CLINICAL PROBLEM SOLVING – NEURODEGENERATIVE DISEASE

For this year’s clinical problem-solving conference, I have chosen the case on neurodegenerative diseases.

This is the link to the semi-structured case:  A 58 year old man with unexplanied dementia, slurring of speech and urinary incontinence since 6 months and forgetfulness since 3 months (jabeenahmed300.blogspot.com)

In this ELog, I have attempted to answer the following questions:

1. What is the timeline of symptoms seen in this patient? What is the mechanism of the symptoms?
2. What are the currently approved treatments for this condition?
3. What are the future prospects in the treatment of this condition?

QUESTION 1: Timeline and Mechanism of Symptoms

The timeline and progression of the symptoms is indicative of Alzheimer's Disease. 

A. Slurred speech and  Delay in response to commands: This is seen when the temporal lobe (specifically the language processing and speech centres) begin to deteriorate. 

B. Apathy: This could be due to the disease spreading to the anterior cingulate cortex 

                

"Apathy in AD is associated with gray matter atrophy in the anterior cingulate cortex and the left supplementary motor area

People with AD and apathy also have more white matter hyperintensities and a mixed pattern of reduced and elevated blood flow in different regions, thereby suggesting that the brain may be trying to compensate for the reduced blood flow. People with dementia and apathy also show a blunted response to d-amphetamine, suggesting problems with the brain reward system"

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299979/

 

      C. Hallucinations, Sleep disturbances, Memory loss: These are common symptoms in middle-to-late stage AD.  Memory loss, specifically, has been hypothesized to be caused by the decline of MTL function.

    "As the disease progresses, delusions, hallucinations, and aggression become more common, whereas apathy is the most persistent and frequent NPS throughout all the stages of AD. Additionally, circadian sleep-wake rhythms become exaggerated as compared with the phase shifts associated with normal aging."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299979/ 

 

"Memory impairments appear to be significantly correlated with medial temporal lobe atrophy and hypoactivation."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684784/ 

 

            

       D. Urinary incontinence: The mechanism of this symptom is very unclear. It could be due to amyloid deposits in the micturition centers of the brain, causing loss of signal. Urinary incontinence can also be attributed to the progressing cognitive decline: It is possible that the patient fails to recognize the need to micturate, or is unable to reach the appropriate place in time.

       E. Dysphagia: The patient showed aversion to both food and water. 

"Swallowing disorders of the AD group may result from sensory impairment in relation to dysfunctions in the temporoparietal areas, whereas the swallowing disorders of VaD group may primarily be caused by motor impairments due to disruptions in the corticobulbar tract. AD with EPS predominantly shows rigidity and bradykinesia."

https://journals.lww.com/alzheimerjournal/Abstract/2009/04000/Dysphagia_in_Patients_With_Dementia__Alzheimer.13.aspx 

QUESTION 2: Currently Approved Treatments

This patient was treated with Donepezil - Cholinesterase inhibitor (10mg/day which was increased to 20mg/day).

The currently accepted drug treatments for AD include:

1.   Cholinesterase inhibitors: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomized controlled trial (nih.gov)

 

P – N = 725 – Mild to moderately severe AD

I – with Rivastigmine 243 – High dose, 243 – Low dose

C – 239 placebo

O – Patients taking placebo experienced a decline in cognitive function. 55% (86/157) of those in the higher dose group improved from baseline measurements compared with 45% (93/205) of those treated with placebo (analysis of observed cases).

 

2.   Memantine (NMDA receptor blocker): Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial - PubMed (nih.gov)

 

P – 404 patients; Moderate to severe AD

I – 203 with Memantine (20mg/day)

C – 201 with placebo

O – Stable doses of donepezil + memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated.

 

3.   Suvorexant (Orexin receptor antagonist): Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial (nih.gov)

 

P – N= 285; Patients suffering from insomnia in mild-to-moderate Alzheimers

I – 142 with suvorexant

C – 143 with placebo

O –  At week 4, the mean improvement‐from‐baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo. The number (%) of patients with ≥50 minute improvement in TST at week 4 was 83 (62%) of 135 in the suvorexant group and 62 (45%) of 139 in the placebo group.

QUESTION 3: Potential Drug Therapies

There have been numerous drug trials targeting different steps in AD pathology. These include disease-modifying therapies as well as symptomatic therapies. 

