Kellyann Niotis: Neurodegenerative Disease — Pathology, Screening, and Prevention

Kellyanne’s Background and Interest in Neurodegenerative Diseases

• First-​​generation American, always interested in biology and chemistry
• Loved learning in medical school, but disappointed in clinical rotations
• Chose neurology due to fascination with the brain

Neurodegenerative Diseases

• Third leading cause of death
• Includes Alzheimer’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson’s disease, Huntington’s disease, ALS, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration

Understanding Different Types of Dementia and Neurodegeneration

• Frontotemporal dementia and vascular dementia: primarily affects the frontal lobe, responsible for executive functions like planning, problem-​​solving, and speed of processing
• Alzheimer’s disease: affects the temporal lobe, responsible for memory and language
• Lewy body dementia: affects the parietal and occipital lobes, responsible for visual-​​spatial processing, depth perception, and hallucinations

Visual Impairment and Neurodegenerative Diseases

• Visual impairment is a risk factor for neurodegenerative diseases
• Visual processing is needed to reinforce neuronal circuitry
• Sensory input and stimulation are necessary to maintain neuronal circuits

Vascular Dementia and Alzheimer’s Disease Overlap

• Difficult to discern clinically
• Frontal lobe is hypometabolic in terms of glucose utilization in both frontotemporal dementia and vascular dementia
• May be related to the vasculature of the brain and sensitivity to glucose metabolism, cholesterol metabolism, and vascular risk factors

Insulin Resistance and Neurodegenerative Diseases

• Intranasal insulin injections temporarily alleviate some symptoms of dementia
• Metabolic syndrome associated with type 2 diabetes may be a marker of underlying vascular problems

• Improving serum biomarkers like high apob can lead to improved speed of processing in patients
  Parkinson’s Disease and Risk Factors

• Parkinson’s disease affects dopamine-​​producing brain cells 
  • Dopamine is necessary for movement and mood regulation
• Possible causes of cell loss in Parkinson’s disease: 
  • Immune system and inflammation
  • Mitochondria and lysosome function
  • Impaired autophagy
• Genetic models for Parkinson’s disease: 
  • GBA gene: glucose cerebrosidase enzyme gets stuck in the endoplasmic reticulum
  • Buildup of chemicals triggers inflammatory cytokines and a vicious cycle
• Causative triggers of Parkinson’s disease: 
  • Pesticide exposure
  • Solvent exposure
• For a 40-​​year-​​old with sleep disturbances predicting Parkinson’s disease: 
  • No perfect answer, but understanding and addressing risk factors is crucial

REM Sleep Behavior Disorder

• Acting out dreams (punching, kicking, moving a lot) during sleep
• Over 90% positive predictive value for developing Parkinson’s or Lewy body-​​like disease
• Diagnosis can be made through polysomnography or by asking if a bed partner notices excessive movement during sleep

ALS and Frontotemporal Dementia

• ALS is a peripheral nerve problem, while Parkinson’s disease is a central problem
• Connection between ALS and frontotemporal dementia through genetic risk factors (e.g., C9ORF)
• Family members may develop either ALS or frontotemporal dementia, but the reason for this is not well understood
  Paraquat and Rodinone Pesticides and Parkinson’s Disease
• Higher prevalence of Parkinson’s Disease in rural areas in the US 
• Epidemiological studies show a “Parkinson’s Disease belt” in the Midwest
• USDA and FDA do not acknowledge the connection between pesticides and Parkinson’s Disease
• Pesticides used for agricultural farming

Parkinson’s Disease: Genetic Factors

• 10% of Parkinson’s Disease cases have a clear genetic etiology
• GBA and LRRK2 are common genes associated with Parkinson’s Disease
• Genetic risk factors are not fully penetrant like Huntington’s Disease
• Genetic understanding of Parkinson’s Disease is far behind that of Alzheimer’s Disease

Addressing Early Warning Signs of Parkinson’s Disease

• Movement assessment is key
• Abnormal movement patterns can be seen years before tremor and slow movements start
• Deconstructing abnormal movement patterns and working on breathing can help
• Reinforcing neglected movements can help build stronger neuronal circuitry

Optimizing Sleep for Parkinson’s Disease Patients

• Patients with REM sleep behavior disorder often don’t get enough REM sleep
• Sleep tracking can be helpful
• Optimizing sleep with sleep hygiene is important for managing anxiety, depression, and stress
  Sleep Trackers and Anxiety
• Sleep trackers can create anxiety for some individuals 
• Knowing about disrupted REM sleep can be helpful, especially for Parkinson’s patients 
  • Melatonin signaling pathway is off in Parkinson’s disease
  • Lightbox therapy can help regulate melatonin signaling and improve REM sleep

Anxiety and Parkinson’s Disease

• Anxiety can be a symptom of Parkinson’s disease
• Disrupted sleep can contribute to anxiety
• Knowing about the risk of Parkinson’s disease can cause anxiety

