The document discusses dementia, including its various types and classifications. It provides details on Alzheimer's disease, including its pathogenesis, clinical features, diagnosis, and prevalence. Alzheimer's disease is the most common cause of dementia, usually having an insidious onset and progressive cognitive decline characterized by amyloid plaques and neurofibrillary tangles in the brain.

1. DEMENTIA
Dr. Ajaz Ahmad Suhaff

2. History….
 17th century – Thomas Willis described post-apoplectic dementia
• 1894 – Otto Binswanger and Alois Alzheimer differentiated between
VaD and neurosyphilis .
• 1910 – Kraeplin concluded that “arteriosclerotic insanity” was the
most frequent form of senile dementia
• 1970s – AD identified as the most common cause of dementia
• At the same time Tomlinson, Blessed and Roth showed that loss of
more than 50-100mL of brain tissue from strokes caused cognitive
impairment and the term “multi-infarct dementia” was coined

3. Dementia is usually a disease of the elderly and is
characterized by progressive global deterioration of
memory and other mental faculties such as
language, judgment, and planning, impairment of
daily activities, and deficiency in social interaction.
Dementia?

4. EPIDEMIOLOGY
• Dementia is one of the major causes of disability in late-life.
• As per the census 2011 of India people aged above 60 years
constitute 8 percent of total population and India is at a unique
risk because of increase in aging population and increased
prevalence of diabetes and hypertension and stroke and lifestyle
changes.
The number of persons with dementia double every 5 years of age.
Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, et al. Alzheimer's disease and vascular dementia in developing countries: Prevalence, management and risk factors.Lancet
Neurol 2008; 7:812-26. Ghosal MK. Dementia: Indian scenario. Neurol India 2012; 60:618-24
Census of India 2011: Census Data Summary

5. The World Health Organization (WHO) predicts
that by 2025, about 75% of the estimated 1.2
billion people aged 60 years and older will reside
in developing countries.
It is estimated that the number of people living
with dementia will almost double every 20 years
to 42.3 million in 2020 and 81.1 million in 2040

6. Depending on the stage of disease and the severity of
symptoms dementia can be classified as:
Mild cognitive impairment: The signs and symptoms of the
disease may be subtle. A person with MCI will score between 27 and 30 on
the Mini-Mental State Examination. They may have some memory trouble
and trouble finding words but they solve everyday problems and handle their
own life affairs well.
Early stages: The symptoms are noticed by other people. They may
interfere with daily living. MMSE score is 20 to 25. The symptoms of early
dementia usually include memory difficulty, but can also include some word-
finding problems (anomia) and problems with planning and organizational
skills (executive function), difficulty in handling financial matters.
Middle and late stages: There is gradual worsening of symptoms with
progressive decline in MMSE score. All areas of cognition like memory,
judgment, problem solving, other executive functions are severely impaired.
Besides various behavioural abnormalities are also seen.

7. Classification…………
1. Cortical & subcortical dementia.
2. Reversible & Irreversible.
3. Anterior & posterior.

8. • Neurodegenerative Diseases
– Alzheimer’s disease
– Parkinson’s disease
– Diffuse Lewy body disease
– Huntington’s disease
– Frontotemporal dementias – e.g. Pick’s disease
– Progressive supranuclear palsy
Etiological classification of dementia

9. • Structural Disease or Trauma
– Normal pressure hydrocephalus
– Neoplasms
– SDH
• Vascular Disease
– Vascular dementia
– Vasculitis
• Heredometabolic Disease
– Wilson’s disease
Etiological classification of dementia

10. • Demyelinating or Demyelinating Disease
– Multiple sclerosis
• Infectious Disease
– Human immunodeficiency virus.
– Tertiary syphilis
– Creutzfeldt-Jakob disease
– TB
– SSPE
Etiological classification of dementia

