Case 1 - cognitive deficits - fundamentals

Question 1

dementia pipeline

Answer 1

diagnosis = multidisciplinary
1. Clinical History and Initial Assessment
2. Physical Examination
3. Cognitive Assessment:
* Commonly used tests include the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA).
4. Neuroimaging: when suspecting something other than dementia
5. Blood Tests: when suspecting somethiing other then dementia
6. Neuropsychological Testing
7. Functional Assessment: ADLs
8. Psychiatric Evaluation
9. Collaborative Diagnosis
10. Follow-Up and Monitoring:

Question 2

ageing brain

Answer 2

1. Cognitive Changes:
   * Affected Domains: Executive and attentional functions are particularly affected in normal aging. Semantic and verbal knowledge seem relatively preserved.
   * Memory Dysfunction: Age-related memory dysfunctions include impaired short-term memory, episodic long-term memory, and working memory.
2. Grey Matter Changes:
   * Patterns: Age-related grey matter changes involve cortical thinning, decreased brain tissue surface, and progressive reduction in brain volume.
   * Regions Affected: Frontostriatal brain regions, especially the prefrontal cortex, show pronounced age-related grey matter volume reductions.
3. White Matter Changes:
   * Characteristics: Age-related white matter changes involve deterioration of fiber connections due to myelin loss, leading to reduced white matter volume.
   * Patterns: Frontal fiber connections are particularly vulnerable to age-related decline.
4. Functional Changes in Brain Activation:
   * Prefrontal Cortex: Age-related changes in functional activation are particularly pronounced in rostral parts of the dorsolateral prefrontal cortex.
5. Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH):
   * Model: CRUNCH suggests that older individuals may show hyperactivation in frontal regions to compensate for reduced working memory capacity, especially at low task demands
6. Functional Connectivity Changes:
   * Definition: Functional connectivity refers to the correlation of activation between different brain regions.
   * Frontal Connectivity Dysfunction: Frontal connectivity, including bifrontal, frontoparietal, and frontostriatal connections, is impaired in older adults.
7. Neurotransmission Changes:
   * Dopamine Reduction: Reduction of dopamine, especially in the nigrostriatal dopamine system, is a significant factor in reduced cognitive performance with age.

Question 3

working memory

Answer 3

Working memory, is a cognitive ability responsible for temporarily storing (short term memory) and manipulating present information needed for various complex cognitive tasks in real time
- The model of working memory, includes different components: the phonological loop responsible for auditory and verbal information, the visuospatial sketchpad for visual and spatial information, and the central executive, which controls attention, integrates information, and manages the flow of data within working memory

Question 4

working memory fundamentals

Answer 4

• Studies revealed that short-term memories require increased pre-synaptic glutamate release as well as changes in post-synaptic glutamatergic receptor activity mediated by the covalent modification of existing proteins at preexisting synapses

Question 5

long-term memory

Answer 5

• Long-term memory is the system in our brain responsible for the storage of information for extended periods, ranging from days to years.
  o Long-term memory involves the relatively permanent storage of a vast amount of information acquired through experiences, learning, and conscious effort.
• Long-term memory is thought to involve structural and chemical changes in the brain that facilitate the encoding, consolidation, and retrieval of memories. hippocampus –> frontalcortex

Question 6

long term memory types

Answer 6

• These memories can be further classified into two primary types:
  o Declarative (explicit) refers to the storage of facts and events that can be consciously recalled and described. It includes two subtypes:
   Semantic memory stores general knowledge and concepts, such as facts, vocabulary, and information about the world.
   Episodic memory involves the storage of personal experiences, events, and specific episodes in one’s life.
  o Non-declarative (implicit) memory: encompasses various types of memories that influence behaviour without conscious awareness.
   This includes procedural memory (e.g., remembering how to ride a bicycle) and other forms like priming and classical conditioning.

