Neuro Test 1

What are the two main pathological hallmarks of Alzheimer's disease?

Beta-amyloid plaques & tau-containing neurofibrillary tangles

First stage of progression of cognitive impairment in AD

Subjective decline: poor performance on testing, decline in mental ability

Second stage of progression of cognitive impairment in AD

MCI: symptomatic in 1+ cognitive domains but still functional

Third stage of progression of cognitive impairment in AD

Dementia: cognitive impairment severe enough to impair independence and affect daily life

What is a neurobiological diagnosis

when it is based on symptoms and biomarkers in CSF & on PET scan

What type of dementia do most people have?

Multi-etiology dementia

What is the relationship between the incidence of MCI and the incidence of dementia at any age?

MCI incidence increases about 2x for dementia at any age

What is the number 1 risk factor for AD?

Increasing age

Lifestyle risk factors for AD

Alcohol abuse, smoking, hypertension, diabetes, low physical activity

What is the glymphatic system

The space around arteries and veins in the brain that CSF flows through to clean out waste

How does the glymphatic system relate to amyloid beta clearance

The glymphatic system clears out debris, and this includes amyloid beta

What are the four receptors that amyloid beta oligomers interact with.

mGluR5, NMDAR, A7 nicotinic acetylcholine R, insulin R

How does the activation of the four receptors that amyloid beta oligomers interacts with affect neural activity?

All but insulin R increases neural activity

What is a potential effect of lower levels of APPsα?

It can lead to a decrease in synaptic transmission modulation

What does increased activity in the amyloidogenic pathway mean for the alpha secretase pathway

Leads to decreased activity in the a-secretase pathway

In what cortical network does beta amyloid mainly accumulate?

In the DMN (default mode network (in cerebral cortex))

How does hyperconnectivity and increased glucose uptake in this network relate to risk of beta amyloid accumulation?

Regions with hyper-connected mobile networks exhibit increased glucose metabolism and display increased levels of beta amyloid

What is the normal role of tau?

Tau stabilizes microtubules

What can cause tau to aggregate?

Post translational modifications/hyperphosphorylation

What are the 2 outcomes that differences in post-translational modifications of tau can affect

Likeliness of seeded aggregation and different processing or trunication

How does tau spread throughout the brain?

Through synaptic transmission

Neurofibrillary tangles relation to tau

They are intracellular tau aggregates

Neurofibrillary tangles relation to tau

Tau fragments in the neuropil (extracellular)

Dystrophic neurites relation to tau

Tau containing degenerated axons & dendrites surrounding AB plaques

Can tauopathy spread beyond the medial temporal lobe without the co-occurrence of beta amyloid plaques?

No, it needs them to expand into other cortices

Do cognitive symptoms relate more to the location of plaques or tangles?

Tangles relate more

What is the specific location of initial tau deposition (tangles)?

Entorhinal cortex

Where does tauopathy begin and spread to

Starts in entorhinal cortex, spreads to medial prefrontal and predial parietal cortex

What is the normal function of ApoE?

It moves lipids and lipid complexes

What are the three common ApoE isoforms

ApoE4, APOE2, APOE3

How does APOE4 relate to AD risk

increases risk because it can cause accumulation of AB

How does APOE3 relate to AD risk

Has neutral impact

How does APOE2 relate to AD risk

Is protective from AD

What is the connection between ApoE isoforms and tau propagation?

APOE4 can increase AB accumulation which increases tau

When does synaptic loss occur in AD

before tauopathy and neurodegeneration

How does AB in and around plaques affect calcium and neural activity

Increases calcium influx which increases neural activity

Are synapses between plaques affected in AD or only those within plaques?

Both between and within

What evidence suggests that soluble forms of Aβ and tau are more toxic to synapses than aggregated forms?