                                                                      Source

    1.   BACE INHIBITORS AND GAMMA SECRETASE INHIBITORS

 

β-site APP cleaving enzyme 1 (BACE1), which is thought to be essential for the production of Aβ peptides. Inhibition of the enzymes that produce the Aβ peptide from its precursor, amyloid precursor protein (APP) can help prevent the first step of AD - accumulation of amyloid plaques. BACE inhibitors have been thought to improve cognitive and functional performance by suppressing Aβ production. Small molecule BACE inhibitors (Elenbecestat) are being evaluated in a Phase III study in early AD patients with confirmed brain amyloid using positron emission tomography (PET) and/or cerebrospinal fluid (CSF) assessment.

                         From <https://f1000research.com/articles/7-1161 

                         From <https://www.ncbi.nlm.nih.gov  

 

2.   GAMMA OSCILLATION

 

Gamma oscillation, a high-frequency brainwave rhythm, is associated with inter-neuronal communication in virtually all brain networks and may help to distinguish between true and false memories. Recently, researchers at the Massachusetts Institute of Technology found that induction of gamma-frequency oscillations led to reduced Aβ deposition and improved cognitive outcomes in an AD mouse model.

  

               From <https://f1000research.com/articles/7-1161/v1>

              Sederberg PB, Schulze-Bonhage A, Madsen JR, et al. Gamma oscillations distinguish true from false                memories. Psychol Sci. 2007;18(11):927-932. doi:10.1111/j.1467-9280.2007.02003.x

 

3.   BEXAROTENE

 

Bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation. It delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could reduce the risk of the onset of Alzheimer's disease.

 https://pubmed.ncbi.nlm.nih.gov/26933687/

4.   HUMAN BRICHOS DOMAIN

A molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. It has been demonstrated in vitro that Brichos binds to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves the minimal formation of beta-amyloid oligomers.

 https://pubmed.ncbi.nlm.nih.gov/25686087/

5.   IMMUNOTHERAPY

 

Immunotherapy involves the injection of an antibody that targets abnormal Aβ and facilitates its removal from the brain. Immunotherapy against Aβ has proven to be ineffective unless it is used during the early stages of AD.

 The selective immunological blockade of specific biding sites for Aβ might be an effective approach at an early stage of AD. In one such study conducted in OBX-mice, immunization with the fragments of extracellular domains of α7-subtype of the acetylcholine or prion receptors, evident improvement has been observed in both spatial memory and morphology of cortical and hippocampal neurons as well as Aβ level lowering. The antibodies to these fragments had to be noticed to exert obvious protective effects on hippocampal cells culture as well.

 

 The potential clinical benefit of immunomodulatory treatment in the earliest stages of AD is dependent on the rate of cognitive decline as well as the severity of the neuroinflammatory response. The activation states of microglia and the neuroinflammatory environment are constantly changing throughout the course of AD progression. Therefore, when choosing the target of modulation, the timing of intervention is highly important.

 

6.   ANTI-INFLAMMATORY

 

This targets the neuroinflammatory pathology in AD. Modulation of cytokine systems has been shown to correct dysregulated neuroinflammation in mouse models of AD and restore efficient Aβ clearance. However, the nature of these cytokines (pro- or anti-inflammatory) along with the specific timing of intervention is also critically important in the outcome.

 

Epidemiological studies suggest that sustained combinatorial NSAID usage can reduce the risk of AD onset by as much as 80% and numerous NSAID compounds have been efficient in reducing microglial activation and amyloid burden in animal models of AD. However, NSAID treatment could be protective if initiated before clinical symptom onset but harmful after the development of cognitive impairment.

 

Numerous cytokine suppressive anti-inflammatory drugs derived from plant polyphenols, including curcumin, apigenin, and resveratrol, carry strong preclinical evidence as potential AD therapies. These compounds inhibit nuclear factor kappa B activity and decrease the production of pro-inflammatory cytokines. Recently etanercept, a TNFα inhibitor, was shown to be well tolerated a provide some therapeutic benefit in an initial phase-II AD clinical trial

 

 https://onlinelibrary.wiley.com/doi/10.1111/jnc.13411

7.   EXOSOMES

Exosomes, a form of nanoscale vesicle, are commonly found in the biological fluids and tissues of the central nervous system. They carry a small amount of molecular genetic material and proteins that play key roles in intercellular communication.

In cellular and animal models of AD, exosomes have been shown to carry and spread toxic Aβ and hyperphosphorylated tau, between neural cells and may then induce cell apoptosis, thus resulting in the loss of neurons. On the other hand, exosomes may also exert positive actions, including the reduction of brain amyloid-beta, or the transfer of neuroprotective substances between neural cells. For example, the up-regulation of exosomes containing nSMase2 secretion enhances Aβ uptake in microglia and significantly reduces the extracellular levels of Aβ.

