Bio Sci 37 Midterm 2

Is dementia part of normal aging?

No —> dementia is characterized by multiple cognitive deficits with memory impairment as a frequent early symptom.

Most significant risk factor for Alzheimer’s Disease

Aging (also the leading cause of dementia)

What is normal aging?

• trouble recalling people or places

• forgetting appts or events occasionally

• taking longer to process info

• sometimes losing track of a convo

• forgetting where item is occasionally

What are symptoms of dementia?

• not remembering the names of close family or friends

• frequently forgetting appts and events

• trouble verbalizing thoughts, frequent pauses in convos, sub common words

• regularly repeating statement or questions

• consistently misplacing items

• frequency confusion

• unable to focus

• becoming lost in familiar places

• mood changes

The trajectories of age-related cognitive change

1. better than avg —> super aging

2. normal aging

3. mild cognitive impairment

   ***independent function in daily living***

4. abnormal aging —> dementia

   ***cannot function w/o assistance due to cognitive loss***

Middle Age

Represents period that shapes future cognitive trajectories and brain health —> brain aging comprises many process that change in different ways.

Does brain volume decrease with age?

Yes

gray matter decreases —> associated with reductions in neuronal number and/or volume

white matter decreases —> associated with reductions in the diameter of the myelin sheath

Synaptic Plasticity

Ability of synapses to strengthen or weaken in response to activity —> often associated with structural changes.

***greater when we are young

What does demyelination in normal aging do?

Contributes to age-related memory changes.

What are subtle cognitive decline in aging brains?

• slower reaction times

• lower attention levels

• slower processing speeds

• decreases sensory and perception function

• changing in sleep pattern (less time in dream and deep sleep)

What is the number one factor that can improve the performance of ages individuals?

Exercise

What are factors that influence brain aging?

• Genetics (eg. family history)

• Environment (eg. levels of education)

• 8 hours of sleep per night (sleep activates healthy clearance mechanism —> removes toxins in brain)

• Immune system, gut, vasculature —> communicate with brain and influences cognition

Neurogenesis

Process by which neurons are generated from neural stem cell (cells in the brain that divide) and progenitor cells —> responsible for populating the growing brain w/ neurons.

Adult Neurogenesis

Neurons are generated from adult stem cells.

Is neurogenesis restricted?

Yes

Where does neurogenesis occur?

• hippocampus (subgranular zone) —> lead cells to repopulate the olfactory bulb (OB)

• subventricular zone (SVZ) —> lead cells to repopulate the granular cell layer in dentate gyrus

Does neurogenesis slow aging?

Yes —> a bit unclear though regarding how it contributes to cognitive processes and aging.

Factors that affect neurogenesis?

• environmental enrichment

• exercise

• neurodegenerative diseases

• depression

• aging

How to delay cognitive decline?

• minimize stress —> decrease cortisol levels (stress hormone) which negatively impacts learning and memory

• exercise —> aerobic

• networking —> active social life

• diet: omega 3 fatty acids, antioxidants, less sugar

• higher education —> mental activity

Parabiosis

“Leaving beside” —> anatomical joining of two individuals artificially in physiological research

eg. joining young and old mouse together —> does this influence learning and memory for the old mouse?

What does parabiosis research show?

• young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice (young blood improves old subject performance)

• aging systemic milieu negatively regulates neurogenesis and cognitive function (old blood impairs young subject performance)

• human umbilical cord plasma proteins revitalize hippocampus function in aged mice (young human blood improves cognitive performance)

• clinical trial finds blood-plasma infusions from young healthy donors is safe to AD patients

• in a small trial, participants receiving blood plasma infusions from young donors showed some evidence of cognitive improvement

What is dementia?

Umbrella term —> abnormal part of aging —> many biological causes

Characterized by problems with:

• thinking

• language

• memory

• judgment

• reasoning

These problems get in the way of daily living

What are activities of daily living?

Basic:

• feeding

• dressing

• bathing

• toileting

Instrumental:

• transportation

• taking medication

• prepping meals

• managing finances

What are diseases under dementia?

• Alzheimer’s Disease

• Frontotemporal Lobar Degeneration

• Parkinson’s Disease-related Dementias

• Progressive Supranuclear Palsy

• Creutzfield Jacob Disease (Prion)

• Huntington’s Disease

• Dementia with Lewy bodies

Types of Brain Disorder

• specific disorders (focal damage) —> depends on the area of the brain affected (where a bullet hits, strokes)

• generalized disorders (widespread damage) —> affects multiple cognitive abilities (closed head injury, dementing disorders, demyelinating diseases, toxic substances)

Dementing Diseases

• loss of cognitive function, sometimes accompanies by personality changes, which interfere significantly with the individual’s daily activities work and social activities

• mild: retain judgment, sustain daily activities, but work and social activities are impaired

• moderate: independent living = hazardous (eg. forgetting to turn off stove) and requires some supervision

• severe: cognitive abilities are so compromised that constant supervision needed

Aphasia

Loss of ability to understand or express speech.

