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DEMENTIA

What is Dementia?Dementia is a term used to describe a cluster of symptoms including: Forgetfulness (progressive) Difficulty doing familiar tasksConfusion Poor judgment Decline in intellectual functioningDementia is not the name of an actual disease Dementia is not a part of normal aging

DementiaReversible:D= Drugs, DeliriumE=Emotions (such as depression) and Endocrine DisordersM=Metabolic DisturbancesE=Eye and Ear ImpairmentsN=Nutritional DisordersT=Tumors, Toxicity, Trauma to HeadI=Infectious DisordersA=Alcohol, ArteriosclerosisDementiaIrreversible:AlzheimersLewy Body DementiaPicks Disease (Frontotemperal Dementia)ParkinsonsHeady InjuryHuntingtons DiseaseJacob-Cruzefeldt Disease

Table 8. Diagnostic Criteria for Dementia (DSM-IV) Memory impairment: impaired ability to learn new information or to recall old information One or more of the following: aphasia (language disturbance); apraxia (impaired ability to carry out motor activities despite intact motor function); agnosia (failure to recognize or identify objects despite intact sensory function); disturbance in executive functioning-impaired ability to plan, organize, sequence, abstract The cognitive deficits result in functional impairment (social/occupational) The cognitive deficits do not occur exclusively solely during a delirium NOT due to other medical or psychiatric conditionsCauses of DementiaAlzheimers disease (approximately 70%) Vascular dementia (Strokes and TIAs)Parkinsons diseaseFrontotemporal dementia (FTD)Normal-Pressure hydrocephalus (NPH)Dementia with Lewy BodiesDelirium/DepressionOther, less common causes

Clinical course

Neuropathorogy and Biochemistry of ADNeuropathology

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex.Reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimer's disease.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.

Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves.

Biochemistry Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

AD has been identified as a protein misfolding disease, caused by accumulation of abnormally folded A-beta and tau proteins in the brain.

Plaques are made up of small peptides, 3943amino acids, called beta-amyloid (also written as A-beta or A). fragment from a larger protein called APP, a transmembrane protein that penetrates through the neuron's membrane. (APP: neuron growth, survival and post-injury repair) Neuropathorogy and Biochemistry of ADBiochemistry In Alzheimer's disease, an abnormal aggregation of the tau protein lead to the disintegration of microtubules in brain cells.

Tau protein(microtubule-associated protein) stabilizes the microtubules when phosphorylated.In AD, tau becoming hyperphosphorylated; creating neurofibrillary tangles and disintegrating the neuron's transport system.Neuropathorogy and Biochemistry of AD

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Genetic: Familial AD and risk factorsThe majority of cases of Alzheimer's disease are sporadicnot genetically inherited although some genes may act as risk factorsaround 0.1% of the cases are familial forms of autosomal-dominant inheritance

Autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein (APP) and presenilins 1 and 2. Mutations in the APP and presenilin genes increase the production of a A42.

The best known genetic risk factor is the inheritance of the 4 allele of the apolipoprotein E (APOE). Between 40 and 80% of patients with AD possess at least one apoE4 allele. Therefore the APOE4 allele increases the risk of the disease.

APP and PS families of proteinsFamilial Alzheimer disease is caused by mutations in at least 3 genes:

PSEN1 - Presenilin 1 (PSEN1 located on chromosome 14)Mutations in this gene cause familial Alzheimer's type under 50 years old. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP.

PSEN2 - Presenilin 2 (PSEN2 located on chromosome 1)The presenilin 2 gene is very similar in structure and function to PSEN1.

APP Amyloid beta (A4) precursor protein Processing of the amyloid precursor proteinMutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 causes familial Alzheimer disease. APP presenilins1 2

PSEN1 14 gene gene APP( ) cleavesed

1 PSEN2 PSEN1 .

APP 21 .

18Secretase

BACE1-amyloid cleaving enzyme1This transmembrane aspartyl protease is directlly involved in the cleavage of APP at the sites of A in APP.