11. • Nutritional deficiency:
– Vitamin B12 deficiency, Folate deficiency, thiamine
deficiency.
• Organ failure:
– Uremic and hepatic encephalopathy
• Endocrine disease:
– Diabetes mellitus,
– hypothyroidism,
– hyperparathyroidism
– Cushing's syndrome
Etiological classification of dementia

12. Dementias – classification
Based on site

17. = Drugs, Delirium
= Emotions (depression)&
Endocrine Disease
=Metabolic Disturbances
=Nutritional Disorders
= Tumors, Toxicity, Trauma to Head
= Infectious Disorders
= Alcohol,
Irreversible / Reversible dementias (15%)
•Alzheimer’s Dementia
•Lewy Body Dementia
•Pick’s Disease
(Frontotemporal
Dementia)
•Parkinson’s
•Heady Injury
•Huntington’s Disease
•Creutzfeldt- Jacob
Disease

18. • Alzheimer’s disease (AD) is the most common
form of dementia, representing approximately 60-
70% of all cases.
• In 1907, Alois Alzheimer first described the
condition that later assumed his name.
• Alzheimer’s disease is a cortical dementia
characterized by a slow, progressive loss of
cognitive functions.
Dementia of Alzheimer’s Type

19. • Characterized by:
– Progressive loss of cortical neurons
– Formation of amyloid plaques (beta-amyloid is
major component)
– Intraneuronal neurofibrillary tangles
(hyper-phosphorylated tau proteins is major
constituent)
Dementia of Alzheimer’s Type

20. • AD is characterized by generalized cerebral cortical
atrophy with widespread cortical neuritic (or senile)
plaques (NPs) and neurofibrillary tangles (NFTs).
Following mechanisms have been attributed for the
development of Alzheimer’s dementia
– Amyloid cascade theory
– Neuronal loss
– Cholinergic hypothesis
– Excitotoxicity
– Genetic factors
Pathogenesis and pathophysiology

21. • Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in
the brain.
• Amyloid originates from part of a larger protein called amyloid precursor protein
(APP), which is normally found in the cell membranes of neurons throughout the
brain. App is normally metabolised by a protease enzyme α–secretase. In AD, the
metabolism of APP is altered by two other enzymes β and γ secretase which
cleave APP producing a protein fragment of 40 or 42 amino acids. This abnormal
form of amyloid is called β amyloid (Aβ).
• Once Aβ is formed, it accumulates into insoluble sheets (called β-pleated sheets).
These deposits are neurotoxic and act as foreign body. They activate inflammatory
reaction resulting in the formation of senile or neuritic plaque.
• This is accompanied by hyper-phosphorylation of tau protein, supporting the
microtubules, resulting in winding up of microtubular structure and these
aggregate to form neurofibrillary tangles.
Amyloid cascade theory

23. • The classic gross
neuroanatomical observation of
a brain from a patient with
Alzheimer's disease is diffuse
atrophy with flattened cortical
sulci and enlarged cerebral
ventricles. There is a
progressive loss of neurons and
their supportive glial cells. The
loss is more marked in the
entorhinal cortex, hippocampus.
Neuronal loss

24.  Levels of acetylcholine, noradrenaline, serotonin, γ-aminobutyric acid
(GABA), glutamate, somatostatin, neuropeptide Y, and substance P have all
been documented to be reduced in the brains of AD patients.
 However, reductions in acetylcholine and choline acetyltransferase are the
most profound, and therefore they have been thought to be the most
important.
 Such reductions are due to neuronal loss in the basal forebrain, which is the
major region from which cholinergic projections originate.
 Only modest improvements in cognitive functions have been achieved with
cholinergic agonists, presumably due to neuronal loss in the cortical targets
that receive cholinergic input.
Cholinergic hypothesis

25. • Excessive release of glutamate into the
synapses.
• Excessive influx of calcium into the cells
leading to cell death called excitotoxicity.
• Also lead to excessive production of Aβ and
tau phosphorylation.
Excitotoxicity