Question 7

LTP

Answer 7

• LTP= is a persistent strengthening of synapses based on recent patterns of activity –> brief high frequency stimulation (tetanus) of a group of afferent fibers resulting in long lasting (hours to weeks) enhanced transmission at synapses
• If you apply multiple tetani the LTP will wear of much slower as compared to 1 tetanus
• Therefore reading a chapter 4 times increases the time for which you will remember the text as compared to just reading it ones
• Early LTP= protein synthesis-independent
• Starts immediately after 1 tetanus (1 high frequency stimulus) and relies on kinase activity
• Late LTP= protein synthesis-dependent
• Starts a few hours after multiple tetani and depends on the activation of the gene transcription

Question 8

Molecular LTP (early)

Answer 8

• Early LTP: –> enhancement of signal transduction in already existing synapses
  1. AMPA receptor binds glutamate and glycine opening the sodium pore
  2. The depolarisation of the post-synaptic neuron causes the NMDA receptor too lose its magnesium ion that was blocking the channel from opening up to calcium (after glutamate binding)
  3. Calcium influx causes more AMPA receptors (which are more responsive towards glutamate) to be placed on the post-synaptic membrane
• The increase in Ca2+ activates several downstream signalling pathways, including calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and tyrosine kinases
• These signalling pathways lead to changes that both enhance the response of the postsynaptic cell to glutamate and increase the amount of glutamate released from the presynaptic neuron (4)
• Repeated stimulation also activates translation in the dendrites of mRNA encoding PKMI an active isoform of PKC. This leads to a long-lasting increase in the number of AMPA receptors in the postsynaptic membrane
  4. The post-synaptic neuron releases retrograde messenger molecules like NO and arachidonic acid to initiate larger glutamate release from the pre-synaptic membrane
  a. This also increases AMPA receptor insertion in post-synaptic (PKC)

Question 9

LTP molecular (late)

Answer 9

• Late LTP: –> formation of new synapse
  1. With repeated tetani the calcium influx also recruits an adenylyl cyclase
  2. This generates cAMP which activates PKA (protein kinase A)
  3. This leads to the activation of MAP kinase (mitogen-activated protein kinase  involved in proliferation, mitosis and gene expression, etc.)
  4. MAP kinase translocates to the nucleus where it phosphorylates CREB-1 (cAMP responsive element binding protein 1)
  5. CREB-1 in turn activates transcription of targets (containing the CRE promoter) that are thought to lead to the growth of new synaptic connections  synaptic plasticity

Question 10

LTD

Answer 10

• Long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus.
  o LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress
• LTD affects hippocampal synapses between the Schaffer collaterals and the CA1 pyramidal cells.
• It depends on the timing and frequency of calcium influx.
• The magnitude of calcium signal in the postsynaptic cell largely determines whether LTD or LTP occurs.
  o NMDA-receptor dependent LTD is induced by moderate rises in postsynaptic calcium levels.
  o When Ca2+ entry is below threshold, it leads to LTD
• LTD arises from activation of calcium-dependent phosphatases (higher affinity than calmodulin) that dephosphorylate the target proteins.
• The activation of postsynaptic phosphatases also causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals

Question 11

cognitive decline in dementia (AD focus)

Answer 11

MCI precedes the following stages of cognitive decline:
1. Episodic Memory Deficits: The initial cognitive symptoms in AD involve difficulties in episodic memory, particularly the learning of new information. AD patients exhibit poor retrieval and recognition performances in learning tasks, primarily due to encoding dysfunction hindering the consolidation of new information into long-term memory.
2. Semantic Memory Impairment: In early stages, semantic memory is affected, leading to word-finding difficulties. Degeneration of semantic networks restricts access to semantic memory content, resulting in poor performances in tasks requiring object identification, such as naming tasks.
3. Orientation and Executive Functioning: AD also impacts orientation and executive functioning. Executive functions, including abstract thinking, cognitive flexibility, attention and inhibition, are affected.
4. Higher-Level Operations: Cognitive deficits extend to higher-level operations, affecting tasks like symbol comprehension and activities essential for autonomy in daily life, such as driving skills.
5. Late-Stage Symptoms: In late stages, AD is associated with aphasia, apraxia, behavioral disorders, affective symptoms, and motor dysfunctions. Immunodeficiency and dysphagia make patients vulnerable to respiratory infections, a common cause of death.
6. Disease Progression: The progression of AD-related cognitive decline varies between early, middle, and late stages. While there is evidence for a slower decline in early and late stages, middle stages may show a faster decline. “Plateaus” of relatively stable cognitive performance are reached, but their number and duration vary widely.

