dementia

Animal study demonstrating CBD’s (cannabidiol) effects on neuroplasticity and memory loss

Virginia Thornley, M.D.
Neurologist, Epileptologist
August 26, 2019
In an animal study, one group demonstrates that Cannabidiol may help with the neuroplasticity in patients with Alzheimer’s disease (1).
LTP in the hippocampus is the long-term potentiation seen that elevates the efficacy of synapses involved in memory. Beta-amyloid peptide is toxic towards this  feature. When animals were pretreated with CBD the neurotoxicity was found to be reduced against beta-amyloid peptide. The same study showed that it did not involve the 5-HT1a, CB1 or adenosine receptors (1).
There have been other previous studies showing that cannabidiol could have protective effects against the toxic effects of beta-amyloid peptide which is involved in the neurodegenerative process seen in Alzheimer’s disease.
More clinical randomized control trials are needed. Animal studies do not always translate into human studies.
Neurologybuzz.com
References
  1. Hughes, B., Herron, C.E., Cannabidiol reverses deficits in hippocampal LTP in a model of Alzheimer’s disease. Neurochem. Res. 2019, Mar. 44(3):703-713

This is medical information not medical advice. Please consult with your physician.

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cannabidiol

How does cannabidiol (CBD) help with skin disorders

Virginia Thornley, M.D.
Neurologist, Epileptologist
April 3, 2019
Introduction
Cannabidiol has been in the news lately blown up by the media as the miracle cure. You see anecdotal information that it works for various conditions. The research has been slow since it was previously a  schedule 1 agent and is now declassified. Attention is now turned to the different conditions where it might work including dermatologic disorders. But what are the mechanisms?
 
Mechanisms how cannabidiol might work in dermatologic disorders.
Melanogenesis occurs as  protection from dangerous factors such as UV radiation exposure. In one study,  cannabidiol increases MITP or microphthalmia associated transcription factor through one pathway involved in MAPK (mitogen activating protein kinase) phosphorylation of p38 as well as p42 MAPK.
Potential effects on acne vulgaris
Cannabidiol was found to reduce the multiplication of sebocytes, the cells in the sebaceous glands by activating the TPRV channels (transient receptor potential of vanilloid). It reduces the production of the oily substances from the skin. It controls inflammation by inhibition of the NF-kB signalling
Potential effects on psoriasis
Cannabinoids are found to reduce proliferation of cancer cells in cell lines in some studies. One study sought to study reduction of keratinocytes in an inflammatory condition such as psoriasis. It was found it can reduce the proliferation but may not contribute significantly to the process.
References
  1. Kim, M.O., Kang, M., Oh, S.W., Nho, Y.H., Park, S.H., Lee, J., Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact 2017, Aug;273:107-114
  2. Olah, A., Toth, B., Borbiro, I, Sugawara, K., Szoliosi, A.G., Czifra, G., Pal, B., Ambrus, L., Kloepper, J., Camera, E., Ludovici, M., Picardo, M., Voets, T., Zouboulis, C.C., Paus, R., Biro, T. Cannabidiol exerts sebostatic and anti-inflammatory effects on human sebocytes, J. Clin Invest. 2014 Sep; 124(9):3713-24
  3. Wilkinson, J.D., Williamson, E.M. Cannabinoids inhibit keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J. Dermatol. Sci 2007 Feb; 45(2):87-92
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cerebral atrophy

Can anti-psychotic agents reduce brain volume?