 

Since neuron-derived exosomes (NDEs) exist in both cerebrospinal fluid and peripheral blood, targeting changes in the exosomes during the pathogenesis of AD might provide a new alternative approach with which to treat AD.

 

A research study showed that the intravenous delivery of Mesenchymal Stem Cells allowed transport across the blood-brain barrier and subsequent migration to sites of neural injury without inducing tumorigenic or immune responses. MSCs can exert their action through exosomes.

MSCs have also been shown to promote cognitive function in various pathological conditions, including neuro-regeneration, neuroprotection, the reduction of Aβ deposits and tau-related cell death, and the down-regulation of pro-inflammatory cytokines. 

                   From <https://www.ncbi.nlm.nih.gov  

8. TARGETING TAU PHOSPHORYLATION

Another step that can be targeted in AD pathology is tau hyperphosphorylation and NFT formation. Several potential therapeutic approaches have been identified: modulation of tau phosphorylation, prevention of tau aggregation, promotion of tau clearance by intracellular and extracellular proteolysis and phagocytosis, and anti-tau-directed immunotherapies. Only a few drugs that target tau phosphorylation and aggregation have reached late-stage clinical trials. This may be due to differences in structure, conformation, and complexity of changes during AD of tau protein compared to Aβ (while Aβ consists of 36–42 amino acids, the human central nervous system expresses six tau isoforms that comprise from 352 to 441 amino acids with four sequence repeats in normal). Moreover, changes in Aβ and tau during the progression of AD are very different. Extracellular Aβ modifications during AD progression involve slow polymerization into oligomers that further aggregate. Initial tau modifications in AD progression are intracellular. Therefore, targeting tau protein as the therapeutic approach proves to be more complex than targeting Aβ. 

                         https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839593/

9.   UNCONVENTIONAL METHODS - AROMATHERAPY

    

     Unconventional methods like aromatherapy and light therapy have also shown promising results in improving sleep, abstract function, and conceptual understanding in AD patients. It has been suggested that aromatherapy may bring some feeling of relief and the ability to act on outside influences that can help cope with the obstacle to action in senile dementia.

 The action of aromatherapy begins from a smell molecule combined with an acceptor peculiar to each specific odor. The smell molecule passes along the nasal cavity and adheres to the olfactory epithelium. The stimulus is transmitted to the hippocampus or cerebral limbic system and amygdaloid body through the olfactory nerve system currently concentrated on the olfactory epithelium. The odor is recognized and the stimulus sends information to the hypothalamus on which it was projected by the cerebral limbic system, which then adjusts the autonomic nervous system and the internal secretory system, guiding a series of vital reactions in the hippocampus or amygdaloid body, such as the discharge of neurotransmitters.

 

This study explored the effects of aromatherapy on cognitive functions of AD and dementia patients. The oils used in aromatherapy were lemon, rosemary, lavender, and orange. The lemon and rosemary mix was believed to activate the sympathetic nervous system to strengthen concentration and memory, whereas the lavender and orange fragrance activated the parasympathetic nervous system to calm patients' anxiety. The mixtures used in the mornings and evenings were changed to synchronize the autonomic nervous system to the circadian rhythm: the sympathetic nervous system works predominantly after stimulation by rosemary–lemon oil in the morning, whereas the parasympathetic nerve system works predominantly after activation by the lavender–orange oil at night.

 

The study concluded that a significant improvement was seen in GBSS-J-A-13 (abstract function) in the mild-moderate AD group. Some improvement was seen in the overall score for the TDAS and in concept understanding in all patient groups. 

            https://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x

 DISCUSSION

 The pathogenesis of AD has 3 components - Accumulation of Aß amyloids, Formation of neurofibrillary tangles, and Neuroinflammation.

1. Aß amyloids and tau proteins

 Amyloid Precursor Protein (APP) is an integral membrane protein expressed mainly in synapses of neurons. It regulates synapse formation, synaptic plasticity, antimicrobial activity, and iron export. APP is cleaved by ß secretase to produce APP C99, which undergoes further cleavages by gamma-secretase to produce amyloid ß peptides. Disruption of this cleavage process, specifical mutations in gamma and beta-secretases, can lead to the abnormal production of Aβ. Aβ can then trigger a cascade leading to synaptic damage and neuron loss. 

