Dementia

Dementia

Prof.elham aljammas 5thof march 2017

Dementia

Dementia
Definition Diagnostic criteria Epidemiology Differential diagnosis typical features and treatment of certain dementia syndromes

Dementia: Definition

Dementia is a clinical syndrome characterised by a decline of intellectual function in comparison with the patient’s previous level of cognition.Social and occupational activities and behaviour are also influenced.A decline in the activities of daily living (ADL) often accompanies first two.

Dementia: Criteria

DSM IV Criteria for the dementia: Development of multiple cognitive deficit including memory impairment and at least one of the following: aphasia apraxia agnosia executive functioning disturbance The cognitive deficit must, be sufficiently severe to cause impairment in occupational and social functioning. represent a decline from a previous higher level of functioning.

Dementia: Criteria, definition of key terms

Aphasia: is a language disorder that affects ability to comprehend or express spoken or written language or both. The term apraxia is defined as inability to correctly perform learned skilled movements with the arms etc. no weakness, no ataxia, no seizure, no involuntary movement Agnosia can be defined as inability to recognise familiar objects, faces, sounds or words. perception, memory, language intellectual function
normal

Dementia: Criteria

DSM IV Criteria for dementia: Development of multiple cognitive deficit including memory impairment and at least one of the following: aphasia apraxia agnosia executive functioning disturbance The cognitive deficit must, be sufficiently severe to cause impairment in occupational and social functioning. represent a decline from a previous higher level of functioning.

Dementia: Criteria

DSM IV Criteria for the dementia: Diagnosis should not be made if the cognitive deficits occur exclusively during the course of delirium. Dementia may be etiologically related to a general medical condition, to the persisting effects of the substance abuse (including toxin exposure), or to a combination of these factors.

Dementia: Epidemiology I

Over 65, about 5-10 percent of population has some kind of cognitive decline. This ratio reaches, 20-50 percent of all population in the age of 85. Dementia is a health problem both for the developed and developing countries.

Dementia: Epidemiology II

Dementia: Epidemiology III

Classification of dementias - I

Primary degenerative dementiasDementia pure: neurodegenerative disorders primarily involving cerebral cortexAlzheimer’s diseaseFocal degenerationsDementia plus: neurodegenerative disorders involving additional brain areas such as basal ganglia or other subcortical structuresDementia with Lewy bodiesParkinson’s diseaseFTD-Parkinsonism-17; FTD with motor neuron diseaseMSACorticobasal degenerationPSPHuntington diseaeSome forms of SCAFamilial multiple system taupathyProgressive subcortical gliosis


Classification of dementias - II
Secondary forms of dementia Disorders damaging the brain tissue directly Vascular-ischaemic causes Infections Demyelinating disorders Inborn metabolic disorders Traumatic brain injury Post-radiation dementia Some brain tumors Parasitic cysts or brain abscess Disorders changing intracranial contents and distorting brain structures Normal pressure or obstructive hydrocephalus Subdural or intraparenchymal haematoma Primary or metastatic brain tumors Systemic diseases or conditions affecting the brain Metabolic-nutritional Endocrine Toxic Systemic immune-mediated or inflammatory disorders

Dementia: Differential diagnosisPseudo-dementia of depression

Dementia: Differential diagnosis:Dementia vs Delirium

Dementia: Differential diagnosis:Cortical vs Subcortical

Disease Groups Can Present as Pure Dementia I
Space- Occupying LesionsNeoplasmNormal-pressure hydrocephalusSubdural hematomaParasitic cyst, brain abscessesInfectious OrganismsHIVSyphilisHerpes simplexLyme diseaseWhipple’s disease Nutritional-Metabolic-Toxic Wernicke-Korsakoff disease Chronic alcoholism B12 deficiency Pellegra Organic solvent exposure Heavy metal intoxication Hepatic encephalopathy Immune Inflammatory Paraneoplastic limbic encephalitis Systemic lupus Cerebritis associated with collagen-immune diseases

Disease Groups Can Present as Pure Dementia II

Vascular DiseaseMultiple infarctsBinswanger’s diseaseVarious arteritidesCADASIL*Storage DiseasesMetachromatic LeukodystrophyKuf’s diseasePrion DiseasesCreutzfeld-JacobFatal familial insomnia Primary (degenerative) Neuronal DiseasesAlzheimer’s diseaseFocal atrophies (frontotemporal dementia, primary progressive aphasia)Pick’s diseaseDiffuse Lewy body diseaseHereditary taupathies * CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Diseases that can present with sensory- motor deficits + dementia

Parkinson’s diseaseProgressive supranuclear palsyCortico-basal ganglionic degenerationHuntington’s diseaseWilson’s diseaseHallervorden-Spatz disease


Treatable Dementias
Thyroid diseaseB12 deficiencyThiamine deficiency (Wernicke’s encephalopathy) PellegraAlcoholHepatic encephalopathyNormal- pressure hydrocephalusSub-dural haematomaBenign brain tumorsChronic meningitisAbscessCyst

Alzheimer’s Disease (AD): Genetics, prevalence, risk factors I In 5-10 % of AD patients disease shows an autosomal dominant trait.It’s onset is at 30s or 40s.APP (chromosome 21), presenilin1(chromosome 14) and presenilin2 (chromosome 1) mutations cause this type of inheritance.All of them result in excessive production of insoluble Я amyloid .In patients with Down syndrome the AD pathology occurs when they are 30-40 years old because of the over-production of Я amyloid due to the existence of an extra chromosome 21.

