Brain Preservation 

Summary

• According to the AD/PD 2024 program, Dr. Timo Grimmer is expected to present further information on Anavex's 2b/3 Alzheimer's trial. Based on the abstract, this information is likely to be related to brain atrophy and the ability of Blarcamesine to slow this degradation.

• What we already knew: "validated biomarkers of amyloid beta pathology, plasma Aβ42/40 ratio increased significantly (P= 0.048), demonstrating strong anti-amyloid effects of Blarcamesine in Alzheimer’s disease patients, while MRI revealed significant reduction in brain volume loss, including whole brain (P = 0.0005), comparing treatment to placebo."

• What we now know: significant reductions were found in the Whole Brain, Grey Matter, Parietal Lobe, Frontal Lobe, Limbic Lobe, Insular Cortex, and the Temporal Lobe.

• What we can do with this: By understanding grey matter's role within the brain, the function of each region, known disease pathology, and benefits to reducing atrophy, conclusions regarding Blarcamesine's impact to cognition and disease-stopping power can be elucidated. 

Grey Matter Matters

Grey (Gray) matter is a major component of the CNS and consists of neuron bodies, dendrites, axon terminals, and unmyelinated axons. Grey matter is where synapses fire in deeply integrated communicatory systems. It is where command initiation takes place. Messages travel from neuron to neuron and then travel down the axon (white matter) for further processing within the brain. Grey matter is distributed at the surface of the cerebral hemispheres, as well as the cerebrum (thalamus, hypothalamus, basal ganglia, etc.), cerebellum, and brainstem (substantia nigra [important in Parkinson's], cranial nerve, etc.); which underscores grey matter importance in regions of the brain dictating muscle control, sensory perception, sight, auditory processing, memory, emotions, speech, decision-making, and self-control. 

In 2020, "Grey matter network trajectories across the Alzheimer’s disease continuum and relation to cognition" was published in the Brain Communications journal. The study compared 190 healthy patients against 523 individuals with abnormal amyloid on the cognitive continuum (preclinical, prodromal, Alzheimer’s disease dementia), to try to identify patterns in grey matter loss and networks. In our opinion, the key findings of this study are in bulleted format below: 

• Grey matter, which is found throughout the entire brain, is primarily made up of synapses, axons, and other “connection” apparatuses, which enables whole-brain connectivity. (Note: Increased CDK5 exacerbates neuronal loss and irregulates axon guidance. When overactivated CDK5 substrates also cause irregular axon formation, neuronal migration, neurite outgrowth, neurite morphology, spine density, excitatory synapse, vesicle release, synaptic plasticity, synaptic homeostasis, calcium influx, nuclear translocation, APP localization, DNA damage response, mitochondrial fission, insulin, and more. As we know, CKD5 is significantly lowered with Blarcamesine therapy.)

• Lower grey matter volume and length had been studied extensively in the article above for cognitively normal, preclinical, prodromal, and Alzheimer’s patients. It was found that lower volume and smaller grey matter length correlated directly to worse scores in memory recall, memory speed, neurophysiological, and MMSE assays. 

• Cognitively normal patients still decline in grey matter and brain region volume during normal aging (of course). 

• Preclinical patients saw accelerated grey matter loss corresponding to lower test scores.

• Prodromal patients saw the greatest acceleration and dips in scores, indicating a time zone where therapeutics are likely to drop in efficacy as brain volume drops extend to levels that are probably irreversible. It also indicates that the gray matter connectivity system has probably corrupt beyond a fixable degree, causing degradation in wide-spread brain areas whereas in preclinical stages, the degradation was still isolated to mostly fixed or local sites.

• It was found in Alzheimer’s patients that the majority of the brain had now been corrupted with lower volume across the board. It was also found that there was now little acceleration, as if degeneration hits a relative ceiling with slow decline to death.

