease pathologyby cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25:1904-13
  2. Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G.,  Cuadrado, A., de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflam. 2012, 9:8
  3. Lopez, A., Aparicio, N., Pazos, M.R., Grande, M.T., Barredo-Manso, M.A., Benito-Cuesta, I., Vazquez, C., Amores, M., Ruiz-Perez, G., Garcia-Garcia, E., Beatka, M., Tolon, R.M., Dittel, B.N., Hillard, C.J., Romero, J. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflam. 2018, May, 15:158
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autism

Medical marijuana: effects on pediatric patients with autism and the developing brain

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

Medical cannabis is being more and more commonly used in medical conditions specifically neurological. The CB1 receptor is found predominantly within the nervous system and in a few other organs on a lesser basis. The CB2 receptor is mainly in the immune system and found in other organs to a lesser extent.

Recent arguments have arisen promoting medical cannabis in children particularly in those with autism and attention deficit hyperactivity disorder.  It has already been well-established in patients with epilepsy. However, the effects on the developing brains of children have not yet been well-documented as it is not yet widely used or studied in the pediatric population. There are many animal models but this does not always correspond to translate into similar human findings.

Effect in autism in animal models and clinical studies

A current topic of debate is not only using THC in pediatric patients but those with autism. Autism is part of the pervasive developmental disorder consisting of social inhibition and isolation including poor eye contact, delayed language skills, aggressive behavior and may be characterized as having stereotypies such as flapping of the arms. Self-injury, eating and sleep disorders may occur. The etiology may be related to genetic, neurobiochemical or environmental and the exact cause is unclear.

In one animal model study, mice with induced Dravet syndrome-like symptoms was noted to improve in autistic-like social interactions with the addition of low dose cannabidiol (2) of 10mg/kg. At low doses, the DS mice interacted more with stranger mice. At higher doses, this was not noted. Dravet syndrome is a type of epileptic syndrome affecting the SCN1A gene causing medically refractory seizures combined with autism.  However, this was an animal model. Scientific studies do not necessarily translate into positive human clinical results.

There was one case report of a six-year-old boy with early autism. Dronabinol  (delta-9-THC) was administered at 3.62mg a day and followed for 6 months. Using the ABC scale (aberrant behavior checklist), the patient improved in terms of stereotypies which were less, lethargy was reduced, hyperactivity improved, and inappropriate speech improved (4).

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Endocannabinoid system and mechanisms in relation to autism

There are several lines of thinking regarding the role of the endocannabinoid and autism. It is thought that the endocannabinoid system plays a role in neurological development, but can also be modulated by outside cannabinoids. Another line of thinking is that autism spectrum disorders may be related to disrupted pathways that have been affected by the endocannabinoid pathway (5). In one animal study, it was found that the oxytocin peptide may be responsible for disrupting normal signaling pathways giving rise to autism spectrum disorders. Oxytocin appears to be crucial in mediating social reward which is impaired in autistic patients. Anandamide seems to play a role in the signaling pathways for oxytocin which is responsible for the social reward.   Social reward is aberrant in those with autism and this pathway thought to play a key role in causing its pathogenesis. By increasing anandamide at the CB1 receptor, ASD and social impairment is improved (5).

Effect on a fetus

Tetrahydrocannabinol is lipophilic and crosses the blood-brain barrier. It can get stored in the fatty stores which are likely the reason it may have a long-lasting effect.  Cannabinoids have been found to cross the placenta and affect the fetus. It may result in hyperactivity and impulsivity in babies with cannabinoid exposure in utero.

 

Effect on early cerebral development

It was found that in adolescents who used cannabis, there is a reduction in the IQ by the age of 38. It was found that cannabinoid receptors influence axonal migrations as well as subcortical projections within the cerebrum. This affects synaptic connections during childhood and adolescence(3).