Question 12

frontotemporal dementia

Answer 12

• Brain Areas Affected: Primarily involves atrophy in the frontal and temporal lobes, impacting behavior, personality, and language. Specific variants may affect different regions within these lobes.
• Epidemiology: Accounts for a significant proportion of early-onset dementia (45-65) cases. Prevalence varies, with the behavioral variant being the most common form. It is often underdiagnosed due to symptom overlap with other disorders.
• Mechanism of Degeneration: Involves abnormal accumulation of proteins (tau, TDP-43) leading to degeneration. Genetic factors play a role, and FTD can be sporadic or familial.
• Behavioral variant frontotemporal dementia (bvFTD): This subtype is characterized by changes in behavior, personality, and social conduct. Individuals with bvFTD may exhibit socially inappropriate behaviors, a lack of empathy, impulsivity, and diminished personal hygiene. Memory and visuospatial skills are usually preserved in the early stages.
• Semantic variant primary progressive aphasia (svPPA): This subtype primarily affects language skills. Individuals with svPPA may have difficulty understanding or finding words, and their speech may become slow and hesitant. As the disease progresses, individuals may lose the ability to comprehend language and have difficulty recognizing familiar faces and objects.
• Nonfluent variant primary progressive aphasia (nfvPPA): This subtype is characterized by a progressive loss of speech and language abilities. Individuals with nfvPPA may have trouble forming grammatically correct sentences, and their speech may become effortful and slow. Unlike svPPA, which primarily affects comprehension, nfvPPA primarily affects the production of speech.

Question 13

vascular dementia

Answer 13

• Brain Areas Affected: Results from impaired blood flow to the brain, impacting various regions depending on the location of vascular damage. Commonly affects subcortical structures.
• Epidemiology: Often follows a stroke or series of strokes. Its prevalence is second only to Alzheimer’s disease. Risk factors include hypertension, diabetes, and cardiovascular disease.
• Mechanism of Degeneration: Caused by reduced blood flow to the brain, leading to ischemic damage. Can result from large strokes or small vessel disease.  diffuse white matter lesions
• Symptoms: Cognitive decline, memory loss, and executive dysfunction. Symptoms may occur suddenly after a major stroke or gradually with cumulative damage.

Question 14

lewy body dementia

Answer 14

• Brain Areas Affected: Characterized by abnormal protein deposits (Lewy bodies – alfa-synuclein) in the brain, affecting cortical and subcortical areas. Includes the cerebral cortex, limbic system, and brainstem.
• Epidemiology: One of the most common forms of dementia, often underdiagnosed. Prevalent in elderly populations. Can coexist with Alzheimer’s pathology. More in men then in women.
• Mechanism of Degeneration: Accumulation of alpha-synuclein in Lewy bodies. Neurotransmitter changes, especially involving dopamine, contribute to symptoms.
• Symptoms: Fluctuating cognition, visual hallucinations, parkinsonism (motor symptoms), and REM sleep behavior disorder. Distinguishing features include pronounced visual hallucinations and motor symptoms resembling Parkinson’s disease.

Question 15

AD genetics

Answer 15

• Three causative genes have been associated with autosomal dominant familial Alzheimer’s (APP, PSEN1, and PSEN2) and 1 genetic risk factor (APOEε4 allele)
• APP –> amyloid precursor protein
• APOE –> Apolipoprotein E
• PSEN1 –> presenilin 1
• PSEN2 –> presenilin 2

Question 16

APOEe4

Answer 16

• APOE is not considered a causative risk allele because, many carriers of the APOE risk allele (ε4) live into their 90s, which suggests the existence of other LOAD genetic and/or environmental risk factors that have yet to be identified.
• In the brain, apoE is the primary cholesterol carrier protein that facilitates delivery of cholesterol from astrocytes, where it is synthesized, to neurons.
• APOE ε4 – the mutagenic variant – carries less lipids than the normal E2 (protective variant) and E3 (standard) variants and has decreased affinity for aggregated beta amyloid which could increase plaque formation

Question 17

APP

Answer 17

• Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons where it functions as a cell surface receptor and is involved in neural plasticity
• Normally cleaved by alfa and gamma, in AD it is cleaved by beta and gamma –> BA42 fragments
• APP is best known as the precursor molecule whose proteolysis generates amyloid beta
• There are 32 known missense mutations that cause early onset dominant AD
• Mutations can cluster around the γ-secretase cleavage site, although the most famous APP mutation (APP-swe) causes a change in amino acids adjacent to the BACE1 cleavage site  gives rise to altered APP derivatives including beta amyloid