• This study from 2020 was ground breaking in that it proved that grey matter atrophy begins in the earliest stages of disease course whereas it was prior thought to onset well after amyloid accumulation. In fact, amyloid and grey matter atrophy appear to occur simultaneously BUT often in different portions of the brain before eventually converging in preclinical & prodromal stages. Additionally, they found direct correlation of connectivity loss to higher tau levels.

• The temporal lobes were affected first, followed by frontal and parietal. All three of these regions had slowed degeneration or stagnation in the 2b/3 Alzheimer’s trial. By affecting the temporal lobes first, this further validates the thought that memory functions are affected first in disease course (the hippocampus and amygdala both in the temporal region).

• Finally, it was found that by the time a patient hits clinical Alzheimer’s, the course of brain deterioration becomes mostly random/unpredictable, making it very difficult to target late stages with therapies or predict next stages.

Grey Matter Summary:  Grey matter deteriorates as a normal part of aging. According to "One-Year Brain Atrophy Evident in Healthy Aging" published in the Journal of Neuroscience, healthy patients [76-79 y/o] lost -0.35% of their cerebellum grey matter the first year of study, which had increased to -0.94% by the second year. Alzheimer's patients on the other hand lost -0.99% of their cerebellum grey matter the first year alone. Seeing as how grey matter envelops our brains in intricate communicatory networks, it's atrophy or degradation has large affects on our neuronal circuitry and ability to conduct synaptic actions. Furthermore, as mentioned earlier, at the prodromal stage it is likely that damage to grey matter networks becomes virtually irreversible, and the grey matter has become corrupt enough that atrophy is no longer isolated to individual brain areas. Rampant deterioration ensues through the whole brain before hitting a ceiling of atrophy in clinical Alzheimer's. This shows the importance of prescribing a medication or cocktail treatment that can preserve or reduce brain atrophy to a meaningful extent. By meaningfully slowing grey matter atrophy, a drug could drastically slow a patients descent through the Alzheimer's continuum - which could extend earlier, manageable disease stages by 5, 10, 15+ years. More on this topic will be addressed at the end of the report.

Parietal Lobe

The parietal lobe is important for processing and interpreting somatosensory inputs, such as heat, pressure, or needles against our skin. The parietal lobe is also instrumental in our understanding of how our body parts move and position. It helps us navigate new areas, but more importantly, helps us remember how to navigate areas we have already been. A good way to think of the parietal lobe is akin it to a reflex. It helps us do things naturally that we have done hundreds of times. That is why it is of no surprise that damage or atrophy of the parietal lobe causes difficulty drawing objects (like the famous clock test), difficulty distinguishing left or right, navigation difficulty, problems reading, difficulties with basic math, neglect to our body parts and their positioning (perhaps closing a door on a hand), and motor complications. Overall, the parietal lobe helps deal with and react to our environment and is abundant with neurons for sensory input.

Frontal Lobe

The frontal lobe is the largest of the four lobes and consists of four sections known as gyri:

• Precentral Gyrus: contains the primary motor cortex which controls voluntary movements of specific body parts.

• Superior Frontal, Middle Frontal, Inferior Frontal Gyrus: three horizontally arranged subsections of the frontal gyrus which contain most of the dopaminergic neurons in the cerebral cortex, associated with reward, attention, short-term memory, planning, and motivation.

The frontal lobe uses its dopaminergic pathways to limit and select sensory inputs from the thalamus to the forebrain. Overall, the frontal lobe is responsible for executive functions such as planning for the future, judgement, decision-making skills, attention span, and inhibition. Damage or atrophy of the frontal lobe causes issues in motivation, emotion regulation, and the aforementioned executive functions. Beyond Alzheimer's, damage to the frontal lobe is also associated with Downs Syndrome, Frontotemporal Dementia, depression, and Schizophrenia, which all have deficits in executive function and emotional swings.