The adolescent brain is still not fully matured and likely still subject to neuronal plasticity and changes. It may be affected by substances. One study showed that the frontal lobe is vulnerable to cannabis in adolescents who used it heavily and that cannabis use may impact working memory. (1)

 

 

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During adolescence, when cannabis is initiated it may affect the neuronal circuitry developing in the immature brain. The richest regions in the brain with cannabinoid receptors are the prefrontal cortex, medial temporal lobes, striatum, white matter connections, and cerebellum. When cannabis is introduced during this neurocritically important time of development, these regions can become dysfunctional although some functional studies have shown altered, weakened, strengthened or combination of changes (6).

Some of the most common adverse effects

At high doses in chronic users, it was found to induce anxiety, panic attacks. It can increase blood pressure. However, clinically, it may control seizures

 

In summary

There is a small body of evidence from a scientific standpoint that cannabis may work to help alleviate autism-like symptoms based on the animal models. There is a not enough evidence from a clinical evidence standpoint in human studies to support its use in pediatric patients, with one case report that it helped with impulsivity, reduced lethargy, and inattention. Randomized placebo-controlled clinical trials are needed.

Research has found that cannabinoids may help oxytocin and disrupted signaling pathways that play a role in social reward which is impaired in autism. At present, there is evidence that cannabis may affect neurocognitive development but these are studies in pregnant mothers who used it heavily recreationally and adolescents who used it heavily. It is unclear if there may be a similar impact when used in the pediatric population at a medical dosage and administration as there are not enough studies to expound on this.

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Reference

  1. Jager, et al, “Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter fMRI study,” J. Am. Acad. Child Adolesc. Psychiatry, 2010, Jun., 49(6):561-572.
  2. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.. 114 (42):11229-11234.
  3. Scott, et al, “Medical marijuana: a review of the science and implications for developmental-behavioral pediatric practice,” J. Dev. Behav. Ped., 2016, Feb., 36 (2):115-123.
  4. Kurz, et al, “Use of dronabinol  (delta-9-THC) in autism: a prospective single-case study with early infantile autistic child,” Cannabinoids, 2010, 5 (4):4-6.
  5. Wei, et al, “Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment,” Cannabis Cannabinoid Research, 2016, 1(1):81-89
  6. Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.

 

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Epilepsy

Epilepsy surgery in temporal lobe epilepsy due to mesial temporal sclerosis: the timeline in investigative work-up from the neurologist’s office to the O.R.

Virginia Thornley, M.D. Neurologist, Epileptologist

March 27, 2018

Introduction

Temporal lobe epilepsy is one of the most common types of seizures. The most common cause and one of the most successfully treated causes of temporal lobe epilepsy treated through surgery is mesial temporal sclerosis. This article focuses on mesial temporal sclerosis and does not include discussions of other types of temporal lobe epilepsy due to other causes such as tumors, cystic lesions or head injury or non-lesional temporal lobe epilepsy.  In order to identify a patient, the symptoms are generally stereotypical which suggest localizing towards one focus.  An early age of identification may portend a better outcome since frequent temporal lobe seizures may cause the development of circuitry to the opposite side causing another focus to develop on the opposite temporal lobe. In addition, it is important to control temporal lobe epilepsy because of the location of the seizures are in the hippocampus which is important in memory. Many patients complain of poor memory which will continue to progress should seizures remain poorly controlled. Epilepsy surgery is the definitive treatment for temporal lobe epilepsy in mesial temporal sclerosis.

Identification

To identify an appropriate candidate for surgery, the patient should have stereotypical seizures which localize towards one focus. While the focus may cause contralateral clinical symptoms, automatisms of the limb are generally ipsilateral to the focus.  Once a patient has been identified, further diagnostics tests are needed in order to confirm this focus including a routine electroencephalogram and an ambulatory 48-72 hour EEG which can be performed out-patient. The only downfall with an ambulatory EEG is that it is subject to the artifact, since the electrodes may be displaced causing poor adherence of the electrode to the scalp causing resistance manifested as artifact and a poor recording. However, it is still a good screening test to determine whether there may be a single focus versus multiple regions affected. Temporal lobe epilepsy may be seen with high voltage epileptiform spike and wave. It may be accompanied by focal delta slowing within the temporal lobe, suggesting temporal lobe dysfunction due to recurring seizures. If a patient is deemed an appropriate candidate, a referral may be made to an epilepsy center where more in-depth investigations are performed.