26. • People without ApoE4 have an estimated risk of between 9-20% for
developing AD by age 85.
• In people with one copy of the gene the risk is between 25-60%.
• In people with two copies, the risk ranges from 50-90%. (Only 2%
of the population carry two copies of the ApoE4 gene)
• About 40 % of patients have a family history of dementia of the
Alzheimer's type.
• The concordance rate for monozygotic twins is higher than the rate
for dizygotic twins (43 percent vs. 8 percent, respectively).
• Alzheimer's type dementia has shown linkage to chromosomes 1,
14, and 21.
Genetic factors

27. Prevalence and incidence
The prevalence of dementia has risen and
continues to rise alarmingly. It was estimated
that in 1997 there were approximately 2.3
million persons with dementia with a further
360 000 new cases arising annually
(Brookmeyer et al. 1998).

28. It is estimated that in 2008 there were
approximately 5.2 million persons with
dementia in the USA, with over 410 000 new
cases arising annually
(Alzheimer’s Association 2008, Alzheimer’s Disease Facts and fi gures
www.alz.org/national/documents/report_alzfactsfi gures2008.pdf).

29. • In the UK there are an estimated 750 000 people
with dementia and,
• Globally over 24 million people, with these
prevalence figures forecast to rise to over 80
million by 2040 (Ferri et al. 2005).
• Altogether dementia now ranks as the third most
common cause of death in the USA, on a par with
cardiovascular disease (Ewbank 1999).

30. Females outnumber males by a ratio of 2 or 3 : 1,
with the exception of the early-onset familial forms
of the condition, which as an autosomal dominant
inherited condition occurs equally in males and
females.

31. • Early onset: < 65 years; familial types; 1, 14
and 21 chromosomes.
• Late onset: >65 years usually in 70s; sporadic
form; 10, 11 and 12 chromosomes.
• very late-onset AD occurring after age 80–85
Diagnostic types

32. Familial Multiple System Taupathy with Presenile
Dementia.
• A recently discovered type of dementia, familial
multiple system taupathy, shares some brain
abnormalities found in people with Alzheimer’s
disease. The gene that causes the disorder is
thought to be carried on chromosome 17. The
symptoms of the disorder include short-term
memory problems and difficulty maintaining
balance and walking.
• The onset of disease occurs in the 40s and 50s,
and persons with the disease live an average of
11 years after the onset of symptoms.

33. Dementia – diagnostic approach

34. Major Neurocognitive Disorder
Diagnostic Criteria
A. Evidence of significant cognitive decline from a
previous level of performance in one or more cognitive
domains ( attention, executive function, learning and
memory, language, perceptual-motor, or social cognition)
based on:
1. Concern of the individual, a knowledgeable informant,
or the clinician that there has been a significant decline
in cognitive function; and
2. A substantial impairment in cognitive performance,
preferably documented by standardized
neuropsychological testing or, in its absence, another
quantified clinical assessment.

35. B. The cognitive deficits interfere with independence in
everyday activities (i.e., at a minimum, requiring
assistance with complex instrumental activities of daily
living such as paying bills or managing medications).
C. The cognitive deficits do not occur exclusively in the
context of a delirium.
D. The cognitive deficits are not better explained by
another mental disorder (e.g., major depressive disorder,
schizophrenia).

36. Specify whether due to:
Alzheimer’s disease .
Frontotemporal lobar degeneration.
Lewy body disease.
Vascular disease.
Traumatic brain injury.
Substance/medication use.
HIV infection.
Prion disease .
Parkinson’s disease.
Huntington’s disease.
Another medical condition.
Multiple etiologies .
Unspecified

37. Specify:
Without behavioral disturbance: If the cognitive disturbance is not
accompanied by any clinically significant behavioral disturbance.
With behavioral disturbance (specify disturbance): If the cognitive
disturbance is accompanied by a clinically significant behavioral
disturbance (e.g., psychotic symptoms, mood disturbance, agitation,
apathy, or other behavioral symptoms).
Specify current severity:
Mild: Difficulties with instrumental activities of daily living (e.g.,
housework, managing money).
Moderate: Difficulties with basic activities of daily living (e.g., feeding,
dressing).
Severe: Fully dependent.