-secretaseThis multiprotein catalytic complex includes PS1 and PS2; nicastrin (Nct), a type 1 transmembrane glycoprotein; and Aph-1 and Pen-2, two multipass transmembrane protein.APP and PS families of proteins Secretase family BACE1 -amyloid cleaving enzyme1 transmembrane aspartyl protease APP A-beta site APP cleavage -secretase multiprotein catalytic complex PS1 PS2 type 1 transmembrane glycoprotein nicastrinmultipass transmembrane protein Apha1 Pen-2 .

Processing of APP by secretases

-Secretase cleavage APP NTP((APPs-) APP CTF(C83) -secretase P3 A-beta peptide APP intracellular domain(AICD)fragment A domain amyloidogenesis .

APP -secretase APP NTF(APPs-) APP CTF(C99) Amyloidogenic pathway C99 fragment -secretase A AICD . snile plague .

APP intracellular domain (AICD):nuclear signaling

20Genetic models of A amyloidosis and AD-linked taupathiesA amyloidosis

Amyloid beta is a peptide of 39-43 amino acids Main constituent of amyloid plaques in the brains of Alzheimers disease patients.A is proteolytically derived from a larger integral membrane protein, the amyloid precursor protein (APP).

AD-linked taupathies

Taupathies are a class of neurodegenerative diseases resulting from the pathological aggregation of tau protein in so-called neurofibrillary tangles (NFT) in the human brain.

A amyloidosis taupathy A-beta 39-43 amyloid plaque . A-beta amyloid precusor protein integral membrane protein

taupathy .

Taupathy neurofibrillary tangles() tau protein aggregation neurodegenerative diseases

21Targeting of genes encoding amyloidogenic secretasesTo understand the function of some of the proteins thought to have roles in AD: targeted a variety of genes including BACE1, PS1, Nct, and Aph-1.

BACE1-/- MiceBACE1 is a key enzyme in the generation of the A peptide that plays a central role in the pathogenesis of Alzheimer's disease.

PS1-/- Mice PS1 knock-in mice exhibited NFT-like tau pathology in the absence of A deposition.PS1 mutations contribute to the onset of AD not only by enhancing A142 production but by also processing that lead to neurodegeneration.

protein gene target KO

BACE1 KO mice BACE1 A-beta peptide key enzyme .

PS1 KO mice A deposition tau pathology neurofibrillary tangles A142 production .

22ALZHEIMER DISEASE progressive neurologic disorder that results in memory loss, personality changes, global cognitive dysfunction, and functional impairments. Loss of short-term memory is most prominent early. In the late stages of disease, patients are totally dependent upon others for ADLS the most common form of dementia in the elderly, accounting for 60 to 80 % of casesestimated to affect more than 4 million Americans Diagnosis Clinical diagnosis History, mental status evaluation, physical examination, limited laboratory testing, and in many cases, neuroimaging, more extensive neuropsychological testing and a depression screen. An MRI finding of bilateral hippocampal atrophy suggests AD, but is not specific or sensitive The laboratory testing includes a CBC, electrolytes, glucose, BUN and creatinine, serum B12, TSH and liver function tests.

MMSE score

CDRCDR (Clinical Dementia Rating) digunakan untuk menilai gejala klinis dan menentukan stadium dari demensia

Penilaian CDR :0: tidak ada demensia (healthy)0,5: demensia dipertanyakan (questionable)1: demensia ringan (mild dementia)2: demensia sedang (moderate)3: demensia berat (seviere)Atrophic hippocampus in AD