 

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Admission to an epilepsy center

Expect to stay at least 1 week or more in order to allow the capture of typical seizures and to obtain an adequate sampling of ictal periods and pinter-ictal periods during wakefulness and sleep. A team of specialists is involved with the work-up including a clinical epileptologist who manages the medications and clinical aspect, a clinical neurophysiologist who interprets the video EEG monitoring and correlates it with the clinical symptoms, a neuropsychologist who performs the WADA testing and a slew of clinical EEG technicians who ensure that the electrodes are properly attached throughout the hospital stay. In-depth conferences are held to review the studies of the patients and evaluate which patients are suitable epilepsy candidates. Sometimes, multiple admissions are necessary before seizures can be captured.

Hospitalization

During admission, seizures are captured and correlated with the electroencephalographic recordings to determine the focus. More than one focus correlates with a poor outcome, a single focus is necessary. The clinician may provoke seizures by tapering medications safely in the hospital setting. Other techniques include sleep deprivation and encouraging any triggers. The full spectrum of clinical seizures must be captured in order to ensure adequate localization. Bitemporal foci portend a poor outcome.

Neuroimaging

A high-quality MRI of the brain using epilepsy protocol with thin cuts through the temporal lobes of 1.5mm to 2mm is essential. Coronal views are the best way to visualize the hippocampi to evaluate for hippocampal sclerosis which characterizes temporal lobe epilepsy. Usually, the hippocampus affected is much smaller than the contralateral one with hyperintensity on T2. As a result of excessive seizures, burning off of the cells in the hippocampus occurs so that is it is now atrophic. Although an MRI of the brain may have already been obtained pre-work-up, a higher resolution and exceptional quality brain MRI is likely to be repeated. This will serve as the visual point on which the neurosurgeon operates. Seeing a sclerotic hippocampus gives a high correlation with mesial temporal sclerosis.

 

Ictal SPECT

Spectroscopy is obtained in-house, where hexamethylpropylenamine oxime (HMPAO) injection is done 30 minutes before an ictus. When the patient has a seizure, the HMPAO perfuses to the area of interest showing where the seizure localizes. Images are obtained. This test has an added value of further localizing the focus. The drawbacks, however, include not being able to predict when a seizure is about to occur and missing the ictus. It is not unusual for this test to be repeated for it to be meaningful. In addition, it can only be done during office hours so that nocturnal seizure will be missed due to lack of adequate staff.

Magnetoencephalography

This is a costly examination which may not be available in some epilepsy centers. It uses a 3-dimensional modality for localizing the focus. The MEG dipoles are superimposed on the MRI images.

WADA testing

A neuropsychologist examines the patient’s memory and language by temporarily putting the opposite side of the brain to sleep through injection of amobarbital into the internal carotid artery. Short-term memory and language are examined. The neuropsychologist must determine that there is adequate memory on the contralateral temporal lobe for temporal lobe surgery to be successful. If both temporal lobes are impaired in terms of memory, the patient will suffer from poor memory following the surgery. Other tests are done by the neuropsychologist to check for cognition, any personality disorders and assess for evidence of mood disorders.

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Electrocorticography

This is one of the final steps in the investigation where the cranium over the temporal lobe of interest is removed and electrodes are placed directly on top of the cerebrum. Depth electrodes are placed in order to capture epileptiform discharges buried deep inside the hippocampus which cannot be adequately detected by electrodes laying on top of the temporal lobe. The seizures are recorded and a more accurate mapping of the seizure focus is obtained.