38. Mild Neurocognitive Disorder
Diagnostic Criteria
A. Evidence of modest cognitive decline from a previous level of performance
in one or more cognitive domains ( attention, executive function, learning and
memory, language, perceptual motor, or social cognition) based on:
1. Concern of the individual, a knowledgeable informant, or the clinician that
there has been a mild decline in cognitive function; and
2. A modest impairment in cognitive performance, preferably documented by
standardized neuropsychological testing or, in its absence, another quantified
clinical assessment.
B. The cognitive deficits do not interfere with capacity for independence in
everyday activities (i.e., complex instrumental activities of daily living such as
paying bills or managing medications are preserved, but greater effort,
compensatory strategies, or accommodation may be required).

39. C. The cognitive deficits do not occur exclusively in the context of
a delirium.
D. The cognitive deficits are not better explained by another
mental disorder (e.g., major depressive disorder, schizophrenia).
Specify whether due to:
Alzheimer’s disease.
Frontotemporal lobar degeneration .
Lewy body disease.
Vascular disease.
Traumatic brain injury.
Substance/medication use.
HIV infection.
Prion disease.
Parkinson’s disease.
Huntington’s disease.
Another medical condition.
Multiple etiologies .
Unspecified

40. Specify:
Without behavioral disturbance: If the cognitive
disturbance is not accompanied by any clinically significant
behavioral disturbance.
With behavioral disturbance (specify disturbance): If the
cognitive disturbance is accompanied by a clinically
significant behavioral disturbance (e.g., psychotic
symptoms, mood disturbance, agitation, apathy, or other
behavioral symptoms).

41. Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. There is insidious onset and gradual progression of impairment in
one or more cognitive domains (for major neurocognitive disorder, at
least two domains must be impaired).

42. C. Criteria are met for either probable or possible Alzheimer’s disease
as follows:
For major neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if either of the following is
present; otherwise, possible Alzheimer’s disease should be diagnosed.
1. Evidence of a causative Alzheimer’s disease genetic mutation from
family history or genetic testing.
2. All three of the following are present:
a. Clear evidence of decline in memory and learning and at least one
other cognitive domain (based on detailed history or serial
neuropsychological testing).
b. Steadily progressive, gradual decline in cognition, without extended
plateaus.
c. No evidence of mixed etiology (i.e., absence of other
neurodegenerative or cerebrovascular disease, or another neurological
mental, or systemic disease or condition likely contributing to cognitive
decline).

43. For mild neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if there is evidence of
a causative Alzheimer’s disease genetic mutation from either
genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no evidence
of a causative Alzheimer’s disease genetic mutation from either
genetic testing or family history, and all three of the following
are present:
1. Clear evidence of decline in memory and learning.
2. Steadily progressive, gradual decline in cognition, without
extended plateaus.
3. No evidence of mixed etiology (i.e., absence of other
neurodegenerative or cerebrovascular disease, or another
neurological or systemic disease or condition likely contributing
to cognitive decline).
D. The disturbance is not better explained by cerebrovascular
disease, another neurodegenerative disease, the effects of a
substance, or another mental, neurological, or systemic disorder.

44. Clinical features
• usually insidious onset
• Three main phases .
• The first, often lasting for 2 or 3 years, is
characterised by failing memory, muddled
inefficiency over the tasks of everyday life and
spatial disorientation.

45. • The second stage brings more rapid progress
of intellectual and personality deterioration
and focal symptoms appear.
• Aphasia, Apraxia, Agnosia and Acalculia.

