Perception
use of previous knowledge to gather and interpret stimuli registered by the senses

• visual recognition
• auditory recognition
• attention - concentration of mental activity
• consciousness - awareness people have of the outside world and of their perceptiosn, images, thoughts, memories, and feelings

Bottom-up Processing
Importance of stimulus in object recognition

Top-down Processing
How a person's concepts and higher level mental processes influence object recognition

<65 Early Onset incidence of FTLD and ADD almost equal

• ADD: aberrant production of amyloid

> 65 Late Onset - FTLD considerably lower than ADD
95%

• ADD: faulty clearance of amyloid

Diagnosis

• Short-term Memory Deficits (e.g. repetitive questioning)
• Need impairment of one other cognitive fucntion for diagnosis

Diagnosis Requirements

• Temporal association of cognitive deficits with stroke
• Evidence of cerebrovascular disease in exmaination and imaging

Diagnosis
The diagnosis is Parkinson's disease dementia when a person is originally diagnosed with Parkinson's based on movement symptoms, and dementia symptoms don't appear until a year or more later.

• diagnosis if appearance of dementia and PD symptoms are within one year
  

• if cognitive symptoms predate physical symptoms from more than a year

3 autossomal dominant genes - reponsible for amyloid cleavage - associated with early onset-ADD

Symptoms

• Changes in thinking and reasoning
• Confusion and alertness that varies significantly from one time of day to another or from one day to the next
• Parkinson's symptoms, such as a hunched posture, balance problems and rigid muscles
• Visual hallucinations
• Delusions
• Trouble interpreting visual information
• Acting out dreams, sometimes violently, a problem known as rapid eye movement (REM) sleep disorder
• Malfunctions of the "automatic" (autonomic) nervous system
• Memory loss that may be significant but less prominent than in Alzheimer's

Diagnosis

The diagnosis is DLB when:
Dementia symptoms consistent with DLB develop first
When both dementia symptoms and movement symptoms are present at the time of diagnosis
When dementia symptoms appear within one year after movement symptoms.

Disturbances of motor (movement or muscle) function
e.g.Amyotrophic lateral sclerosis (ALS), Corticobasal syndrome, Progressive supranuclear palsy (PSP)

Failure of UPS

• overexpression of a-synuclein and mutations i---> accumulation of toxic oligomeric fibrillary species--> nhibits the proteasome (unfolds an degrades)--> toxic species to accumulate and Lewy bodies formation
• 3 ubiquitin enzymes: E1, E2, E3 --> muation in 1 (UCH-L1) and 3 (Parkin) --> inhibition UPS --> familial PD --> autossomal recessive PD (mitochondrial dysfucntion)
  
  

Mutation in Parkin (can induce mitophagy) --> no Lewy bodies + mito pathology + + vulnerability to oxidative stress

Muattion PINK1 --> no Lewy bodies

Act in common pathway - PINK is upstream Parkin --> may quaratine damaged mitochondria before clearance

high mito membrane potenial > PINK1 into mito --> degraded --> low levels of PINK1 in basal conditiond
low (unoupling agent CCCP)--> acummulation of PINK1 in surface > recruit Parkin --> translocation of Parkin into mito --> ubiquinates proteins in outer membrane --> recruits adaptor proteins (p62) --> phagophores --> autophagosome --> lysosome --> degradation

Parkin --> neuroprotective role against cell death in stress situations

Mutation in UCH-L1 --> autossomal dominant PD slow progresssion
Mutation in LRRK2 --> early onset of autossomal dominant

autophagy suggested too!

Brain Structures

• loss of dopaminergic neurons from substancia nigra in pars compacta -- deficiency in release to caudate and putamen
  
  

D1 - excitatory; D2 inhibitory ---> increase of cortical output --> in PDD --> loss of thalamic output

Alpha-synuclein

• disorderd protein - no defined secundary structure
• mutations on N-terminal (A30P, E46K, A53T) --> promote Lewy body formation
• NAC (non-amyloid B component) domain --> protein aggregation = toxic (in cytoplasma and mitochondria - inhibs complex I of e~transport chain)
• maybe by inducing mitochondrial fragmentation --> dysfunction -->death
• maybe triggers inapropriate + excessive mitophagy

Mitochondrial Dysfunction

PINK1--> has canonical mitocn«hondrialtargeting sequence (n-Terminal)

MPTP --> stret heroin --> similar symptoms -_>oxidated MPP+ inhibits cellular respiration by complex 1 in dopaminergic neurons

Therapies

• Levodopa - treats symptoms
• COMT inhibitors + MAO-O inhibitors (rasgiline) + L-dopa --> receptor activation and prolongation of bioavaliability
• cell replacement therapy
• electrode implantation- ?
  
