Revealing the invisible rhinoceros: paying attention to adult ADHD

Adult attention deficit hyperactivity disorder (ADHD) is a key psychiatric disorder. It is characterised by some core clinical features which are hyperactivity, inattention, impulsivity, disorganisation, and low stress tolerance. People with ADHD have several life impediments that characterise their day-to-day lives; these include difficulty starting tasks, struggling to prioritise, and failing to pay attention to details. Enduring chaotic lifestyles, they struggle to keep up with their academic, employment, and relationship commitments.

ADHD. Practical Cures on Flickr. https://www.flickr.com/photos/practicalcures/23280349432

For the public and for most physicians, ADHD is recognised only as a childhood disorder. But 10-60% of childhood onset ADHD persist into adulthood. Furthermore, about 4.5% of adults have ADHD. The failure to recognise ADHD as an adult problem therefore means it is easily missed in adult psychiatry and neurology clinics. Referring to this in a review published in the journal Psychiatry (Edgmont), David Feifel labelled adult ADHD as the invisible rhinoceros (you must read the article to understand why it is not the elephant in the room). Concerned that many adults with ADHD are misdiagnosed as suffering with anxiety or depression, he urged psychiatrists to routinely screen for adult ADHD in every adult presenting with these disorders.

Southern White Rhino. William Murphy on flickr. https://www.flickr.com/photos/infomatique/34467891470

The scale of the failure to diagnose adult ADHD was emphasised by Laurence Jerome in a letter to the Canadian Journal of Psychiatry. Titled Adult attention-deficit hyperactivity disorder is hard to diagnose and is undertreated, his letter highlighted the finding of the US ADHD National Comorbidity Survey which concluded that most adults with ADHD have ‘never been assessed or treated’. He argued that this oversight places heavy lifetime burdens on adults with ADHD such as impaired activities of daily living, academic underachievement, poor work record, marital breakdown, and dysfunctional parenting. A great burden indeed, but a preventable and treatable one!

ADHD. Bob on Flickr. https://www.flickr.com/photos/contortyourself/5016270276

How is all this psychiatry relevant to the general neurologist? Well, many manifestations of ADHD are the stuff of the neurology clinic. Cognitive dysfunction for example is prevalent in adult ADHD, and it may present to the neurologist as impaired short term memory, executive dysfunction, impaired verbal learning, and, of course, impaired attention. Sleep related disorders are also frequent in adult ADHD, and these include excessive daytime sleepiness (EDS), restless legs syndrome (RLS), periodic leg movements of sleep (PLMS), and cataplexy. There are also several other neurological co-morbidities of adult ADHD such as epilepsy and learning disability.

ADHD. Jesper Sehested on Flickr. https://www.flickr.com/photos/153278281@N07/38447999522

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It is therefore high time for neurologists and psychiatrists to reveal the invisible rhinoceros!

How bright is the future for Alzheimer’s disease?

Alzheimer’s disease (AD) is scary. It is the most prevalent cause of dementia, and the name strikes terror, especially to those with a close family history of the condition. It is disturbing when a person loses the concept of ‘self’. It is devastating when parents fail to recognise their children.

Any progress in finding the cause or the cure for this neurodegenerative disease should therefore be celebrated. Following on my previous post, Alzheimer’s disease: a few curious things, here are my top 10 breakthroughs giving hope for Alzheimer’s disease.

Deep brain stimulation (DBS)

By Andreashorn - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40251125
By AndreashornOwn work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40251125

 

I have waxed lyrical on the widening influence of neurostimulation in the context of epilepsy, stroke and vagus nerve stimulation (VNS). I was however taken aback by the potential role of deep brain stimulation (DBS) in dementia. This headline from Alzheimers.net reports the Benefits of Deep Brain Stimulation for Alzheimer’sand refers to a study published in eLife. This doesn’t sound a very ‘peer-reviewed’ source, but the title is scientific enough: Ventromedial prefrontal cortex stimulation enhances memory and hippocampal neurogenesis in the middle-aged rats. I should warn you here that most of the studies in this post involve furry little creatures! The study reports that chronic electrical stimulation of the brain increases the activity of memory-related genes, and this in turn increases the number of memory nerves in the hippocampus. Alzheimers.net puts it bluntly-Using Deep Brain Stimulation to Create New Brain Cells.