Question 18

PSEN1/2

Answer 18

• Mutations in the PSEN1 gene, encoding presenilin-1 (PS1), are the most common cause of familial Alzheimer’s disease (FAD). PS1 functions as the catalytic subunit of γ-secretase, an intramembranous protease that cleaves a variety of type 1 transmembrane proteins, notably including the amyloid precursor protein (APP) and Notch
• Two distinct but not mutually exclusive hypotheses have been proposed to explain how PSEN1 mutations cause FAD (2, 3). The amyloid hypothesis proposed that PSEN1 mutations initiate disease pathogenesis by increasing production of Aβ42
• The presenilin hypothesis offers an alternative view of disease pathogenesis, proposing that PSEN1 mutations cause a loss of essential presenilin functions in the brain, which in turn triggers neurodegeneration and dementia in FAD (presenilin is essential in memory and learning)

Question 19

Senile plaques

Answer 19

• Brain atrophy caused by neuronal loss is a prominent pathological feature of Alzheimer’s disease (AD).
• Amyloid beta, the major component of senile plaques, is considered to play a central role in neuronal cell death.
• Excess amount of beta-amyloid evokes multiple cytotoxic mechanisms, involving increase of the intracellular calcium level (due to ion channel formation by beta-amyloid molecules and due to ER stress induced by beta-amyloid and hyperphosphorylated tau proteins), oxidative stress (calcium can cause mitochondrial dysfunction), and receptor-mediated activation of cell-death cascades.
• Such diversity in cytotoxic mechanisms induced by beta-amyloid clearly indicates a complex nature of the AD-related neuronal cell death
• AB42 –> bad one – AB40 –> not too bad

Question 20

neurofibrillary tangles

Answer 20

• Neurofibrillary tangles (NFTs) are intraneuronal aggregates of hyperphosphorylated and misfolded tau that become extraneuronal (“ghost” tangles) when tangle-bearing neurons die.
• NFTs have a stereotypical spatiotemporal progression that correlates with the severity of the cognitive decline
• The traditional understanding is that tau binds to microtubules and assists with their formation and stabilization.
• However, when tau is hyperphosphorylated, it is unable to bind and the microtubules become unstable and begin disintegrating.
• The unbound tau clumps together in formations called neurofibrillary tangles
• The change in phosphorylation can be due to mutation or brain injury (the haemorrhaging may cause iron induced hyperphosphorylation)
• The progression of NFTs follow a standard pattern begin scarcely and first appear in large quantities in the hippocampus then spread more to the limbic system and later the cortical areas

Question 21

lipid disbalance

Answer 21

• AD is associated with abnormal lipid metabolism
• The main lipid classes known to be disrupted in AD include cholesterol, sphingolipids, phospholipids, and glycerolipids including gangliosides.
• The brain contains a high amount of endogenous cholesterol which is abundant in myelin sheaths. Disruptions to normal levels of cholesterol could arguably lead to neuronal dysfunction.
• The important evidence that implicates cholesterol in AD pathogenesis is that a genetic variant of apolipoprotein E (APOE), APOE ε4 (encoded by the APOE ε4 allele) is the highest genetic risk factor for late-onset AD
• In the brain, apoE is the primary cholesterol carrier protein that facilitates delivery of cholesterol from astrocytes, where it is synthesized, to neurons.
• Sphingolipids (often act as second messengers) are enriched in myelin and are also associated closely with cholesterol in lipid rafts where transmembrane proteins such as BACE1 and γ-secretase (unconventional cleavage of beta-amyloid that causes aggregation) are expressed. Therefore, abnormal metabolism of sphingolipids could contribute to AD.
• (Sphingomyelin turns into) Ceramide is increased in AD has been shown to induce apoptosis  more in aged cells

Question 22

APOE and Amyloid

Answer 22

• Interaction between APOE and AB:
• APOE, a protein involved in lipid metabolism, plays a crucial role in the clearance of AB from the brain.
• AB peptides have an affinity for lipoproteins, including those formed by APOE.
• Mechanism:
• APOE is associated with AB through binding interactions. The APOE-AB complex is involved in various processes:
• Clearance: APOE facilitates the clearance of AB from the brain by binding to it and promoting its uptake by cells.
• Transport: APOE transports AB across the blood-brain barrier and contributes to its elimination from the central nervous system