Neurodegenerative Disease Management

Neurons, or nerve cells, constitute the functional unit of the brain and the nervous system. They form an intricate neural network in the brain responsible for almost all bodily functions including motor, sensory and cognitive functions such as thinking, movements, spatial awareness and memories. As we age, these neurons alter their structure and undergo a decline in numbers. This loss of normally functioning neurons is defined as neurodegeneration.

Abnormal neurons disrupt the brain's ability to regulate essential cognitive and motor functions, leading to a range of debilitating motor and cognitive symptoms. Unlike other cells in the body, neurons do not readily regenerate, making their loss particularly critical. The most prevalent neurogenerative diseases are Alzheimer’s and Parkinson’s diseases.

Alzheimer’s Disease (AD)

Currently, about 55 million adults worldwide suffer AD, carrying a healthcare burden of over $305 billion annually. It has been over 100 years since its discovery yet, we have not fully understood the pathology that causes AD. Modern technological and laboratory advancements have enabled us to better understand the pathophysiology of AD including atrophy of the hippocampus and other cortical and subcortical structures, abnormal protein accumulation (tau proteins, amyloid plaques), oxidative stress, inflammation, genetic factors and metabolic changes, all contributing to the development of dysfunctional neurons that result in impaired neurotransmission.

AD starts with short term memory loss and progresses to dementia with deficits in other cognitive domains such as language impairment, spatial disorientation and decline in executive function and judgement. Non-cognitive symptoms such as apathy, agitation, urinary incontinence, mood disorders and sleep disturbances are also seen.

To diagnose AD, physicians may use a combination of medical history, mental status tests, physical and neurological exams, CSF and blood tests and brain imaging. Diagnosis is established clinically by a steady decline in learning, memory and other cognitive functions using tests such as the Mini-Mental State Examination. MRI shows disproportionate medial temporal lobe and hippocampi atrophy. Early diagnosis is essential to improve treatment outcomes and quality of life.

Current state in medical therapies and recent advances

Millions of dollars are invested annually in Alzheimer’s research, and yet, no curative therapy exists. Acetylcholinesterase inhibitors such as rivastigmine, donepezil and galantamine and NMDA receptor antagonists such as memantine improve neurotransmission, thereby improving memory and thinking. Comorbidities such as agitation or psychosis are managed with low dose antipsychotics such as brexpiprazole and insomnia is treated with suvorexant. Depressive symptoms are typically managed using anti-depression medications such as SSRIs like citalopram.

In January 2023, the FDA approved Lecanemab, a monoclonal antibody directed against amyloid proteins, the accumulation of which contributes to the development of AD. This was following the completion of the Clarity AD trial showing reduced brain amyloid levels and improved Clinical Demetia Rating scores at the end of 18 months in patients with mild cognitive impairments and confirmed amyloid deposition using PET scan or CSF studies. The drug is currently under extended-term studies to assess safety and efficacy.

Most recently, in July 2024, the FDA approved Donanemab, another antibody that reduces amyloid buildup, following results from the TRAILBLAZER-ALZ 2 randomized clinical trial. This trial demonstrated approximately 32% reduction in clinical disease progression at approximately 18 months for patients with early mild cognitive impairment and confirmed amyloid deposition in the brain through PET scan.

Aducanumab, also aimed at reducing plaque formation and cerebral edema, was approved in 2021 but is set to be discontinued by the manufacturer by the end of 2024.

Artificial Intelligence and Machine Learning in Alzheimer’s disease

Deep neural networks were trained using a large number of MRIs and PET scans, laboratory, structural and metabolic data to predict an individual’s age. This yields two different ages for any one individual: the Chronological age and AI-Brain age. Higher brain age gap (chronological - AI age) was noted in individuals with neurodegenerative diseases, reflecting accelerated aging of the brain and possible progression to dementia. AI based learning essentially provides a measurable biomarker that has groundbreaking advantages in Alzheimer disease prediction, screening, staging and monitoring.