Alzheimer’s Disease (AD): Genetics, prevalence, risk factors II In 90-95 % of the patients AD does not show an autosomal dominant transmission. The disease onset is at about their 65s. But in this group, some of the patients come from the families where the prevalence of AD is higher than general populations (nondominant familial AD). The rest of the patients comes from families, their prevalence of AD is similar to that of the general population (sporadic AD).

Alzheimer’s Disease (AD): Genetics, prevalence, risk factors III The most important risk factor for AD is age. Prevalence doubles for every 5 years after the age of 65 (10%) and reaches 40% among those older than 85. Head injury, female gender and a positive family history are other known risk factors. An additional risk factor has been linked to chromosome 19 that encodes apolipoprotein E (ApoE). The e4 allele frequency is 20% in the general population and 40% in AD.

APP Degradation

b-secretase 1. aa
a-secretase 16. aa
g-secretase 38,39,40,42,43. aa
b- amiloid precursor protein 695, 751, 770 aa b- amiloid 1-40 ve 1-42


AD: Clinical Picture (ABC’s of AD) AD is an amnestic dementia with an insidious onset and indolent course.It causes disturbances in daily living activities, behavioural symptoms and cognitive decline.Diagnosis death about 15-20 years.Symptoms change as the pathology of the disease progresses.

Neuro-psychiatric Symptomatology in AD

AD: Initial Stage I
Memory problems forgets names, repeat themselves, misplaces their belongings, makes lists may fluctuate in intensity, good for remote events and recent events with high emotional impact. poor for ordinary recent events clues and multiple choices are useful.

AD: Initial Stage II

Language and behavioural problems speech becomes less fluent and loses spontaneity. difficulty in word finding. Self awareness of impairment may elicit depression. may keep working, especially when he/she is protected by understanding staff in his/her office. may have some difficulties in choosing dress, complex financial tasks. may keep house, pay bill, drive car, participate social activities

AD: Intermediate Stage I

Memory problems recognition difficulties (forgets remote events) forgets faces inability to use clues or lists spatial orientation disturbances (getting lost in unfamiliar environment) inability to store new data (even for minutes)

AD: Intermediate Stage II

Language and behavioural problems word finding difficulty in ordinary conversations increased misunderstanding become indifferent to their symptoms, depression subsides. paranoid ideation (spousal infidelity, stolen personal object due to misplacement) sun downing (worsening of cognitive and behavioural symptoms at the end of the day) Independency in housekeeping, dressing, bathing, grooming, paying bills are gradually lost

AD: Final Stage I

Memory problems living in past inability to recognize family members family members recognized as if they are not themselves (they recognized as their imitations) getting lost even in familiar surroundings inability recognize home and rooms

AD: Final Stage II

Language and behavioural problems incoherent speech loss of speech wandering purposeless movements crying agitation difficulties in moving and feeding, bathing, continence towards the end of stage myoclonus, rigidity, gait difficulties become bedridden and death due to infections or emboli.


Neuropathology

Regional distribution of pathology

Distribution of pathology in AD is not random, but starts in transentorhinal cortex and ends in neocortex

Hippocampus

Cortex
N. basalis of Meynert
Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978
Thalamus
Affected neurotransmitter systems in AD
Acetyl Choline Serotonin Noradrenaline Dopamine

Bringing it all together (1)

Mutations in APP/PS-1
Environment
Age
Increased Ab42 formation and deposition
Oxidative damage
Inflammatory response
APOE4
Tau phosphorylation and aggregation
Neuronal death
3
2
1
4
5
6

Bringing it all together (2)

Transentorhinal cortex
Temporal/parietal cortex
Tangle
Plaque
Normal
Alzheimer’s disease Increased non-amyloidogenic metabolism
Increased amyloidogenic metabolism
PKC
PKC
GSK-3
GSK-3
Tau phosphorylation
Tau phosphorylation

Clinical and laboratory diagnosis

No lab. test for definitive diagnosis in a living patient. Biopsy or autopsy is gold standard The NINCDS-ADRDA criteria have been purposed to probable AD (PRAD). Post mortem confirmation studies revealed a 90 % or higher concordance with criteria in diagnosis of PRAD

NINCDS/ADRDA Criteria for Alzheimer's Disease I

Criteria for clinical diagnosis of Probable AD include: Dementia established by clinical exam and documented by, confirmed by further neuropsychological tests. Deficits in two or more areas of cognition. Progressive worsening of memory and other cognitive functions. No disturbance of consciousness. Onset between the ages of 40 and 90. Absence of systemic diseases or other brain diseases that could explain the cognitive changes.
The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations 1984

NINCDS/ADRDA Criteria for Alzheimer's Disease II

The diagnosis of Probable AD is supported by: Progressive deterioration of specific cognitive functions such as language, motor skills, and perception (aphasia, apraxia, agnosia, respectively). Impaired activities of daily living. Positive family history, particularly if documented neuropathologically. Lab results: Normal lumbar puncture, EEG, and evidence of cerebral atrophy on CT or MRI.