46. • The third or terminal stage consists of
profound apathetic dementia in which the
patient becomes bedridden and doubly
incontinent. Gross neurological disability may
sometimes develop, such as spastic
hemiparesis and tremor. Forced grasping and
sucking reflexes.

47. History of seizures was reported in 3% of one
series (Burns et al. 1991a)
In the terminal phase of the disease, bodily
wasting may be rapid despite adequate
preservation of appetite.

48. Mr. J, a 70-year-old retired businessman, was brought to psychiatric services on
referral by the family physician. His wife claimed that Mr. J had become so forgetful
that she was afraid to leave him alone, even at home. Mr. J retired at age 62 years
after experiencing a decline in work performance during the previous 5 years. He
also slowly gave up hobbies he once enjoyed (photography, reading, golf) and
became increasingly quiet. However, his growing forgetfulness went basically
unnoticed at home. Then one day while walking in an area he knew well, he could
not find his way home. From then on his memory failure began to increase. He
would forget appointments, misplace things, and lose his way around the
neighbourhood he resided in for 40 years. He failed to recognize people, even those
he knew for many years. His wife had to start bathing and dressing him because he
forgot how to do so himself.
On examination, Mr. J was disoriented in time and place. He was only able to
recall his name and place of birth. Mr. J seemed lost during the interview, only
responding to questions with an occasional shrug of his shoulders. When asked to
name objects or to recall words or numbers, Mr. J appeared tense and distressed.
Mr. J had difficulty following instructions and was unable to dress or undress himself.
His general medical condition was good. Laboratory examinations showed
abnormalities on Mr. J’s EEG and CT scans.

49. Behavioural and psychological symptoms
Psychosis,
Affective symptoms
Behavioral disturbances

50. • 30% - 50% of pts suffer from delusions and 10% -
25% of pts suffer from hallucinations.
• Delusions are frequently paranoid and most
common delusion is of theft.
• Visual hallucinations are more common than
auditory.
Psychosis

51. S.N Characteristics Psychosis with AD Schizophrenia
1 Prevalence 35%-50% of AD 1% of general population
2 Bizarre or complex delusions Rare Frequent
3 Misidentification of caregivers Frequent Rare
4 Common forms of hallucinations Visual Auditory
5 Schneiderian first rank symptoms Rare Frequent
6 Active suicidal ideations Rare Frequent
7 Past history of psychosis Rare Frequent
8 Eventual remission of psychosis Frequent Uncommon
9 Need for years of maintenance
antipsychotic therapy
Uncommon Very common
Comparison of psychosis of alzheimer’s disease with
schizophrenia in older patients

52. • Misidentification syndromes
(One very common manifestation of a misidentification syndrome is where family
members are mistaken for one another.)

53. • Depression is a risk factor for alzheimer’s disease.
• Depression can be confused with dementia (pseudodementia)
• A MDD is found in 10% of the AD patients.
• Depression is more common in early than in late stages of disease
• Elation, disinhibition and hypomania all can occur in Alzheimer’s
disease.
• Elevated mood is found in only 3.5 % of pts with AD (Burns et al).
Mood

54. S.N Pseudodementia Dementia
1 Informant aware of memory disturbance
and can date the onset accurately
Onset is insidious and informant usually can
not date onset.
2 Patient complains enthusiastically about
the memory loss
Unlikely
3 Questions about cognitive functions lead
to DON’T KNOW RESPONSE
accompanied by irritation
Try their best but are incorrect
4 History is usually short and often there is
a previous history of depressive episode
History is long and depressive episode may
or may not be present
5 Depressed patients perform better on
memory tests.
Don’t perform well.
6 Memory complains are accompanied by
insomnia, diurnal variation etc.
May or may not be present

55.  There is relentless decline in patient’s condition. The typical
duration of illness is 8 to 12 years but the course can range
from 5 to 25 years.
 Roth(1955) reported that 80% of the patients with this
diagnosis died within 2 years of admission to the hospital.
 But the figure was less for coming years because demented
patients were being admitted to hospital sooner and because
the care was better by the time (ROTH 1986).
Course of Alzheimer's disease