Iron-reducing treatments

By Vaccinationist - PubChem, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=43392593
By VaccinationistPubChem, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=43392593

 

Based on a premise that high brain iron levels are related to the pathology in Alzheimer’s disease, researchers have looked at iron reducing therapies. This isn’t a new idea because an article in Lancet from 1991 was titled Intramuscular desferrioxamine in patients with Alzheimer’s disease. This study showed that the progression of Alzheimer’s disease could be slowed down by reducing the iron levels in the brain. New Scientist has brought this therapeutic strategy back into contention in its article titled Iron levels in brain predict when people will get Alzheimer’s. The article tantalisingly refers to a link between high iron levels and ApoE4, a gene associated with Alzheimer’s disease. Watch this space.

Ultrasound therapy

By Unknown - Popular Science Monthly Volume 13, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11085835
By UnknownPopular Science Monthly Volume 13, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11085835

 

New Alzheimer’s treatment fully restores memory function, so blares this headline in Science Alert. It refers to a study in mice which shows that focused therapeutic ultrasound stimulates microglia, the cells responsible for clearing the brain’s waste products. The paper, published in Science Translational Medicine, is titled Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. The authors report that that by clearing amyloid, this technique restored memory in about 75% of mice models of Alzheimer’s disease. Human trials must surely beckon.

Dampening amyloid production

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12274694
By NephronOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12274694

 

The idea of dampening the production of amyloid comes from the discovery of a new chemical pathway in the brain; I didn’t realise there were any more pathways left to discover! My ignorance was dispelled by this article in MNT titled A newly discovered molecular feedback process may protect the brain against Alzheimer’s. The article discusses WAVE-1, a protein which is central to a pathway involved in ß-amyloid production. How could scientists could suppress this pathway and improve the clearance of ß-amyloid? By somehow enhancing an inhibitory feedback loop thereby reducing WAVE-1 production. The scientific details are published in Nature Medicine titled APP intracellular domain–WAVE1 pathway reduces amyloid-β production

Monoclonal antibodies

B0007277 Monoclonal antibodies Anna Tanczos. Wellcome Images images@wellcome.ac.uk http://images.wellcome.ac.uk
B0007277 Monoclonal antibodies
Anna Tanczos. Wellcome Images
images@wellcome.ac.uk
http://images.wellcome.ac.uk

 

It would be surprising if monoclonal antibodies did not crop up in this post, being the rage in many other diseases. The monoclonal antibody raising hopes in Alzheimer’s disease is Solanezumab. I came across this in Russia Today (yes…RT) in an article titled Alzheimer’s breakthrough? First ever drug found that may slow disease. ‘First ever’ is obviously hype, but there does seem to be some benefit of Solanezumab, even if this is restricted to those with early disease.  The phase 3 trial of Solanezumab, called EXPEDITION 3, will study this effect further. More hope, less hype!

Boosting the brain’s immune system

B0007277 Monoclonal antibodies Anna Tanczos. Wellcome Images images@wellcome.ac.uk http://images.wellcome.ac.uk
B0007277 Monoclonal antibodies
Anna Tanczos. Wellcome Images
images@wellcome.ac.uk
http://images.wellcome.ac.uk

 

Microglia, the brain’s waste disposal cells, also play a key role in it’s immune system. In this way they protect the brain from damage by ß-amyloid. This immune function is however countered by EP2, a prostaglandin receptor protein found on the surface of the microglia. In other words EP2 functions to restrict the activity of the microglia. Researchers have now shown that the nuisance effect of EP2 could be blocked, as reported in an article titled Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models, and published in Journal of Clinical Investigation. Enhancing the activity of microglia therefore raises hope for the treatment for Alzheimer’s disease… if it could be translated to humans.