  

Possible:

• endogenous neurotrophic factors
• chelation of iron and other heavy metals? - prevent inflammation
• reduction of alpha synuclein aggragation
• immunotherapy
• inhibition of neuroinflammation
• caffeine and adenosine receptors
• antioxidant - creatine - delay worsening
• selective noradrenaline reuptake inhibitor atomoxetine
• acetylcholinesterase inhibtor - donepezil

Amyloid beta-protein

• various molecular species --> most common 40 residues long
• increased production of C-terminally extended forms

• Soluble forms --> toxic --> responsible fro synaptic function

  
  

• Produced from normal protein - from APP by secretases:

  
  

  --> non-amyloidogenic --> release p3 fragment + sAPPapha (neuoprotective and memory-ehancing effects)

  
  

  --> amiloidogenic --> release Abeta (no action of alpha secretase, beta secretase instead)

  
  

• oligomers block LTP -->

  
  
  

Mutations in APP, PS1, PS2 --> early onset of familial aurtosomal dominant

PS1 + PS2 --> presenilins __> components of gamma-secreatse --> enhance production of A-beta42 --> tends to form stable trimeris/tetrameric oligomers

Alelles for apoliprotein E4 + alpha2 macroglobulin --> increased risk for late onset

mGluR5 - coreceptor for Abeta oligomer

APP mutations + what is more toxic + linking of vascular dysfunction

ApoE4 - isoforms linked by breakdown of beta amyloid - >
Alzheimer's disease - 2015/6 - lancet- philip sheletons

Tau

• helps stabilize microtubules
• changes --> microtubules colapse + clump together --> tangles
• phosphorilated --> inhibts binding --> depolimerization
• abnormally phosphorilated __> aggregates --> paired helical filaments

ApoE

• recycles lipids after neuronal degenration --> for proliferation, membrane repair and remyelination of new axons
• when no lipids --> stable complex with Abeta peptides --> may increase accumulation and plaque formation

Treatments

• cholinesterase inhibtors - donepezil, galantine
• NMDA receptor antagonist - memantine (due to glutamatergic excitotoxicity)
• ssris
• sleep aids
  
  

General cognitive enhacing - ACh - basal forebrain, hippocampus

Research on:

beta-amyloi

• agonist and partial agonists of M1-subtype
• nicotinic acetylcholine alpha7 receptor
• RAGE inhibitor - multi-ligand receptor on membrane that binds Abeta - promotes influc into CNS
• TNF-alpha reduction by monoclonal antibody
• omega-3 polyinsaturated fatty acids (docosahexaenoic) and antioxidants (vit. E)
  . diabetes mellitus treatments due to comorbidity e-g- direct admnistration of insulin
• microtubule stabilizers - epothilone
• upregulation of alpha secreatse - etazo - gabaa modulator
• GSK3 beta inhibitors - lithium, valproate
• methylene blue - behavioural improvements
• tau hyperphosphoru
  
  

abeta - most startegies through anibodies

• active immunisation - use of full length - meningoencephalitis
  

                                 - six aas - prevent pveractive t-cells
  

Ivig - take antibodies from healthy and give to AD - beneficial because human - likely that it will accept - drawback: not reproducible source of medication

• passive immunisation - preformed antibodies - bazineuzumab agains Abeta; solanezumb, gatenerumab
  
  

chimeric antibodies - localizing effect but not so much anti-inflammatory effect

anti-inflammatory agents -preventative - non steroidal (stroidal- suppress immune)

• mitochondrial dysfunction
• oxidative stress
• neurodegeneration (loss of synapses and neurons - e.g. glutamatergic excitotoxicity)
• glial dysfunction
• cellular and molecular risk factors
• mechanism for different lengths (APP)
• apoptosis/necrosis/autophagy