Virginia Thornley, M.D.
Neurologist, Epileptologist
July 10, 2019
Can medications cause cerebral atrophy. Cerebral atrophy refers to shrinkage of the cells causing the appearance of the brain to have less volume than usual.
This question was asked last week. An anti-epileptics such as phenytoin is well-known in the literature and clinically to cause cerebellar atrophy. But what about other agents such as anti-psychotics?
Animal studies
In one animal study, exposure to anti-psychotic drugs showed a reduced volume of brain on volumetric studies. The number of cells remained the same but the volume was increased for cells in the anterior cingulate gyrus which is in the  limbic lobe. The limbic lobe subserves emotions and has influence on memory. Animal studies do not always correlate with human responses.
Human studies
One small study showed that the thalamic volume was reduced after olanzepine administration. This was a small study of 10 patients (2).
While there is some information in the literature, the studies are animal studies and a small human study. More information is needed. Based on the current literature, there are not enough significant studies to correlate atrophy with use of anti-psychotics.
Neurologybuzz.com
References
  1. Vernon, A.C., Crum, W.R., Lerch, J.P., Chege, W., Natesan, S., Modo, M., Cooper, J.D., Williams, S.C., Kapur, S. Reduced cortical volume and elevated astrocyte density in rats chronically treated with anti-psychotic drugs-linking magentic resonance imaging findings to cellular pathology. Biol Psychiatry. 2014, Jun. 15, 75(12):982-90
  2. Khorram, B., Lang, D.J., Kopala, L.C., Vandorpe, RF.A., Rui, Q., Goghari, V.M., Smith, G.N., Honer, W.G. Reduced thalamic volume in patients with chronic schizophrenia after switching from typical anti-psychotic medications to olanzepine. Am J sychiatry. 2006, Nov. 163 (11):2005-7
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dementia

Can anti-cholinergics cause dementia?

Can anti-cholinergics cause dementia?
Virginia Thornley, M.D., Neurologist, Epileptologist
July 1, 2019
In one study, they found that anti-cholinergic agents shows an increased risk of dementia. In the study, certain anti-depressants and urologic agents were found to correlate more with the risk of dementia including dosulepine, duloxetine and amitriptyline for the anti-depressants and tolteridine and oxybutinin for the urologic agents (1).
There are thoughts that there is a risk of dementia even 2 decades after the exposure. Certain anti-Parkinson’s agents were found to possible correlate with dementia. Anti-cholinergic agents have consistently been associated with problems with short-term memory.
Neurologybuzz.com
Reference
1.Richardson, K., Fox, C., Maidment, I, Steel, N., Loke, Y, Arthur, A., Myint, P., Grossi, C., Mattishent, K., Bennett, K., Campbell, N., Boustani, M., Robinson, L., Brayne, C., Matthews, F., Savva, G. Anti-cholinergic drugs and risk of dementia: case-control study, BMJ, 2018; 361
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multiple sclerosis, Uncategorized

The impact of immunomodulating agents used in multiple sclerosis on the risk of cancer

Virginia Thornley, M.D., Neurologist, Epileptologist
June 14, 2019
Introduction
Multiple sclerosis is already an illness where the immune system recognizes the nervous system specifically the white matter tracts as foreign and attacks it. The complex cascade of mechanisms make adequate treatment challenging. Many treatments focus on the inflammatory mechanism with little attention on the degenerative mechanism involved.
Presentation of symptoms come in a wide variety depending on the the location of the multiple sclerosis plaque in the brain.
Patients may have concomitant morbidities which may make treatment challenging.
 
Immunomodulating agents and its impact on cancer
Many of the newer treatments for multiple sclerosis work at the level of the immune system through immunosuppression, the newer ones tend to be very potent. With greater efficacy comes greater risks including the risk of cancer.
Some of the newer medications can potentially increase the risk of cancer. Higher risk of cancer was found in many reports to occur with use of cyclophosphamide, azathioprine and mitoxanthrone. Fingolimod, natalizumab and alemtuzamab  can potentially increase the risk of cancer, these agents lack long-term data and work through the immune system. Dimethyl fumarate, terifluonimide, ocrelizumab, daclizumab and cladribine merit mandatory risk management plans to detect cancer before its use.
Reference
  1. Lebrun, C., Rocher, F., Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs. 2018, Oct. 32(10):939-949 doi:10.1007/s40263-018-0564-y
Disclaimer: This is medical information only not medical advice. Please consult your physician
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cerebellar ataxia