Neurotrophic factors

Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382
Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382

 

What if we could boost the activity of cells that have not yet been affected by Alzheimer’s disease? An experimental drug called J147 might just do that. According to researchers, J147 is a neurotrophic drug which enhances nerve activity in mice. The research, appropriately published in the journal Aging, shows that J147 improves cognitive function in mice which have been modified to age fast. The article is titled A comprehensive multiomics approach toward understanding the relationship between aging and dementia. I personally prefer the headline in Neuroscience News which simply says Experimental Alzheimer’s Drug Slows Clock on Key Aspects of Aging. Too soon to speculate, but could we be talking age reversal here? Perhaps competition for klotho.

Enhancing proteasome activity

By User:KGH - User:KGH, <a href="http://creativecommons.org/licenses/by-sa/3.0/" title="Creative Commons Attribution-Share Alike 3.0">CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=552918
By User:KGHUser:KGH, <a href=”http://creativecommons.org/licenses/by-sa/3.0/&#8221; title=”Creative Commons Attribution-Share Alike 3.0 
“>CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=552918

 

We can’t get too far away from waste clearance in this post. This time it’s a drug called Rolipram which seems to enhance the brains waste disposal system. It does this by increasing the activity of proteasomes. Neuroscience News describes a proteasome as ‘a hollow, cylindrical structure which chews up defective proteins into smaller pieces that can be recycled into new proteins needed by a cell‘. The scientific paper is published in Nature Medicine titled Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. The authors show that Rolipram also reduces the levels of tau, another toxic product involved in Alzheimer’s disease. For an easier read see the Neuroscience News article titled Slowing Alzheimer’s by Speeding Up Brain’s Waste Disposal.

Gene therapy

There is no getting away from it, and gene therapy had to crop up in this post. And yes, it may have a role in the future of Alzheimer’s disease. Researchers genetically treated 10 Alzheimer’s disease patients using nerve growth factor (NGF) gene, and then waited and waited, …and then studied the brains of the subjects. They reported their findings the Journal of the American Medical Association (JAMA) under the title Nerve Growth Factor Gene Therapy Activation of Neuronal Responses in Alzheimer Disease. The details of the study are rather complicated, but it appears the nerve growth factor treatment triggered nerve growth. Doesn’t sound like rocket science but imagine the potential. I only wished they had used a more straightforward title. I prefer the layman’s version in The Guardian simply titled Gene therapy rescues dying cells in the brains of Alzheimer’s patients. Scientific journals really need better headline writers!

Reprogramming astroglia

A cocktail mixture which transforms the brain’s supporting cells into proper nerve cells? Not science fiction it seems. A group of scientists have developed a mixture which could reprogram glial cells into functional brain cells. I came across this in Neurology Times under the title Transforming Glial Cells. For a change, the original research paper is well headlined; it is published in Cell under the title Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. The authors show that the cocktail of nine small molecules do the trick by inhibiting glial pathways and activating neuronal pathways. And this all happens within 8-10 days! Too good to be true? Hopefully not.

 

Looking for more? Here are 13 headlines to further raise the spirits of people with Alzheimer’s disease:

Please share your thoughts

Are magnets transforming neurological practice?

The armoury of the neurologist is traditionally a cocktail of tablets and injections. The neurosurgeons and neuroradiologists seem to have all the fancy gadgets. This may however be changing with techniques that are gradually creeping into neurological practice. One such technique is transcranial magnetic stimulation (TMS). This is a non-invasive method of stimulating specific parts of the brain using a magnetic field generator or coil.