56. Dementias – history and clinical
examination
• When obtaining a history from a demented
person and relative, establish rapport: rate of
intellectual decline, impairment of social function,
general health and relevant disorders (e.g. stroke,
head injury), nutrition status, drug history, family
history of dementia.
• Tests to assess intellectual function are
designed to check: memory, abstract thought,
judgement, specific focal cortical functions.
The Mini Mental State Examination (MMSE)
• On neurological examination note: focal signs,
involuntary movements, pseudobulbar signs, gait
disorder.

57. Dementias – further investigation
• Blood tests (to exclude hypothyroidism, vitamin B12,
thiamine and folate deficiency, Lyme disease, HIV
infection, metabolic disorders and inflammatory
diseases).
• Cranial imaging (CT or/and MRI)
• PET and SPECT?
• EEG (slowing in AD, normal in pseudodementia,
periodic complexes in CJD)
• Genetic testing (rarely – Huntington mutation,
apolipoprotein E4 mutation in AD)
• Brain biopsy (if treatable cause is suspected)

58. Investigations
Neuroimaging
• Computed tomography (CT)
• Magnetic resonance imaging (MRI)
Hippocampal volume has most consistently been shown to be
reduced early in AD and to be a marker of progression.(in medial
temporal lobe structures)
• Serial positron emission tomography
(demonstrated substantial decreases in both cerebral blood flow
and oxygen utilisation in SDAT, affecting both grey and white
matter and implicating the parietal and temporal regions most
severely.)

59. • Electroencephalography
• Electroencephalography (EEG) shows abnormalities more
frequently in AD than in any other form of dementia. The
early stage consists of reduction of alpha activity, which may
sometimes disappear entirely. This is particularly
characteristic of AD and is perhaps of some value in
distinguishing it from other varieties, in particular FTD where
the EEG remains normal even relatively late in the disorder
(Förstl et al. 1996).

60. • Later in the disease course in AD, diffuse slow
waves appear, typically irregular theta activity
with superimposed runs of delta.

61. Neuritic plaques
• These lesions are extracellular deposits of an
amyloid, defined as an aggregated protein
that has a high proportion of β-pleated sheet
and shows birefringence when stained with
Congo red.
• The plaque is found in all cortical areas of
brain and also occurs in striatum and the
cerebellum (Braak et al.1989; Braak and Braak 1990,
1991).

62. Neurofibrillary tangles
• Tangles are intraneuronal aggregates of a
protein, tau, normally found in the axon.
• Tangles occur first in the entorhinal cortex and
spread in a systematic fashion through
hippocampus to wider cortical structures but
always sparing the cerebellum.
(Braak et al. 1994; Braak & Braak 1998).

63. • Vascular dementia refers to cognitive decline
caused by ischemic, hemorrhagic, or oligemic
injury to the brain.
• Vascular dementia is the second most common
cause of dementia after Alzheimer's disease.
• Prevalence rates range from approximately 1.5
percent in people aged 70 to 75 years of age to
approximately 15 percent in people older than 80
years of age.
Vascular dementia

64. History
• Kraepelin first described “arteriosclerotic
dementia” in 1896. This described cognitive
impairment as a direct result of
arteriosclerotic disease in the brain.
• Hachinski described “multi-infarct dementia”
as dementia related to a series of multiple
cerebral infarcts..

65. Major or Mild Vascular Neurocognitive Disorder
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The clinical features are consistent with a vascular etiology, as
suggested by either Of the following:
• 1. Onset of the cognitive deficits is temporally related to one or
more cerebrovascular events.
• 2. Evidence for decline is prominent in complex attention
(including processing speed) and frontal-executive function.
C. There is evidence of the presence of cerebrovascular disease from
history, physical examination, and/or neuroimaging considered
sufficient to account for the neurocognitive deficits.