Parkinson’s Disease (PD)

Parkinson’s disease, the second most common neurodegenerative disorder after AD, affects 8.5 million people worldwide. WHO has reported PD to be the fastest growing neurological disease with over 100% increase since 2000. PD is a result of progressive depletion of the ‘dopaminergic’ neurons in an area of the brain called substantia nigra (SN). This area is normally responsible for initiating and fine-tuning all movements of our body from standing and walking to writing or holding a glass of water. The pathophysiology of PD is predominantly in the aggregation of abnormal proteins such as alpha-synuclein, ubiquitin and neurofilament within neuronal cells known as Lewy bodies. Reactive giosis, interferon signaling dysregulation and depigmentation of the SN is also seen within the areas of degeneration.

PD symptoms include bradykinesia (slower movements such as walking), tremors (resting tremors that improve with voluntary movements), rigidity (cogwheel type), and postural instability that may lead to falls.  These motor symptoms are unilateral, asymmetrical and progress over time leading to a poor quality of life. Visual hallucinations, mood disorders, masked facial expression and dementia are also commonly seen late in the disease course.

Diagnosis of PD is made after a thorough history and physical examination including complete neurological examination. Imaging and laboratory studies are not required though MRI may show nonspecific atrophic changes are seen in the substantia nigra. Levodopa challenge test may be used to support diagnosis in which patients with PD show symptom improvement after administration of Levodopa.

Current state in medical therapies and recent advances

Currently approved PD medications include:

• Dopaminergic medications: levodopa-carbidopa, pramipexole, ropinirole, apomorphine
• MAO-B inhibitors: selegiline
• Anticholinergics: benztropine, Trihexyphenidyl
• NMDA antagonist: amantadine
• COMT inhibitors: Entacapone

Deep Brain Stimulation (DBS) is an FDA-approved procedure that delivers electrical stimulation through an electrode placed into deeper brain structures, primarily the subthalamic nucleus and globus pallidus internus. DBS is the current standard of care in patients with medication-resistant motor symptoms.

In 2023, a groundbreaking study identified mitochondrial DNA (mtDNA) damage as a root cause of the development of PD in animal models. Damaged mtDNA leads to dysregulated oxidative stress and abnormal signaling pathways contributing to motor symptoms and dementia seen in PD. This finding is crucial, as it paves the way for novel disease monitoring techniques and therapeutic approaches that may slow or halt the progression of the disease.

2023 marked yet another leap in PD symptom management with the development of a neuroprosthesis using epidural electrical stimulation in the lumbosacral spinal cord region (STIMO-PARK clinical trial). The device helped a 62-year-old man with a 30-year history of PD with severe gait impairments to walk like a healthy individual with stable longer strides providing real-time control over voluntary leg movements. This patient is able to use the prosthetic for over 8 hours a day, turning it off only during rest and sleep.

Similarly for hand tremors, a hand glove was developed that uses sensory feedback to sense and then recalibrate motor signals sent to the hand to reduce tremors and produce smooth hand movement while performing tasks such as writing or holding a cup of coffee, tremendously improving the quality of life. So far, 50 patients have used the device with improved motor function. Currently, the research team is focused on improving the glove’s accuracy and reducing its size and cost.

Other treatment modalities currently under study

Gene therapy - Uses a viral vector to deliver DNA sequences that code for genes involved in dopaminergic neurotransmission. The aim is to increase the bioavailability of Dopamine in the substantia nigra via direct enhancement of enzymes involved in dopamine production and maintaining healthy dopaminergic neurons through endogenous neuronal growth factors such as Glial cell-line derived neurotrophic factor and Neurturin.

Levodopa–Carbidopa Intestinal Gel (LCIG) - Dopamine enhancing medication is delivered via a portable pump connected to a percutaneous transgastric jejunostomy with greater efficacy in motor symptoms not relived by oral formulations. Subcutaneous levodopa-carbidopa formulation is also currently being explored.

Continuous subcutaneous apomorphine infusion (CSAI) - Apomorphine acts on dopamine, serotonin and alpha-adrenergic receptors and simulates physiological neuronal stimulation.

Radiofrequency ablation, stereotactic radiosurgery, MRI-guided focused ultrasound, and laser-guided thermal therapies - Target key brain regions associated with Parkinson's disease, including the ventral intermediate nucleus of the thalamus, globus pallidus internus, and subthalamic nucleus.