Genetics of Hereditary Cerebellar Ataxia and Hereditary Spastic Paraplegia

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 18, 2019
Introduction
Cerebellar ataxias are rare disorders, only a few types are treatable. This reviews some of the research regarding the genetics of cerebellar ataxias.
Next generation sequencing is a revolutionary way of DNA sequencing that can sequence an entire genome in one day which previously took 10 years. Clinical applications are still pending (1).
Genetics of hereditary cerebellar ataxias
In one study of 87 patients, the genetics were studies. In the probands meaning the first in a genetic line, triplet repeat testing was done. 58% were male. Genetic variants included ANO10, CACNA1A, SPG7 and DRKCG. The detection rate in probands for the trinucleotide repeat was about 13.8%. Those with variants may have a longer duration of disease and a slower progression of the disorder (2).
 
Genetic testing in hereditary spastic paraparesis
In another study where 306 were genetically tested, next generation sequence testing was performed and different genes were found. These include ATL1 (atlastin 1, SPG3),
PAST (spastin, SPG4),  ITPR1, WASHC5 (SPG8),  KIF1A (SPG30), SPG11 spastacsin), KIF5A (SPG10), CYP27A1, and SETX (3).
There are overlapping genetics and clinical symptoms with spinocerebellar ataxia and amyotrophic lateral sclerosis.
Reference
  1. Behjati, S., Tarpey, P., What is next generation sequencing? Arch Dis Child Educ Pract Ed. 2013 Dec; 98(6)236-238
  2. Kang, C., Liang, C., Ahmad, K.E., Gu, Y., Siow, S.F., Colebatch, J.G., Whyte, S., N, K., Cremer, P.D., Corbett, A.J., Davis, R.L., Roscioloi, T., Cowley, M.J., Park, S.J., Sue, C.M., Kumar, K.R. High Degree of Genetic Hetereogeneity for Hereditary Cerebellar Ataxias in Australia, Cerebellum, 2019, Feb. (1):137-146
  3. Elert-Dobkowska, E., Stepniak, I., Krysa, W., Ziora-Jakutowicz, K., Rakowicz, M., Sobanska, A., Pilch, J., Antczak-Marach, D., Zaremba, J., Sulek, A. Next-generation sequencing reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes. Neurogenetic, 2019, Feb, doi:10.1007/s10048-019-00565-6
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Sleep

Does chronic sleep deprivation affect cognition in shift workers?

Virginia Thornley, M.D.
Neurologist, Epileptologist
March 6, 2019
Introduction
What is the impact of sleep on cognition of shift workers?
 
Does circadian misalignment have impact on cognition?
Those with circadian misalignment such as night shift workers are most affected in terms of sustained attention, visual-motor performance and processing of information(1).
CAA11F12-A957-4FAF-B74D-6C7D2CE6E613
 
One study sought to clarify the relationship of circadian cycle misalignment with cognition. It found that on the first night of shift work, attention is markedly impaired which improves after the same schedule is followed. This did not hold true for areas in visual-motor or cognitive throughput. Cognitive throughput means the summation of data going through a network.
Declarative memory is stable while attention was greatly impacted. This may be because memory is not impacted by areas where the sleep-wake cycle is important.
 
Mechanism

It is thought that there is increased GABAergic tone at night which could depress cognition. The natural circadian rhythm allows for maximum cognitive abilities during the daytime. . This is when we get our peak performance. The worse time for vulnerabilities in cognition occurred in the hours between 4-6am(1).
The neurobiology is thought that lack of sleep at night affects the conduction of nerves including the local potential field which affects neuronal activity. This results in reduced reaction time and speed for visual motor performance and tasks requiring sustained attention (2).
Reference
  1. Chellappa, S.L.,Morris, C., Scheer, F.A. Effects of circadian misalignment on cognition in chronic shift workers. Sci. Rep., 2019, 9:699. published online 2019 Jan 24. doi: 10.1038/s41598-018-36762-w
  2. Nir, Y., Andrillon, T., Marmelshtein, A., Suthana, N., Cirelli, C., Tononi, G., Fried, I. Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med. 2017, Dec: 23(12)1474-1480
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