Early Detection and Intervention

• Early detection and intervention can potentially delay the onset of symptoms or slow the loss of dopaminergic cells
• Lifestyle interventions and supplements may help move the needle in the right direction

Biomarkers for Parkinson’s Disease

• Alzheimer’s disease is a tauopathy with amyloid and tau proteins
• Parkinson’s disease and Lewy body dementia are alpha-synucleinopathies
• Alpha-​​synuclein is a misfolded protein that forms Lewy bodies and causes degeneration of brain cells
• Currently, no blood-​​based biomarkers for alpha-synuclein

Alpha-​​synuclein and Dopaminergic Cell Death

• Alpha-​​synuclein accumulation is directly proportional to the death of dopaminergic cells
• Patients with Parkinson’s disease and Lewy body dementia have different levels of alpha-​​synuclein accumulation
• Neurodegenerative diseases share underlying mechanisms, such as neuroinflammation and autophagy problems

Alzheimer’s Disease

• At least 6 million people in the United States have Alzheimer’s disease
• Incidence is rising, possibly due to better diagnosis or increased risk factors
• Alzheimer’s disease is characterized by amyloid and tau protein accumulation
• Amyloid-​​beta (Aβ) is a peptide produced by the cleavage of the amyloid precursor protein (APP)
• Tau is a protein that stabilizes microtubules in neurons; in Alzheimer’s disease, tau becomes hyperphosphorylated and forms neurofibrillary tangles

Toxic Proteins in Neurodegenerative Diseases

• Toxic proteins, such as amyloid-​​beta and tau in Alzheimer’s disease or alpha-​​synuclein in Parkinson’s disease, contribute to the degeneration of brain cells
• The pathogenic mechanisms driving the deposition of these abnormal proteins are shared among neurodegenerative diseases
• Targeting the commonalities between these diseases may help improve outcomes for many patients
  Amyloid Protein and Neurodegeneration
• Amyloid protein can misfold into amyloid plaques 
  • Sticky and fold up into cells in the brain, causing neurodegeneration
• Tau protein develops into neurofibrillary tangles in cells
• Alpha-​​synuclein develops into Lewy bodies
• These proteins accumulate inside neurons
• The relationship between the protein and inflammation may be the critical problem

Amyloid PET Scan

• FDG PET scan: looks at glucose hypometabolism in the brain 
  • Less signal in an area indicates less metabolic activity, correlating to neurodegeneration
• Amyloid PET scan: tracers tag onto amyloid deposition in the brain 
  • More signal in an area indicates more amyloid deposition
  • However, amyloid deposition can be seen in cognitively normal people

Tau Protein and Neurodegeneration

• Tau scan: FDA approved in 2020, not covered by insurance and high radiation
• School of thought: Amyloid -> Tau -> Neuroinflammation -> Neurodegeneration 
  • Not universally agreed upon
• Tau scan may be more sensitive at detecting Alzheimer’s specific tau
• Positive tau on scan indicates a higher likelihood of developing cognitive decline

Clearing Amyloid and Tau

• Sleep is a powerful tool to clear amyloid

• It is unclear if the same is true for tau, as it has not been studied as extensively
  Serum Biomarkers for Alzheimer’s Disease

• Percivity test: a serum biomarker for amyloid 
  • Shows amyloid beta 40 to 42 ratio
  • Encompasses someone’s APOE status
  • Provides an amyloid probability score
  • 80–81% accuracy at predicting a positive amyloid scan
• Tau 217: a new biomarker for research purposes 
  • Looking at ratios of phosphorylated to non-​​phosphorylated ptau to 17
  • Increases accuracy to around 90% for amyloid scans

Cognitive Testing for Neurodegenerative Disorders

• Olfactory testing
  • Cranial nerve number one (olfactory nerve) is one of the first parts of the nervous system to degenerate in Alzheimer’s, Lewy body, and Parkinson’s diseases
  • Olfaction is strongly related to memory
• Memory function testing 
  • Auditory and visual registering of information
  • Encoding process
  • Immediate learning, working memory, and delayed memory
• Attention tasks and speed of processing tasks 
  • Important to minimize distractions and optimize conditions for testing
• Visual spatial processing and episodic memory 
  • Remembering the sequence of objects seen
• Executive function and problem-solving 
  • Verbal learning and pronouncing tricky words as a proxy for IQ
  • Helps understand a person’s cognitive reserve
    Language Bias in Cognitive Testing
• Different versions of cognitive tests for non-​​native English speakers 
• Challenging to administer due to different norms and forms
• Remote testing possible since COVID, with some pen and paper tasks

Cognitive Test Duration

• Typically takes an hour to an hour and a half

Retesting Frequency

• Change forms to avoid administering the same test multiple times
• APOE4 carriers can be retested in about six months without learning effect

FDA and Cognitive Test Endpoints

• FDA looks at tests like Mini Mental Status and Montreal Mocha Test
• Basic 30-​​question tests for cognitive impairment