Apraxia

Inability to link skilled motor movements to ideas or representations (eg. I want to tie my shoes, but I physically cannot).

Agnosia

Deficit in recognizing objects that occurs in the absence of deficits in sensory processing (eg. see a cup and shoe —> cannot distinguish objects).

Acalculia

The inability to perform simple mathematic calculations the patient previously knew.

Types of Dementias —> clinical classification

cortical, subcortical, and mixed

Cortical

Co-occurence of many cognitive deficits (aphasia, apraxia, agnosia, acalculia, visuospatial deficits, and memory problems) —> eg. Alzheimer’s, frontotemporal dementias, Creutzfeldt-Jakob (prion diseases)

Subcortical

More likely to manifest first as personality changes, attention deficits, slowness in cognitive processing, difficulties w/ tasks requiring strategy —> eg. Parkinson’s, Huntington’s

Mixed

Both cortical and subcortical involvement, patterns of cognitive performance midway between cortical and subcortical types —> eg. Vascular dementia, Lewy body dementia

What is the molecular classification of dementia?

Accumulation of abnormal protein aggregates in neurons and glia and also in extracellular compartments, in vulnerable regions of the brain.

What neurodegenerative proteinopathies does non-vascular dementia fall into?

• Amyloid-B (AB)

• Microtubule-associated protein tau

• TAR DNA-binding protein 43 (TDP-43)

• Fused in sarcoma (FUS)

• Alpha synclein

• Prion protein

Alzheimer’s Disease

• impaired memory

• impairment in at least one other cognitive domain

• impaires social or occupational functioning

• gradual onset and continual decline

What is found in many neurodegenerative diseases?

Abnormal protein deposits/aggregates —> protein misfolding disorders.

What types of protein aggregates are associated with certain neurodegenerative diseases?

• Alzheimer’s —> plagues and tangles

• Huntington’s —> intranuclear inclusions

• Parkinson’s —> lewy bodies

• Prion —> amyloid plaques

• Amyotrophic Lateral Sclerosis Aggregates

Are there genetic associations in Alzheimer’s Disease?

Yes —> if we know mutation is in “X” gene, then this will lead to this disease.

Mutations can be direct causes or increase risk of Alzheimer’s

***there are a lot of unknown mutations however (we do not know what caused the Alzheimer’s)

Is Alzheimer’s a public health issue?

Yes —> more women have Alzheimer’s, number of people age 65 and older with the disease is increasing through the years, very prevalent in California

Frontotemporal Dementia

• No amnesia in early stages

• Associated with shrinkage of frontal and temporal lobes

• Impulsive, bored, listless

• Inappropriate social behaviors (eg. hypersexual)

• Neglect of personal hygiene

• Repetitive or compulsive behavior

• Speech problems, semantic deficits

What are the three types of frontotemporal dementia?

• Behavioral-variant

• Semantic dementia

• Progressive nonfluent aphasia

Behavioral-variant frontotemporal dementia

• changes in social conduct and behavior

• loss of empathy

• apathy

• disinhibition

• lack of insight

Semantic dementia

• loss of semantic knowledge, impaired word comprehension, and object naming

• fluent speech and spared repetition

Progressive nonfluent aphasia

• apraxia and effortful speech

• spared object knowledge and word comprehension

Dementia with Lewy Bodies

• Lewy bodies (alpha synuclein neuronal inclusion bodies —> protein in Parkinson’s disease too)

• similar to Alzheimer’s in terms of cognitive features

• defining symptoms: bradykinesia, rigidity (like Parkinson’s), recurrent and well-formed hallucinations

• memory deficits less severe than AD but visuospatial deficits are more sever than AD

Stages of Lewy Body Dementia

• early: delusions, restlessness, REM sleep disorder, movement difficulties, urinary issues

• middle: motor impairment, speech difficulty, decreased attention, paranoia, confusion

• later: extreme muscle rigidity and speech difficulties, sensitivity to touch, susceptible to infections

Vascular Dementia (VAD)/Multi-Infarct Dementia (MID)

• caused by blockages in brain’s blood supply (not by protein aggregates)

• second most common form of dementia (1st = Alzheimer’s)

• may cause or worsen Alzheimer’s (complicates diagnosis as vascular factors contribute to AD)

• cognitive abilities more impaired than AD patients on executive function (planning, organizing, control impulses, achieve goals)

• less impaired on episodic memory

What are the risk factors of Vascular Dementia?