Compare central sulcus of Alzheimers patient with normal 81 year old woman

From Whole Brain Atlas at http://www.med.harvard.edu/AANLIB/home.html

74 year old AD patient: reduced blood flow on SPECT in temporal areas

Normal vs AD Brain

Normal brainAlzheimers brainPathology of ADThere are 3 consistent neuropathologicalhallmarks:Amyloid-rich senile plaquesNeurofibrillarytanglesNeuronal degenerationThese changes eventually lead to clinical symptoms, but they begin years before the onset of symptomsAcetylcholinesterase InhibitorsDrugs used to treat Alzheimers disease act by inhibiting acetylcholinesterase activityThese drugs block the esterase-mediated metabolism of acetylcholine to choline and acetate. This results in:Increased acetylcholine in the synaptic cleftIncreased availability of acetylcholine for postsynaptic and presynaptic nicotinic (and muscarinic) acetylcholine receptorsVASCULAR DEMENTIA The onset of cognitive deficits associated with a stroke Abrupt onset of symptoms followed by stepwise deterioration Findings on neurologic examination consistent with prior stroke(s) Infarcts on cerebral imaging criteria for probable vascular dementia Cerebrovascular disease evident on history, examination or imagingTwo disorders must be related by onset of dementia within 3 months orabrupt, fluctuating or stepwise progressionFeatures that make vascular dementia uncertain or unlikelyEarly memory loss and progressive deterioration in the absence of corresponding focal lesions on imagingAbsence of focal neurological signsAbsence of cerebrovascular lesions on CT or MRI

Clinical features supportive of vascular dementiaEarly gait disorder Frequent fallsUrinary incontinence or frequency early in disorderPseudobulbar palsyPersonality and mood changes

FRONTOTEMPORAL DEMENTIA characterized by focal atrophy of the frontal and temporal lobes in the absence of Alzheimer pathology Pick's disease was the first recognized subtype of FTD, one that is characterized pathologically by the presence of Pick bodies (silver staining intracytoplasmic inclusions) in the neocortex and hippocampus. Clinically, presents with language abnormalities and behavioral disturbances. FRONTOTEMPORAL DEMENTIAoccurs between the ages of 35 and 75 years, and only rarely after age 75; the mean age of onset is the sixth decade Both sexes are equally affected. Familial occurrence occurs in 20 to 40 percent of cases and may be associated with a variety of identified mutations in the tau gene on chromosome 17 Frontotemporal Lobe Dementia Core Features Insidious onset and gradual progression Early decline in social/interpersonal conduct Early impairment in personal conduct Early loss of insight Early emotional bluntingSupportive Features Behavior disorder hygiene, grooming, mental rigidity, dietary changes, perseverative behavior Speech and language perseveration, mutism, economy of speech Physical signs akinesis, rigidity, tremor, labile BPNormal-Pressure Hydrocephalus a condition of pathologically enlarged ventricular size with normal opening pressures on lumbar puncture triad of dementia, gait disturbance, and urinary incontinence reversible by the placement of a ventriculoperitoneal shunt Core And Supportive Features For Clinical Diagnosis Of DLB The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational functionTwo of the following core features are essential for a diagnosis of probable DLB, and one is essential for possible DLB. Fluctuating cognition with pronounced variations in atten- tion and alertness Recurrent visual hallucinations that are typically well formed and detailed. Spontaneous motor features of parkinsonism. 3. Features supportive of the diagnosis are repeated falls syncope transient loss of consciousness neuroleptic sensitivity systematized delusions hallucinations in other modalities. Dementia with Lewy Bodiesthe most common dementia syndrome associated with parkinsonism the second most common form of neurodegenerative dementia after Alzheimer disease (AD). characterized by dementia accompanied by delirium, visual hallucinations, and parkinsonism. Other common symptoms include syncope, falls, sleep disorders, and depression. The presence of both Lewy bodies and amyloid plaques with deficiencies in both acetylcholine and dopamine neurotransmitters suggests that dementia with Lewy bodies represents the middle of a disease spectrum ranging from Alzheimers disease to Parkinsons diseaseParkinsons diseaseCardinal motor featuresBrady- and akinesia Rigidity Resting tremor Postural instability Dementia typically occurs in the last half of the clinical course of PD, whereas it is often one of the presenting features of DLB. Progressive supranuclear palsy also known as Steele Richardson Olszewski syndromea rare syndrome that can mimic PD in its early phaseCharacteristic features of PSPvertical supranuclear palsy with downward gaze abnormalities postural instability with unexplained falls Bradykinesia and rigidity are typically symmetrical in onsetApathy, disinhibition, dysphoria, and anxiety are common classic neuropathologic features of PSP globose neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau proteins. These lesions and accompanying neuronal loss are seen primarily in the substantia nigra, subthalamic nucleus, globus pallidus, superior colliculus and midbrain, and pontine reticular formation. Cortical involvement is more variable but predominately affects the frontal lobes. AD PrognosisAlzheimers has a slowly progressive decline. These meds can slow the progression, NOT halt it.