Increased AB increases calcium, increased tau alters firing rate, increased AB & tau decreases neural activity in parital cortex

What is reactive synaptogenesis

The brains attempt to form new synapses after injury

What causes reactive synaptogenesis in the AD hippocampus

The loss of the perforant pathway

What tags synapses for removal

Microglia tags

How do microglia tags connect to neuroinflammation and AD

The tags become chronically activated in AD which causes neuroinflammation

Where are AB and B CTF mainly generated within

Endosomes

What are the first neuronal organelles known to exhibit AD-specific neuropathology

endosomes

What are the main sites for clearance of intracellular AB and B CTF

Lysosomes

In AD what does abnormal accumulation of AB and B CTF impair the function of

lysosome function

What does the impairment of lysosome function lead to the failure of

autophagy

What is presenilin

The part of a secretase complex and is necessary for lysosomal acidification

How is presenilin involved in dysfunctional proteostasis

Mutations/deletions of this interfere with the proton pump and Cl-Channel

How does the APOE ε4 allele affect ELN function?

It accelerates & accentuates dysfunction, impedes exosome release, & causes lysosomal expansion & membrane permeabilization

What is the dual role of autophagy in AD

In early AD, it’s neuroprotective against age and disease-related oxidative stress. In later, it overwhelms lysosomal system which leads to faster autophagy failure & neurode generation.

What does genetic risk for AD tell us about the potential role of microglia and neuroinglammation?

It suggests the role of microglia & neuroinflammation in AD

How do microglia contribute to AD

In AD, activated microglia release cytokines which lead to increased neurodegeneration (this is further elevated when autophagy is impaired)

How are presentations of AD modified by the co-presence of non-AD pathology

Other diseased in a patient affect how AD will present in a person

What are the characteristics of a prototypical AD patient.

Amnestic MCI progressing impairment of language, spatial cognition, executive function & working memory, and co-occurrence of psychiatric symptoms

What does the progression of symptoms follow the spread of

tauopathy

the 3 main non-amnestic presentation of AD

Visual variant/visuospatial deficits, Logopenic form of primary progressive aphasia & Dysexecutive presentation

Visual variant/visuospatial deficits description

• Reading

• Face recognition

• Processing complex visual scenes

Visual variant/visuospatial deficits, Logopenic form of primary progressive aphasia description

• Non-fluent aphasia

• Prominent word-finding pauses

• Naming and repetition difficulties

Dysexecutive presentation description

• More frequent in younger patients

• Preserved memory function

• Problems with executive function, multi-tasking, decision making, and behavioral changes

How do medical practitioners determine the presence and severity of cognitive impairment?

• Info from someone familiar with patient’s daily life

• Cognitive evaluation of patients (mental status examination)

• Neuropsychological testing

Besides AD, identify 5 other potential causes of MCI or dementia

Any neurodegenerative or cerebrovascular disease, Depression, Medication misuse, Obstructive sleep apnea, Will also screen for hypothyroidism, B12 deficiency, structural brain lesions (neoplasms, subdural hematomas), Dementia, Lewy body disease, Frontotemporal degenerations, Hippocampal sclerosis

2 reasons AD screening in the absence of cognitive complaints is not recommended?

Not enough data on improved outcomes with cognitive screening, & Tests not precise enough for detection of milder cognitive impairment

What is the A-T-N approach?

Classifies people along AD spectrum to determine most meaningful combo of biomarkers

What is the difference between state and stage biomarkers?

State are for presence of feature and stage is for severity/progression

What are MRI/CT biomarkers used for in AD

To assess macroscopic brain atrophy, detect microbleeds, rule out other causes of cognitive impairment

What are FDG-PET biomarkers used for in AD

To visualize how the brain uses glucose, frequently see temporal/parietal/ hippocampal hypometabolism, even before volume loss, in AD

What are AB-PET biomarkers used for in AD

To visualize plaques and measure β-amyloidosis changes over time, more precise diagnosis, useful for detecting and monitoring Aβ in early stages of AD

What are Tau-PET scans used for in AD

Detects largely AD-specific tauopathy, predictive of subsequent cognitive decline, regional patterns map onto AD phenotype, measure changes over time

Why is global brain volume loss alone not useful for diagnosing AD?