Limbic Lobe

The limbic lobe makes up a wide portion of the cortex, is deeply centrally located, and thus includes parts of the frontal, parietal, and temporal lobes, including part of the temporal lobe's hippocampus. Primarily, the limbic lobe plays a large part in our motivational drive, emotional behaviors to include fear and our heart's response to stimulus, sexual stimulation/attraction, and long-term memory. It is important to note that there is not a consensus on the exact make-up of the limbic lobe because it spans the other lobes aforementioned. It's central location is part of what makes the limbic lobe so important from a degradative point of view. Corruption of the limbic lobe has immediate consequences for the rest of the brain. 

Insular Cortex

The insula is important for taste, sensorimotor processing, risk-reward behavior, autonomic function of the nervous system, pain pathways, hearing, and balancing. Much like the limbic lobe, the insular cortex is central and deep within the brain; therefore, the cortex has links to the frontal, parietal, and temporal lobes, the limbic cortex, and basal ganglia. It has been found that the brain regulates peripheral immunity (immune response) largely through the insular cortex which stores immune-related information. Specifically, the insular cortex appears to be a key area for immunological memory, essentially how our brain triggers immune response to act on pathogens in ways that were successful in previous infections. This includes inflammatory response. Many of the articles we read on insular cortex mention empathy, self awareness, emotional processing, and long-term memory based on sensory experience (like remembering a food poisoning incident caused by a specific restaurant or specific food years prior). 

Temporal Lobe

The temporal lobes sit behind the ears and are the second largest lobe, and are the most important lobe pertaining to encoding memories. Many consider the temporal lobe to be the primary construct housing the hippocampus and amygdala - although as mentioned earlier, some associate these two structures more to the limbic system. In addition to encoding memories, the temporal lobe plays an important role in processing emotions, language, and aspects of visual perception. Each brain has two temporal lobes, a dominant lobe and a non-dominant lobe. The dominant lobe is typically on the left side of most people and is involved in understanding language, learning, and verbal information. The non-dominant lobe is on the right side of most people and is involved in learning and non-verbal information such as visuo-spatial information and music. Damage or atrophy to the temporal lobe results in difficulty in understanding spoken words (does not include written words), issues in attention, learning and retaining information, impaired long-term memory, onset of persistent non-flow language, difficulty recognizing language, abnormal sexual arousal, and emotional distress such as agitation or aggression. Overall, the temporal lobe is the most important region for memory and learning, and has special important in language/voice-related deficits. 

Brain Atrophy, Life Span and Disease Progression

Along with the references already mentioned, "Structural progression of Alzheimer’s disease over decades: the MRI staging scheme" published in Brain Communications had a fantastic roll-up of brain atrophy and its implications on life span and disease progression. In Graphic 3 & 4 below you can visualize these implications.

As seen in Graphic 3, the hippocampus and the amygdala are the first structures to begin atrophy, decades earlier than most other structures. Not only do they atrophy earlier than the other structures, they also experience heavier degradation than the other structures as is evidenced by the deep red shading near end-of-life. As Alzheimer's is characterized by memory loss and mood disturbances, it makes sense that the hippocampus and the amygdala would be the first two structures degraded during disease course. In Graphic 4, one can visualize the atrophies affect on life span. The black lines are healthy controls and the red lines are Alzheimer's patients. In the hippocampus and the amygdala there is clear separation between the black and red lines - indicating a significant increase in Alzheimer's-caused atrophy over healthy control. The yellow line at the bottom helps to showcase how atrophy in those regions is correlated to a significantly dampened life span. By our estimates, compared to healthy aging patients, Alzheimer’s patients with atrophied amygdala have a 315%+ greater likelihood of death and similarly a 220%+ with atrophied hippocampus. Other brain regions showing obviously lower life span include the Middle Temporal Gyrus (temporal lobe), Parahippocampal Gyrus (temporal lobe), Entorhinal Area (temporal lobe), Inferior Temporal Gyrus (temporal lobe), Caudate (striatum), Anterior Insula (insular Cortex), and Posterior Insula (insular Cortex).