Artificial Intelligence and Machine Learning in Parkinson’s disease

A groundbreaking study introduced the use of AI to identify individuals with PD by analyzing breathing patterns during sleep with 90% accuracy, a potential biomarker in PD. Sleep changes are a result of degeneration of neurons within the brainstem and are reported to occur early in the disease course. AI is also used for symptom reporting and disease severity measurement by analyzing videos of finger-tapping.

Holistic Approach to Neurodegenerative diseases management

Inflammation, oxidative stress, and abnormal protein accumulation are key pathological mechanisms implicated in the development of neurodegenerative disorders. While certain genetic predispositions are non-modifiable, the progression of neurodegeneration can be mitigated significantly by slowing these pathological processes through a healthy diet and lifestyle interventions. Preliminary studies show that a combination of nutrient-rich diet, regular exercise and mental health care can improve cognitive function and quality of life in individuals suffering from AD and PD.

Diet, Nutrition and supplements

Various diets such as the mediterranean diet and the MIND diet incorporate foods rich in antioxidants, lean proteins and healthy fats with lower glycemic indices and anti-inflammatory properties.

Turmeric (curcumin) - One of the most extensively studied anti-inflammatory and antioxidant ingredients, unique due to its ability to cross the blood-brain-barrier. As such, it reduces the concentration of cytokines and inflammatory cells in neural tissue.

B group vitamins – Essential in the majority of bodily functions including the synthesis of neurotransmitters essential for communication between neurons in the brain, DNA and RNA replication and repair resulting in memory and cognition support.

Choline – Choline is a precursor to Acetylcholine, essential for brain cell membrane structure. It may improve memory function.

Omega-3 fatty acids – Support nerve cell membrane structure and function, reduce inflammation, increase neurotrophic factors, and reduce oxidative stress.

Probiotics – Reduce inflammation and increase neurotrophic growth factors. Research shows improved cognitive function and memory in patients with AD with regular use of probiotics.

Physical Exercises and Mind-body therapies

While all forms of physical exercise such as walking and swimming are recommended in neurodegenerative diseases, there are two that stand out as beneficial and safe in early neurodegeneration to delay progression and improve symptoms: Yoga and Tai Chi.

Yoga – An ancient practice combining body movements (postures) and breathing exercises. A single 60-minute session has been shown to increase GABA (inhibitory neurotransmitter), dopamine, serotonin and lower norepinephrine levels. This improves motor symptoms associated with PD and associated neuropsychiatric disturbances. A study conducted over 8 weeks showed that in addition to improving physical health by improving flexibility, strength and balance, yoga may decrease hippocampal atrophy, improve synaptic plasticity and increase neurotrophic factors in individuals with AD.

Tai Chi – A traditional Chinese exercise combining mental concentration, balance, muscle relaxation and breathing. Research shows that <6 months of Tai Chi may improve MMSE scores, memory and executive function. It may also improve mood symptoms, and overall quality of life.

Conclusions and prospects

Neuronal injury and death are the baseline characteristic in AD and PD. Therefore, it is safe to assume that neuroprotection and neurogenesis are the most pursued treatment strategies for management. The blood brain barrier is a key obstacle in drug delivery. Perhaps nanoparticle-mediated drug delivery systems offer a promising future harnessing the benefits of technological advancements and AI, but it may also present challenges regarding safety. Currently, neurodegenerative diseases are permanent and incurable. However, we now have a deeper understanding of many diseases, and advancements in medicine and technology have made it possible to manage many of them effectively.

Reference:

1. https://pubmed.ncbi.nlm.nih.gov/36918389/
2. https://jamanetwork.com/journals/jama/fullarticle/2807533
3. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
4. https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/global-health-estimates-leading-causes-of-dalys
5. https://www.nature.com/articles/s41380-023-02251-4
6. https://www.nature.com/articles/s41591-023-02584-1
7. https://pubmed.ncbi.nlm.nih.gov/36017397/
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546763/
9. https://pubmed.ncbi.nlm.nih.gov/36220604/
10. https://www.parkinson.org/blog/science-news/artificial-intelligence
11. https://www.nature.com/articles/s41746-023-00905-9
12. www.frontiersin.org/journals/surgery/articles/10.3389/fsurg.2022.863921/full

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