• high blood pressure (50% caused by hypertension)

• diabetes

• high cholesterol

• family history of heart problems

• obesity

• smoking

Parkinson’s Disease

• progressive neurologic disease

• fourth most common neurodegenerative disease in elderly

• neuropathology —> degeneration of dopamine (DA) producing neurons in the brain (substantially nigra)

• motor symptoms

• neuropsychiatric symptoms

What are the motor symptoms of Parkinson’s Disease?

• tremor

• bradykinesia (slow movement)

• rigidity

What are the neuropsychiatric symptoms of Parkinson’s Disease?

• executive dysfunction

• memory deficits

• attention deficits

• visuospatial deficits

• mood disturbances

• impulse control behaviors (eg. food, drugs, gambling)

Are there trials for dementia?

Yes! —> drugs approved but have minimal effects.

What is preclinical cognitive decline?

• silent phase —> brain changes without measurable symptoms

• individual may notice changes but not detectable on tests

• a stage where the patient knows but the doctor does not

What is mild cognitive impairment?

• cognitive changes are of concern to individual and/or family

• one or more cognitive domains impaired significantly

• preserved activities of daily living

What is dementia (severe cognitive impairment)?

• cognitive impairment severe enough to interfere with everyday activities

#1 Risk Factor of AD

age

What is Alzheimer’s Disease?

An irreversible and progressive neurodegenerative disorder characterized by a gradual loss of memory and other cognitive function, deficits in activities of daily living, behavior, personality and judgment. Accounts for the majority of dementia cases at 65 years of age or older.

• destroys cognition, personality, and ability to function

What are symptoms of Alzheimer’s Disease?

• memory loss

• language deterioration

• impaired ability to mentally manipulate visual info.

• poor judgment

• confusion

• restlessness

• mood swings

What are the early signs of AD?

• forgetfulness

• loss of concentration

***missed because they resemble natural signs of aging

Behavioral symptoms in AD?

• very common

• more distressing for caregivers than cognitive symptoms

• overlapping clusters: depression, apathy, sleep, agitation, psychosis

• others: anxiety, emotional lability, delusions, hallucinations, euphoria, irritability, aberrant motor behavior, appetite/EDs

Is AD fatal?

yes —> a person with AD will depend on others for complete care

• progressive cerebral deterioration

  • bed ridden

  • dysphagia —> difficulty swallowing foods and liquids

  • failure to thrive

***the 6th leading cause of death in the US

Is AD insidious?

yes —> changes happen to the brain years prior, BEFORE symptoms show

What is mild cognitive impairment?

Memory and/or other cognitive problems that

• are a source of complaint

• demonstrable on cognitive tests

• do NOT impair activities of daily living

• do NOT meet criteria for dementia'

***general forgetfulness

Does mild cognitive impairment lead to dementia?

~12-16%/year progress to dementia

• more frequently AD —> especially for those with memory problem or memory/other cognitive problems

• risk is increased for those with supportive evidence of AD

• still, up to 50% do not progress to dementia after 1- years

• 20% revert to normal cognition —> this group remains at an elevated risk for dementia however

What are the stages of AD?

Mild

• recent memory loss

• language impairment

• faulty judgment

• personality changes

Moderate

• aggression (verbal and physical)

• agitation

• wandering

• sleep disturbances

• delusions

Severe

• loss of all reasoning

• bedridden

• incontinent

What does AD do to neurons?

Disrupts the three essential functions of neurons

• neurons must communicate with each other

• carry out metabolism

• repair themselves

Amyloid Plaques

• insoluble extracellular deposits which accumulate in the cortex and hippocampus

• composed of amyloid-beta (AB) protein fragments: AB40 and AB42

Neurofibrillary Tangles

• bundles of insoluble helical fibers within neurons

• composed of hyperphosphorylated tau proteins that are normally associated with microtubules

What does AD do to brain mass?

Since it causes an intensive loss of synaptic contacts and neurons, cortical atrophy occurs —> loss of 1/3 of brain mass

Cause of amyloid plaques?

• incorrect cleavage

• AB 42 cleave product of APP (amyloid precursor protein) —> produces toxic AB 42 cleavage product

  • in the cell membrane. B-secretase or y-secretase cleaves AB —> causes plaque aggregation

  • point mutations in the y-secretase gene can lead to early onset AD inherited in families in an autosomal dominant pattern

  • point mutations in the APP gene located on chromosome 21 can lead to early onset AD inherited in families in an autosomal dominant pattern

  • multiple fragments link —> now a plaque

How to fight against amyloid plaques?

• find drugs that inhibit the secretase

• antibodies against AB

• sleep clears AB

What are the risk factors of AD?

• age (80-90) = #1

• genetics —> known genetic bases (APP, PS-1, PS-2) —> but mostly for early onset, familial AD

• ApoE4 = reliably identified genetic risk factor for AD (does not mean if you have it you will get AD)

  • other genes —> MAPT (tau), SORL1, TREM2)

• non-genetic factors have associated risks —> head trauma, high blood pressure, heart diesease, stroke, diabetes, high cholesterol

How is AD and Down Syndrome connected?