"Transcranial magnetic stimulation" by Eric Wassermann, M.D. - Wassermann, Eric. Transcranial Brain Stimulation. Behavioral Neurology Unit. National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States Department of Health and Human Services. Archived from the original on 2013-10-29. Retrieved on 2013-10-29.. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Transcranial_magnetic_stimulation.jpg#/media/File:Transcranial_magnetic_stimulation.jpg
“Transcranial magnetic stimulation” by Eric Wassermann, M.D. – Wassermann, Eric. Transcranial Brain Stimulation. Behavioral Neurology Unit. National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States Department of Health and Human Services. Archived from the original on 2013-10-29. Retrieved on 2013-10-29.. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Transcranial_magnetic_stimulation.jpg#/media/File:Transcranial_magnetic_stimulation.jpg

 

The classical neurological application of TMS is in the treatment and prevention of migraine. The role of TMS in migraine has been fairly well-studied although the impact on symptoms is modest. There is however enough evidence to convince the National Institute of Health and Care Excellence to issue NICE guidelines on TMS. These, as expected, prescribed hope and caution in equal measure.

A potential application of TMS is in Parkinson’s disease. A recent systematic review and meta-analysis in JAMA Neurology is fairly convincing that TMS improves the motor symptoms of Parkinson’s disease

"Basal ganglia in treatment of Parkinson's" by Mikael Häggström, based on image by Andrew Gillies/User:Anaru - Derivative of File:Basal ganglia circuits.png. Licensed under CC BY-SA 3.0 via Commons - https://commons.wikimedia.org/wiki/File:Basal_ganglia_in_treatment_of_Parkinson%27s.png#/media/File:Basal_ganglia_in_treatment_of_Parkinson%27s.png
“Basal ganglia in treatment of Parkinson’s” by Mikael Häggström, based on image by Andrew Gillies/User:Anaru – Derivative of File:Basal ganglia circuits.png. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:Basal_ganglia_in_treatment_of_Parkinson%27s.png#/media/File:Basal_ganglia_in_treatment_of_Parkinson%27s.png

What of TMS as a cognitive enhancer? I came across the report that TMS may boost memory in Gizmag. OK it’s not a neurology journal but it made a more exciting headline than the original study published in Science  under the elusive title targeted enhancement of cortical-hippocampal brain networks and associative memory. In simple language, TMS may enhance the neural networks in the hippocampus, the brains memory hub. Whilst the study was carried out in people with normal memory, there are implications for cognitive disorders such as Alzheimer’s disease if the potential and promise of TMS are realised.

"Magnet0873" by Newton Henry Black - Newton Henry Black, Harvey N. Davis (1913) Practical Physics, The MacMillan Co., USA, p. 242, fig. 200. Licensed under Public Domain via Commons - https://commons.wikimedia.org/wiki/File:Magnet0873.png#/media/File:Magnet0873.png
“Magnet0873” by Newton Henry Black – Newton Henry Black, Harvey N. Davis (1913) Practical Physics, The MacMillan Co., USA, p. 242, fig. 200. Licensed under Public Domain via Commons – https://commons.wikimedia.org/wiki/File:Magnet0873.png#/media/File:Magnet0873.png

 

A further surprising application of TMS, potential of course, is in dyslexia. This is an emerging field, still under investigation, but imagine the potential this will unleash! There is a helpful review article in Neuroimmunology and Neuroinflammation which discusses the role of rapid rate TMS in the treatment of dyslexia.

"Dislexia nens" by cuidado infantil - cuidadoinfantil.net. Licensed under CC BY-SA 3.0 via Wikimedia Commons - https://commons.wikimedia.org/wiki/File:Dislexia_nens.jpg#/media/File:Dislexia_nens.jpg
“Dislexia nens” by cuidado infantil – cuidadoinfantil.net. Licensed under CC BY-SA 3.0 via Wikimedia Commons – https://commons.wikimedia.org/wiki/File:Dislexia_nens.jpg#/media/File:Dislexia_nens.jpg

 

We’re not quite there yet but there is hope for the neurological arsenal; who knows, we may soon dispense with all these difficult to swallow pills and cumbersome to deliver injections!

 

Medicine 01 by Taki Steve on Flikr. https://www.flickr.com/photos/13519089@N03/4746653392
Medicine 01 by Taki Steve on Flikr. https://www.flickr.com/photos/13519089@N03/4746653392

Interested in delving deeper into TMS?

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