NINCDS/ADRDA Criteria for Alzheimer's Disease III

Other clinical features consistent with diagnosis of Probable AD, after exclusion of other causes of dementia: Plateaus in clinical course. Associated symptoms: depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional, or physical outbursts, sexual disorders, and weight loss. Other neurological abnormalities in some patients, especially with more advanced disease and including motor signs such as increased motor tone, myoclonus, or gait disorder. Seizures in advanced disease. CT normal for age.

NINCDS/ADRDA Criteria for Alzheimer's Disease IV

Features that make the diagnosis of Probable AD unlikely or uncertain: Sudden apoplectic onset. Focal neurological findings such as hemiparesis, sensory loss, visual field deficits, and incoordination early in the course of the illness. Seizures or gait disturbances at the onset or very early in the course of the illness.

Laboratory tests

Routine Optional Blood glucose CBC Chest X-ray Vitamin B12 level ECG Thyroid function tests EEG AST, ALT Drug levels LDH Urinalysis BUN HIV testing Uric acid Heavy metals in urine Sedimentation rate CSF analysis Syphilis serology PET/SPECT CT, MRI

Correcting cholinergic loss in AD

Muscarinic receptor Nicotinic receptor ACh ACh metabolites
AChEIs
Choline
AChE
Lecithin
Acetyl CoA
3
2
1
4

Treatment I

Cognitive symptoms Centrally active cholinesterase inhibitors Donepezil (Aricept 5 mg) 1x1 at bedtime for 1 month then 1x2 Rivastigmin ( Exelon 1,5; 3; 4,5 and 6 mg) 2x1 increase dose one step for one week, max 2x6 mg
Antioxidants Gingko biloba extracts Vitamin E Vitamin C Estrogens (as antioxidant and acetyl choline production enhancer) Anti inflammatory drugs COX-2 inhibitors Indomethasine

Treatment II

Behavioural symptoms Psychotic features Typical neuroleptics (avoid in Lewy body dementia) Haloperidol Thioridazine Chlorpromazine Sulpiride Pimoside
Atypical neurolepticsClozapine(!) agranulocytosisOlanzapine RisperidoneQuetiapine Depressive features(Avoid antidepressants with prominent anticholinergic effect)SSRI’sFluoxetineSertralineCitalopram

Treatment III

SNRI’sVenlafaxineSleep disturbancesTrasodoneAnxietybenzodiazepinesbeta blockers Mood Stabilisers Valproate Na Gabapentine Carbamazepine Lithium

Regional distribution of atrophy in the common dementias

Alzheimer’s disease: predominantly parietal and temporalFrontotemporal dementia: predominantly frontal and temporalDementia with Lewy bodies: as for AD, but with additional subcortical pathologyVascular dementia:vascular distribution Executive functions
Praxia
Perceptuospatial function
Memory
Language
Functional regions FTD AD

Non-Alzheimer Dementias: Frontotemporal Dementia

Early deterioration in social conduct, personality, initiative, insight and attention Rudeness, disinhibition and distractibility Speech--->Non fluent and reduced in quantity Visio-spatial abilities, EEG and memory are normal (at least in the beginning). Familial forms are linked to the chromosome 17 May occurs with parkinsonian symptoms and ALS in the same patient

Non-Alzheimer Dementias:Lewy Body Dementia

Cortex and sub cortical areas(basal ganglia and locus coeruleus) contain Lewy bodies that is made of alfa synuclein as in Parkinson’s disease.Mild parkinsonian symptoms begin with dementia is the hallmark.Symptoms may fluctuate during the dayVisual hallucinations and increased susceptibility to the typical neuroleptics are the other key features

Non-Alzheimer Dementias:Vascular Dementia

National Institute of Neurological Disorders and Stroke (NINDS) criteria: Cerebrovascular disease (CVD) as defined by the presence of focal signs on neurologic examination such as: hemiparesis, facial weakness, Babinski sign, sensory deficit, hemianopia, dysarthria consistent with stroke (with or without history of stroke). Evidence of relevant CVD by brain imaging including multiple large-vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain), as well as multiple basal ganglia and white matter lacunes or extensive periventricular white matter lesions, or combinations thereof. Other criteria include. Any combination of onset of dementia within 3 months following a recognised stroke. Abrupt deterioration in cognitive functions. Fluctuating or stepwise progression of cognitive deficits. Hypertension.