Individuals with Down syndrome are 3-5x more likely than the general population to develop AD —> onset of AD may be as early as 30 in the Down syndrome population (age 50 in general population).

• duplications of a small part of chromosome 21 which includes the APP gene can cause early onset AD

Is there a protective APP mutation?

Yes —> whole genome sequencing on Icelandic population identified a FUNCTIONAL variant protecting against Alzheimer’s disease! —> will be a therapeutic target for AD

• A673T —> prevents cleavage of APP and cognitive decline in the elderly

Amyloid cascade hypothesis

Missense mutations in APP —> accumulation of plaques —> cascade of damage and dysfunction in pathways —> dementia

What molecular pathways are involved in AD?

• amyloid-beta (AB) pathway

• tau protein pathology

• calcium signaling

• excitotoxicity

• genetic factors, inflammation, oxidative stress play a role

What happens to the ventricles in the brain when a person has AD?

Enlarges as surrounding brain tissue shrinks due to neuronal loss and atrophy.

What do Tau proteins do?

• Tau stabilizes MT in neurons (in axonal processes)

• MT main functions —> structure, organize the cytoplasm, serve as tracks for the transport of cellular elements form the cell body to the axonal terminals (synapses)

What leads to neuroinflammation in AD?

• microglia genes are activated by amyloid-beta deposition, leading to the release of pro-inflammatory cytokines and the recruitment of other immune cells.

• microglia SHOULD clear out AB —> but when not regulated, causes problems

• astrocytes are also activated by AB and contribute to inflammation

What are the modifiable risk factors of AD?

Social determinants, which primarily affects underserved and socioeconomically disadvantaged individuals.

How is mild cognitive impairment measured?

• memory complaint corroborated by informant

• measurable, greater-than-normal memory impairment detected with standard memory assessment tests

• still has normal general thinking and reasoning skills

• should have the ability to perform normal daily activities

• several subtypes (the AMNESTIC subtype is more likely to process to AD)

Components of the AD evaluation

• check clinical history —> largely dependent on informant

• physical and neurological exams

• lab tests

• neuroimaging

  • structural (CT/MRI)

  • functional (PET)

• neuropsychological assessment

Which of the following is characteristic of MCI?

memory loss

What does an ABC score depend on?

presence of AB plaques

What does BRAAK staging depend on?

neurofibillary tangles

How does imaging the AD brain work?

• magnetic resonance imaging used

• assesses brain atrophy

  • stage 1-2 —> entorhinal cortex is affected

  • stage 3-4 —> hippocampus, amygdala, parahippocampus

  • stage 5-6 —> neocortex

  • this loss corresponds with NFTs (tangles)

What type of metabolism is reduced in AD brains?

glucose metabolism

What does PET (position emission tomography) imaging show in AD?

Shows hypo metabolism compared to normal patients, in relevant brain areas.

***shows what is missing (such as the loss of glucose metabolism)

What does structural MRI show in AD?

Show amyloid plaque accumulation in the brain and structural changes associated with Alzheimer’s disease.

***shows what is added

How does amyloid PET imaging work to show plaques?

• plaques directly imaged via amyloid tracers

• other ligands FDA- approved —> amyvid, neuroceq, vizamyl

How does amyloid PET imaging work to show NFTs?

• ligands bind to hyperphosphorylated tau aggregates found in NFTs

• several ligands are in development that can highlight tau pathology

Why is AD a public health concern?

• prevalence will increase as population ages

• death from AD has increased

Why is AD an economic concern?

There are billions of dollars needed to care for people with AD.

Why is AD a social concern?

Caregivers face significant emotional and physical strain, impacting families, communities, and their jobs.

Why are biomarkers for AD important?

• helpful for early diagnosis (which is IMPORTANT)

• is this person progressing?

• establishes a baseline

• lets doctor know if a drug is working

Does cerebral spinal fluid help predict progression from MCI to AD?

Yes —> higher risk of progression to Alzheimer's disease because AB is released in CSF

Can AB be prevented?

• no evidence for prevention yet

• cognitive and psychological activities may reduce risk for AD

• phase III prevention trial —> A4 Trial (concluded) (Anti-Amyloid Treatment in Asymptomatic AD)

• targeting older adults with biomarkers for AD (eg. amyloid) but no symptoms of AD using an anti-amyloid agent to see if clearing amyloid prevents AD onset

Can exercise reduce the risk of AD?

yes —> physical activity linked to reduced risk for AD

• small benefits in clinical trials (especially in executive function)

• aerobic and strength training

• sessions longer than 30 minutes show larger effects than shorter sessions

• more studies needed!