Coming full circle to the whole brain, it has been found that every 1% of annual whole brain atrophy over standard aging humans increases the odds of progressing to the next stage of dementia by 30%. As it exists, MCI patients have an annual whole brain atrophy rate of -1.2% (+/- 0.9) and AD patients have an annual whole brain atrophy rate of -1.9% (+/- 0.9) [p=0.003]. Healthy aging patients have an annual whole brain atrophy rate of -0.5 (+/- 0.5) [p=0.05]. If Blarcamesine can reduce whole brain volume to resemble near-healthy-aging, the therapy could dramatically extend patients in the earliest stages of the disease. 

Below we mapped out a hypothetical, linear progression of Alzheimer's staging based on the aforementioned metrics and a 'guestimate' of Blarcamesine's brain preservation capabilities. We emphasize that the Alzheimer's continuum is not linear and that the Blarcamesine atrophy is a best guess until more data is announced.

For those that have been following Anavex a long time, you will recall that during the Alzheimer's 2a study there was a list of caregiver and patient quality of life feedback comments provided. We wanted to bring those back to the table and correlate them with regions of the brain possibly providing the outcome. This information can be found in Graphic 6 below, and SOTC looks forward to more of these real-world evidence/unexpected quality of life reports hopefully as part of the full Alzheimer's 2b/3 data-set. As mentioned previously, the limbic lobe and insular cortex are centrally and deeply rooted, and so those regions may play a part in all of the responses listed in Graphic 6. Grey matter also plays a part in all of these responses and was therefore omitted. 

Summary:

To summarize as a collective, Blarcamesine slows or prevents atrophy in key brain areas with function in executive memory, working memory, behavior, emotion to include empathy and love, movement, and sleep. Importantly, after assaying 2,000 MCI and Alzheimer’s patients, two areas in the brain, the amygdala and hippocampus, are found to have direct and obvious implications in life expectancy. Found in the temporal lobe and interconnected to the limbic system, the amygdala and hippocampus begin atrophying earlier in disease stage than any other area. They also deteriorate the most over any other brain region by end of life. Compared to healthy aging patients, Alzheimer’s patients with atrophied amygdala have a 315%+ greater likelihood of death and similarly a 220%+ with atrophied hippocampus. Every 1% of annual whole brain atrophy over standard aging humans increases the odds of progressing to the next stage of dementia by 30%.

While the exact slowing or preservation of brain matter provided by Blarcamesine therapy is currently unknown, we can surmise considering extremely desirable p-values that the result was robust, and we created Graphic 5 to visualize what the implications of this may be. We excitedly wait to see the full data in order to more meaningfully calculate the exact ‘time saved’ by patients and their ability to now reduce odds of progressing to the next stage of disease course. Even relative stagnation and keeping a patient in early Alzheimer’s or MCI would be stupendously beneficial considering the degree of deterioration seen in later stages; both at the patient level and their willingness to live, and the caregiver level. We have theories on how Blarcamesine is slowing degradation, but this is too complex for this report. It is likely multimodal and includes ameliorating amyloid and tau depositions, reducing endoplasmic reticulum stress, improving oxidative function, rescuing ATP flow, and halting inflammatory processes all the while removing dead and misfolded proteins through proteostasis. These functions cool off neuroinflammation and return rampant protein expression to more normal levels, reducing apoptosis driven cell death and maintaining communicatory circuitry in grey & white matter. 

Current therapies do not preserve brain matter - factually, MABs extend losses of brain atrophy. A graphic showing Leqembi atrophy data can be found here if interested. Blarcamesine continues to position itself as the most efficacious, easiest to administer, safest, and likely inexpensive drug on the cusp of commercialization. Thank you for reading, the Spirit of the Coast Family wishes you Happy Holidays and a Happy New Year.