Alzheimer’s Treatment Drugs

• Limited number of FDA-​​approved drugs
• Timing and stage of intervention crucial for efficacy

Hearing Loss and Dementia

• Association between hearing loss and all forms of dementia
• Causative relationship implies treating hearing loss reduces dementia risk

Role of Visual and Auditory Systems

• Increased cognitive load due to hearing or vision loss
• Sensory input necessary for cognitive functions and brain development

Oral Health and Overall Health

• Poor oral health often correlates with poor overall health
• Importance of maintaining healthy gums and teeth for overall well-​​being
  Oral Health and Alzheimer’s Disease
• Certain red complex pathogens associated with higher risk of amyloid deposition, tau deposition, and inflammation 
  • Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia
  • Gram-​​negative bacteria driving periodontal disease
• High colonization of these bacteria in the mouth increases peripheral inflammation 
  • Especially concerning for individuals with APOE4 gene
• Debate on whether bacteria can migrate to the brain through blood or cranial nerves 
  • Autopsy specimens have identified these bacteria in the brain
  • Inflammation may be the primary cause of damage
• Poor oral hygiene and dental implants, root canals, and external hardware in the mouth can contribute to bacterial colonization 
  • Flossing, water picks, and interproximal brushes can help remove bacteria

APOE4 Gene and Alzheimer’s Risk

• APOE4 gene increases the risk of Alzheimer’s and related neurodegenerative diseases 
  • APOE4 is not the sole determinant of risk; genes are not destiny
  • Interventions can mitigate some of the detrimental effects of APOE4
• Other genes related to Alzheimer’s risk: 
  • APOC1 and TOMM40: tightly associated with APOE4, can swing the balance of risk
  • Clotho (Klotho): offers a protective role against APOE4, affects the rate of cognitive decline 
    • Heterozygous individuals with one protective variant (KL-​​VS) have a more optimistic prognosis
    • Whole genome sequencing required to identify this variant
• Future developments in AI and CRISPR technology could streamline the identification and potential modification of Alzheimer’s risk genes
  Mitochondrial Haplotype and Alzheimer’s Risk
• Mitochondrial haplotype: not a gene, but a classification based on variants in mitochondrial DNA 
  • Mitochondria have their own genome, related to energy production
  • Over 4000 mitochondrial haplotypes exist
• Determining mitochondrial haplotype is difficult 
  • 23andMe uses markers for specific haplogroups, but not perfect
  • Whole genome sequencing with mitochondrial DNA sequencing and specific software needed for accurate determination
• Mitochondrial haplotypes can indicate risk for Alzheimer’s and Parkinson’s 
  • Haplotype H increases risk, especially for APOE4 carriers
  • Haplotype K seems protective, especially for APOE4 carriers
• Knowing haplotype can help tailor preventative strategies 
  • Example: if mitochondria are inefficient energy producers, focus on increasing mitochondrial density through exercise

Exercise and Brain Health

• Exercise has the most potential to improve brain health 
  • Different types of exercise have different benefits 
    • Coordination, balance, and proprioceptive exercises (e.g., dance) improve cognitive reserve and neuroplasticity
    • Zone Two exercises improve energy metabolism and efficiency
    • Strength training improves muscle mass and metabolic health
• Exercise increases BDNF (brain-​​derived neurotrophic factor), which protects and grows new brain cells, especially in memory centers
• Hypertension negatively impacts brain health 
  • Lower blood pressure (e.g., 120/​​70) is better for cognitive outcomes
  • Blood pressure fluctuations, especially at night, can be problematic and difficult to monitor
  • Continuous blood pressure monitoring technology is needed for better understanding and treatment of hypertension
    Alzheimer’s Disease and Gender Differences
• Alzheimer’s disease affects women two to one compared to men 
  • Hormone reduction, such as estrogen and testosterone, may contribute to this disparity
  • Other factors may also be at play, such as the Mgmt gene, which influences Alzheimer’s risk in women

Lewy Body and Parkinson’s Disease Gender Differences

• Lewy body and Parkinson’s disease affect men two to one compared to women 
  • The exact reason for this disparity is unclear, but hormones may play a role

Cognitive Reserve and Movement Disorders

• Higher cognitive reserve may help delay the progression or onset of alpha-​​synuclein-​​based pathologies 
  • Diversifying cognitive experiences and managing vascular risk factors can help optimize brain health
  • Incorporating movement into cognitive testing may help identify problems sooner

Future of Neurodegenerative Disease Research

• In the next five years, researchers hope to: 
  • Better understand the relationship between movement and neurodegenerative diseases
  • Incorporate exercise and movement into disease prevention and treatment strategies
  • View neurodegenerative diseases as a continuum rather than separate entities
  • Use cognitive testing, movement assessments, genetics, and family history to identify early risk factors
  • Develop targeted preventative strategies for individuals at risk for neurodegenerative diseases