Because it is not specific to AD

What forms of Aβ does Aβ-PET detect and not detect?

detects fibrillar Aβ deposits but cannot detect Aβ oligomers or diffuse plaques

Why is CSF Aβ42 decreased in AD?

Because AB42 peptides are cleared from the brain into the CSF and then removed from the central nervous system, and because AD pathology alters amyloid‑β metabolism and transport.

Why is Aβ42 normalized to Aβ40 or to tau?

To control for biological variability, age-related changes, and potential confounding factors, making the ratio a more stable and interpretable biomarker for Alzheimer’s disease (AD) pathology.

Who is CSF AB42 decreased in

People with symptomatic AD & in asymptomatic but will later develop symptoms

Why is P-tau 181 a good AD-specific biomarker?

Because it correlates with neurofibrilly tangles, t-tare, and increased in AD but not other diseases

What two things does p-tau correlate with

Neurofibrilly tangles & t-tau

What tau measurement is a general marker of neurodegeneration?

t-tau

Are current blood-based biomarkers diagnostic or just for screening?

Just for screening

What 3 factors likely contribute to the variability of the rate AD progression

Biology of AD, non AD pathologies, & comorbidities

Which biomarkers are most predictive of progression from MCI to dementia?

Abnormal AB biomarkers

Which ApoE allele and genotype is associated with the fastest progression?

APOEe4 homozygotes

What lifestyle factors have evidence for reducing AD risk?

Exercise, cognitive stimulation, lowering of blood pressure

In what domains are AD patients encouraged to be active?

Anything that decreases risk of cerebrovascular disease related to brain injury

Why are anti-cholinergic drugs avoided in the treatment of AD?

They can worsen cognitive impairment & increase dementia risk

Impairment of what sensory system exacerbate STM loss?

Auditory system

2 difficulties in treating pain in AD patients.

Hard for patients to describe their pain & strong analgesics can cause sedation

2 additional ways that treating comorbidities in AD is different from treating those conditions in patients without cognitive impairment.

Need to lower doses of medication for mental illness, patients may struggle with masks for sleep disorders

selective serotonin inverse agonist

treats Dementia-related psychosis

Atypical antipsychotics

treats Psychotic and behavioral symptoms, to avoid extrapyramidal effects

cholinesterase inhibitors

No effect on biology of AD; to preserve cholinergic transmission

NMDA-R antagonist

No effect on biology of AD; to block a certain type of glutamate receptor

Monoclonal antibodies against beta amyloid

meant to bind to and remove amyloid plaques

the role of secretases in APP processing.

APP is processed by three main secretases — α-, β-, and γ-secretases — whose cleavage patterns determine whether toxic amyloid‑β (Aβ) peptides are produced or not, making them central to Alzheimer’s disease pathogenesis

α‑Secretase (non‑amyloidogenic pathway)

Cleaves APP within the Aβ domain, preventing release of full‑length Aβ, Upregulating α‑secretase shifts APP processing away from Aβ production and toward beneficial sAPPα generation

β‑Secretase (amyloidogenic pathway)

Cleaves APP outside the Aβ domain, initiating Aβ production, This is the rate‑limiting step in Aβ generation; BACE1 inhibition is a major AD drug strategy

γ‑Secretase (final cleavage)

Cleaves both C83 (from α‑secretase) and C99 (from β‑secretase), γ‑secretase activity determines Aβ length and aggregation potential; modulating it can influence plaque formation

What are the 2 main types of neurons affected in ALS?

Upper motor & lower motor neurons

What are the 2 types of onset

Spinal-onset & bulbar-onset

What does bulbar refer to

the brainstem

Dysphagia

Difficulty with swallowing