TimeFunctionEnd-stage DementiaPrognosis < 6 mos:Severe dementia with need for total assistance in ADLs (dressing, bathing, continence), unable to walk, only able to speak a few wordsComorbid conditions aspiration pneumonia, urosepsis, decubiti, sepsis*Unable to maintain caloric intake with weight loss of 10% or more in 6 months (and no feeding tubes)

Complications from dementiaDelusions in up to 50%, most with paranoiaHallucinations in up to 25%Depression, social isolation may also occurAggressive behavior in 20-40% (may be related to above problems, misinterpretation)Dangerous behavior driving, creating fires, getting lost, unsafe use of firearms, neglectSundowning nocturnal episodes of confusion with agitation, restlessness

Treatment of complicationsHallucinations, delusions, agitation, sun-downing may be improved with anti-psychotics like haloperidol, risperdal, mellarilIf any signs of depression, may be beneficial to treatAnxiety may respond to benzodiazepinesBehavioral mod reinforce good behavior, DONT fight aggressive behaviorFamiliarity (change in environments make things worse)Safety key locks, knobs off stoves, take away car keys/cigarettes/firearms, lights, watch stairsAvoid restraints, use human contact/music/pets/distraction

Artificial Nutrition in DementiaMany excellent reviews demonstrate no improvement in quality of life and quantity of life with G-tubes.5% morbidity and mortality with the procedure itselfNo decrease in aspiration with themRisk of infectionCan keep patient comfortable without itComplications from dementiaDelusions in up to 50%, most with paranoiaHallucinations in up to 25%Depression, social isolation may also occurAggressive behavior in 20-40% (may be related to above problems, misinterpretation)Dangerous behavior driving, creating fires, getting lost, unsafe use of firearms, neglectSundowning nocturnal episodes of confusion with agitation, restlessness

Drug treatment in Alzheimers diseaseMany drugs aim to stimulate the cholinergic systemThese drugs have limited positive effects and do not reverse the causes of ADDementia patients are very sensitive to additional disabilitiesIllnessPainMedicationsPoor hearingPoor visionManagement of depression at end of lifePsychotherapy behavioral, cognitive, and other supportive approaches by psychologists, licensed social workers, chaplains, even bereavement counselors may helpNew coping strategies like meditation, relaxation, guided imagery, hypnosis may helpMedications

SuicideWomen attempt it twice as much, but men are 4x more likely to succeedWhite men over 85 are at highest risk to do itAll patients with depressive symptoms should be assessed for itTalking about it can decrease risksHigh risk of attempt if thoughts are recurring or if have thought out the planONE OTHER POTENTIAL EMERGENCY:If risk high DONT leave client alone, immediately consult a psychiatrist may need in-patient care or involvement of authorities69You can commit them for 1-2 days if need beAnxietyMay be a normal response to the situation fears, uncertainty, reaction to physical condition, social or spiritual needsUsually with 1 or more of the following signs agitation, restless, sweating, tachycardia, hyperventilation, insomnia, excessive worry, tensionLook for signs of depression, delirium, alcohol/drug abuse, caffeine abuseAbout 5% are affected by agoraphobiaRelated anxiety conditionsPanic attacks acute onset of palpitations, sweating, hot, shaking, chest pain, nausea, dizzy, derealization, fear, numbness; usually short livedPhobias fears with avoidance, feelings of being trapped, exposedPost-traumatic Stress Syndrome in response to severe trauma, get more intense fear, terror, dreams, feelings of helplessness, detachment that can occur later onAlzheimers Association: http://www.alz.org/National Institute of Neurological Disorders and Strokes page on dementia: http://www.ninds.nih.gov/disorders/dementias/dementia.htmHow to manage difficult behaviors from the Association for Frontotemporal Disorders: http://www.ftd-picks.org/?p=caregiver.managing