[Drug treatments in Alzheimer’s disease (nih.gov)]

 

Tau proteins are microtubule-associated proteins, predominantly expressed in neurons of the CNS. One of the main functions of tau proteins is to modulate the stability of axonal microtubules by interacting with tubulin and promoting its assembly into microtubules. It does this by 2 mechanisms: isoforms and phosphorylation. Tau protein also regulates microtubule-mediated axonal transport. Non-cellular functions of tau include negatively regulating long-term memory and facilitating habituation. This can explain the linkage between tauopathies and cognitive impairment.  Abnormal amyloid plaque can induce the phosphorylation of tau protein, which then spreads almost infectiously via microtubule transport to neighboring neurons, leading to neuronal death.

[https://f1000research.com/articles/7-1161/v1]

 In early AD, the first detectable signs that can be observed in a structural MRI are atrophy in the middle temporal lobe (affecting especially the hippocampus), and a decrease in the thickness of the cerebral cortex in regions that are vulnerable to AD. In asymptomatic carriers of APP mutations, a decrease in hippocampal volume can be identified 2–3 years before the onset of dementia and, in elderly people, this alteration can be detected up to six years before [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888399/]

Memory impairments appear to be significantly correlated with medial temporal lobe atrophy and hypoactivation. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684784/]

As the disease progresses, delusions, hallucinations, and aggression become more common, whereas apathy is the most persistent and frequent NPS throughout all the stages of AD. Additionally, circadian sleep-wake rhythms become exaggerated as compared with the phase shifts associated with normal aging. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299979/]

Swallowing disorders of the AD group may result from sensory impairment in relation to dysfunctions in the temporoparietal areas, whereas the swallowing disorders of VaD group may primarily be caused by motor impairments due to disruptions in the corticobulbar tract. AD with EPS predominantly shows rigidity and bradykinesia. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299979/]

2. Neurofibrillary Tangles

Neurofibrillary tangles are formed by hyperphosphorylation of the aforementioned microtubule-associated protein tau, causing it to aggregate in an insoluble form. These aggregations of hyperphosphorylated tau protein are referred to as PHF or "paired helical filaments".

Intracellular lesions known as pretangles develop when tau is phosphorylated excessively and on improper amino acid residues. These lesions, over time, develop into filamentous neurofibrillary tangles (NFTs) which interfere with numerous intracellular functions. In asymptomatic patients, the presence of neurofibrillary tangles tends to be limited to the entorhinal cortex, while in symptomatic subjects, tangles are much more widespread. 

A recent study looked for a correlation between the quantitative aspects of Alzheimer's disease and aggression frequently found in Alzheimer's patients. It was found that only an increase in neurofibrillary tangle load was associated with the severity of aggression and chronic aggression in Alzheimer's patients. This indicates a correlation between NFT load and the severity of aggression.

  

1.  Lee H. G.; Perry G.; Moreira P. I.; Garrett M. R.; Liu Q.; Zhu X. W.; et al. (2005). "Tau phosphorylation in Alzheimer's disease: pathogen or protector?". Trends in Molecular Medicine. 11 (4): 164–169. doi:10.1016/j.molmed.2005.02.008. hdl:10316/4769. PMID 15823754.
2. ^ Kitazawa, Masashi; Medeiros, Rodrigo; LaFerla, Frank M. (2012). "Transgenic Mouse Models of Alzheimer Disease: Developing a Better Model as a Tool for Therapeutic Interventions". Current Pharmaceutical Design. 18 (8): 1131–1147. doi:10.2174/138161212799315786. ISSN 1381-6128. PMC 4437619. PMID 22288400.
3. ^ Jump up to:^a b c Klein R. L.; Lin W. L.; Dickson D. W.; Lewis J.; Hutton M.; Duff K.; et al. (2004). "Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau". American Journal of Pathology. 164 (1): 347–353. doi:10.1016/S0002-9440(10)63124-0. PMC 1602230. PMID 14695347.

3. Inflammation

a. General Mechanism

 

 

b. Macrophage Activation Theory

 

 

c. Astrocytes

Astrocytes may be more efficient in Aβ1–42 uptake than microglia and show a preference for uptake of neurotoxic oligomeric Aβ rather than the fibrillary formation.

Even though astrocytes are primarily supportive of neuronal function, they can also secrete early-phase pro-inflammatory cytokines in conditions of brain injury that can exacerbate neuroinflammation and neurodegeneration. Thus, therapies targeting neuroinflammation must keep in mind the contribution of astrocytes in the progression of the disease.

[ https://onlinelibrary.wiley.com/doi/10.1111/jnc.13411]

 

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