Discussions

Once all the appropriate investigations are obtained, if all the data points towards a single focus then the patient is deemed an appropriate candidate. Epilepsy conferences are usually held and reviewed by all the specialists involved in the care. Some patients may proceed directly into surgery after mapping. Others may need to go home and return back for another admission to undergo epilepsy surgery. A patient who is still questionable may need to return for more in-depth recording, this may occur in non-lesional epilepsy where the information is not strong enough to justify surgery. The goal of epilepsy surgery is to resect the dysfunctional epileptogenic zone while preserving the functioning surrounding cortex.

After care

Once the surgery is performed, the patient will need to be on anti-epileptic agents for at least 2 years of seizure freedom. In appropriately investigated patients, a favorable outcome of seizure freedom may reach as high as 60%.

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Alzheimer's disease

Alzheimer’s Disease: Living with Alzheimer’s Disease

By Virginia Thornley, M.D., Neurologist
February 15, 2018

Introduction
Alzheimer’s disease is a neurodegenerative disorder affecting memory. It is thought to be caused by progressive loss of cells that control memory and cognition. A substance called acetylcholine is secreted which enhances memory, cognition, and attention. In Alzheimer’s disease, a destructive process occurs in the brain cells with accumulation of plaques composed of beta-amyloid. When this destruction of acetylcholine-producing cells occurs then there is less of the acetylcholine which is necessary for transmitting signals that control memory, attention, and cognition. Risk factors include the presence of certain genes such as the APOE gene.

Keeping Mentally Fit
Engaging in activities that involve the thought processes such as doing crossword puzzles, reading engaging books or novels or doing soduko puzzles may help boost the

 

13887115_10154408543428841_2788314143123562305_n (1)neural connections. The more brain cells are utilized the more their capacity is exercised. This is the reason why those in mentally rich occupations where lifelong complex decision-making skills are made, Alzheimer’s disease is not detected until later stages because the brain was constantly engaged for decades. Engaging in conversations, being social by going out and talking to people increase neural connections. Appreciating the arts, going to the theater engaging your brain will help boost neural connections.

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Talking to neighbors or even buying at the convenience store activate mental processes. Engaging in listening, comprehending and speaking during conversations and interactions also sustain rich neural connections.

Someone sitting at home all day long will perform significantly worse than someone who is actively out and about speaking and engaging. The old adage use it or you lose it rings true.

Staying healthy
It is always a good idea to stay fit and active, even more so when diseases affecting the brain are present. Diseases that affect and constrict the small blood vessels will also affect the end terminal cells.  Therefore, high blood pressure, high cholesterol and diabetes mellitus which all affect small vessels can also cause small blockages in blood flow to the brain. This does not help with Alzheimer’s disease. Consulting with a physician is helpful to ensure that any risk factors are under control.

Cues to help remember
A medicine box helps with memory. Bringing a friend or relative to doctors’ appointments helps with not forgetting medical advice. Writing a list helps with tasks that need to be done for the day. Placing medicine by the toothpaste helps with remembering to take important medications. Writing down doctors’ appointments and placing on the refrigerator in bold letters is another good idea. Little things may be remembered by using cues such as these. However, if forgetting extremely important details such as turning off the stove, leaving the water running or not locking the door at night occur, living alone is not feasible. Supervised living conditions are appropriate. Consult with a physician who can direct towards the correct resources and assistance.

Discussing long-term issues
If a loved one has been diagnosed with Alzheimer’s disease, it is a good time to get affairs in order. It is a difficult topic to discuss but it is the optimal time to formulate long-term plans, while preferences are known. If the disease is progressing such that decline is imminent resulting in greater supervision, steps to come up with long-term plans for care are beneficial.

Another subject which is difficult to broach are wishes in the event anything happens and preferences in the hospital for resuscitation. There are many families who come together during an event such as this only to sadly discover that this topic was never discussed. This results in lengthy discussions during an already trying and emotional time. Preparation for the future is key.

Consult with a neurologist
At this point in time, there are no medications that cure Alzheimer’s disease. Generally speaking, some may slow the progression depending on the severity and can enhance the availability of acetylcholine. Ongoing research continues.

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