1. Sibel Ertan MD Dpt. of Neurology
Dementia
Sibel Ertan MD
Dpt. of Neurology

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

3. 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.

4. 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.

5. 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

6. 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.

7. 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.

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

9. Dementia: Epidemiology II

10. Dementia: Epidemiology III

11. Classification of dementias - I
Primary degenerative dementias
Dementia pure: neurodegenerative disorders primarily involving cerebral cortex
Alzheimer’s disease
Focal degenerations
Dementia plus: neurodegenerative disorders involving additional brain areas such as basal ganglia or other subcortical structures
Dementia with Lewy bodies
Parkinson’s disease
FTD-Parkinsonism-17; FTD with motor neuron disease
MSA
Corticobasal degeneration
PSP
Huntington diseae
Some forms of SCA
Familial multiple system taupathy
Progressive subcortical gliosis

12. 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

13. Dementia: Differential diagnosis Pseudo-dementia of depression

14. Dementia: Differential diagnosis: Dementia vs Delirium

15. Dementia: Differential diagnosis: Cortical vs Subcortical

16. Disease Groups Can Present as Pure Dementia I
Space- Occupying Lesions
Neoplasm
Normal-pressure hydrocephalus
Subdural hematoma
Parasitic cyst, brain abscesses
Infectious Organisms
HIV
Syphilis
Herpes simplex
Lyme disease
Whipple’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

17. Disease Groups Can Present as Pure Dementia II
Vascular Disease
Multiple infarcts
Binswanger’s disease
Various arteritides
CADASIL*
Storage Diseases
Metachromatic Leukodystrophy
Kuf’s disease
Prion Diseases
Creutzfeld-Jacob
Fatal familial insomnia
Primary (degenerative) Neuronal Diseases
Alzheimer’s disease
Focal atrophies (frontotemporal dementia, primary progressive aphasia)
Pick’s disease
Diffuse Lewy body disease
Hereditary taupathies
* CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

18. Diseases that can present with sensory- motor deficits + dementia
Parkinson’s disease
Progressive supranuclear palsy
Cortico-basal ganglionic degeneration
Huntington’s disease
Wilson’s disease
Hallervorden-Spatz disease
Spinocerebellar ataxias
Amyotrophic lateral sclerosis
Multiple sclerosis
Gerstmann-Sträussler-Scheinker disease
Kuru

19. Treatable Dementias Thyroid disease B12 deficiency
Thiamine deficiency (Wernicke’s encephalopathy)
Pellegra
Alcohol
Hepatic encephalopathy
Normal- pressure hydrocephalus
Sub-dural haematoma
Benign brain tumors
Chronic meningitis
Abscess
Cyst

20. 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 ß amyloid .
In patients with Down syndrome the AD pathology occurs when they are years old because of the over-production of ß amyloid due to the existence of an extra chromosome 21.

21. Alzheimer’s Disease (AD): Genetics, prevalence, risk factors II
In % 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).

22. 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.

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

24. 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 years.
Symptoms change as the pathology of the disease progresses.

25. Neuro-psychiatric Symptomatology in AD

26. 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.

27. 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

28. 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)

29. 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

30. 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

31. 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.

32. Neuropathology
The disease process begins from entorhinal cortex and in the earliest detectable stage of dementia at least 50% of neuronal loss can be found in the layer II neurons. The neuronal loss then become detectable in the superior temporal sulcus as the disease and the cognitive decline increases. As the neuronal loss continues, the two core pathological features of AD; neurofibrillary tangles (NFT) and neuritic plaques become more prominent in the pathological specimens. The occurrence and density of NFT seems more related to the progression of symptoms and the disease process in the brain than plaques.
Bamyloid precur

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

36. Affected neurotransmitter systems in AD
N. basalis of Meynert
Hippocampus
Cortex
The main neurotransmitter system that is affected in Alzheimer’s brain is cholinergic system and the main structure is the nucleus basalis of Meynert, which is the source of the cortical cholinergic innervation. The hyperphosphorylated tau protein which is essential in NFT formation begins to accumulate in the Meynert’s nucleus with the increasing age and this is considered to play a major role in age associated memory impairment. Cortical cholinergic receptor density is also decreased in Alzheimer’s brain. Ovarian hormones play an important role in promoting the synthesis of Acetyl choline in Meynert’s nucleus. Thus, the increased risk of AD in post menopausal women may be a projection of this phenomenon.
Deficiencies in serotoninergic, noradrenergic and dopaminergic pathways. possibly contributing especially to the genesis of depression and the other behavioural abnormalities have been reported.
Acetyl Choline
Serotonin
Noradrenaline
Dopamine
Thalamus
Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978

38. Bringing it all together (1)5
Oxidative damage 6
Inflammatory response
Mutations in APP/PS-1
APOE4
Increased Ab42 formation and deposition
Tau phosphorylation and aggregation
Neuronal death
Environment 3 2 4 1
Age

39. Bringing it all together (2)
Tangle
Transentorhinal cortex
Temporal/parietal cortex
Plaque
Increased non-amyloidogenic metabolism
Normal
PKC
GSK-3
Tau phosphorylation
Alzheimer’s disease
PKC
GSK-3
Tau phosphorylation
Increased amyloidogenic metabolism

40. 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

41. 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

42. 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.

43. 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.

44. 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.

45. 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

46. Correcting cholinergic loss in AD
Muscarinic receptor
Nicotinic receptor
ACh
ACh metabolites 4 3 1
Choline
Lecithin
Acetyl CoA
AChE 2
AChEIs

47. 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

48. Treatment II Behavioural symptoms Psychotic features
Typical neuroleptics (avoid in Lewy body dementia)
Haloperidol
Thioridazine
Chlorpromazine
Sulpiride
Pimoside
Atypical neuroleptics
Clozapine(!) agranulocytosis
Olanzapine
Risperidone
Quetiapine
Depressive features
(Avoid antidepressants with prominent anticholinergic effect)
SSRI’s
Fluoxetine
Sertraline
Citalopram

49. Treatment III Mood Stabilisers Sleep disturbances SNRI’s Valproate Na
Venlafaxine
Sleep disturbances
Trasodone
Anxiety
benzodiazepines
beta blockers
Mood Stabilisers
Valproate Na
Gabapentine
Carbamazepine
Lithium

50. Regional distribution of atrophy in the common dementias
Alzheimer’s disease: predominantly parietal and temporal
Frontotemporal dementia: predominantly frontal and temporal
Dementia with Lewy bodies : as for AD, but with additional subcortical pathology
Vascular dementia: vascular distribution
Executive functions
Praxia
Functional regions
FTD AD
Language
Perceptuospatial function
Memory

51. 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

52. 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 day
Visual hallucinations and increased susceptibility to the typical neuroleptics are the other key features
Lewy body dementia: In 15-20% percent of the patients with the diagnosis of AD, subcortical areas such as basal ganglia and locus coeruleus contain Lewy bodies as is typical in Parkinson’s disease. But the patients also have this pathology in their cortical areas. Lewy body dementia has been considered as between AD and idiopathic Parkinson’s disease clinically. Patients show mild bradykinesia, masked face, flexed posture and gait difficulty without resting tremor. Dementia is not as severe as in AD. Symptoms may fluctuate during the day and increased susceptibility to the neuroleptics considering extrapyramidal side effects are the key features.

53. 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.