66. • D. The symptoms are not better explained by another brain
disease or systemic disorder. Probable vascular
neurocognitive disorder is diagnosed if one of the following
is present; otherwise possible vascular neurocognitive
disorder should be diagnosed:
• 1. Clinical criteria are supported by neuroimaging evidence
of significant parenchymal injury attributed to
cerebrovascular disease (neuroimaging-supported).
• 2. The neurocognitive syndrome is temporally related to one
or more documented cerebrovascular events.
• 3. Both clinical and genetic (e.g., cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy) evidence of cerebrovascular disease
is present. Possible vascular neurocognitive disorder is
diagnosed if the clinical criteria are met but neuroimaging is
not available and the temporal relationship of the
neurocognitive syndrome with one or more cerebrovascular
events is not established.

67. • Hypertension
• Arrhythmia
• Diabetes mellitus
• Vasculitis
• Pulmonary disease
• Substance abuse
• Hyperlipidemia
• Low level of B12 & Folate associated with
increased homocysteine levels- risk of stroke
Risk factors for vascular dementia

68. • Smoking
• Obesity
• High cholesterol levels,
• Atrial fibrillation
• Cerebral amyloid angiopathy.
• Another key risk factor is the hereditary condition
cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy, or
CADASIL.

69. • Vascular etiology may range from large vessel
stroke to microvascular disease; the
presentation is therefore very heterogeneous,
stemming from the types of vascular lesions
and their extent and location. The lesions may
be focal, multifocal, or diffuse and occur in
various combinations.

70. • Many individuals with major or mild vascular
NCD present with multiple infarctions, with an
acute stepwise or fluctuating decline in
cognition, and intervening periods of stability
and even some improvement.

71. • Major or mild vascular NCD with a gradual
onset and slow progression is generally due to
small vessel disease leading to lesions in the
white matter, basal ganglia, and/or thalamus.

72. VASCULAR DEMENTIAS
• LARGER ARTERY SYNDROMES (MULTI-INFARCT
DEMENTIA)
– CARDIAC, CAROTID, VERTEBRAL OR INTRACRANIAL
ATHEROSCLEROTIC DISEASE.
– RISK FACTORS/MECHANISMS ARE NUMEROUS:
HYPERTENSION, HYPERLIPIDEMIA,TOBACCO SMOKE,
DIABETES, CORONARY ARTERY, DISEASE ATRIAL
FIBRILLATION, CARDIOMYOPATHY, VALVULAR
DISEASE, PARADOXIC EMBOLISM.

73. Multi-infarct dementia (MID)
• This is an overdiagnosed condition which accounts for less than
10% of cases of dementia.
• MID is caused by multiple strokes - SILENT STROKES
• Dementia occurs ’stroke by stroke‘, with progressive focal loss
of function.
• Clinical features of stroke profile – hypertension, diabetes, etc.
– are present. More often in males.
• Diagnosis is obtained from the history
and confirmed by CT or MRI scan
(the presence of multiple areas of
infarction).

74. SMALL VESSEL SYNDROMES (
SUBCORTICAL DEMENTIA )
– BINSWANGER SYNDROME
– LACUNAR STATE ( WITH OR WITHOUT SUBCORTICAL HEMORRHAGES ).
– RISK FACTORS: HYPERTENSION, DIABETES, HYPERLIPIDEMIA, TOBACCO
SMOKE.
– VASCULITIDES (ISOLATED CNS, SYSTEMIC, ANTI-CARDIOLIPIN,
MICROANGIOPATHIES SUCH AS TTP)
– CADASIL, (AND NOW CARASIL)
• STRATEGIC INFARCT DEMENTIA ( THALAMUS, PCA INARCTION INVOLVING
TEMPORAL LOBE, ETC.)
• HEMORRHAGIC DEMENTIAS ( SUBARACHNOID HEMORRHAGE, SUBDURAL
HEMORRAGE, RECURRENT LOBAR HEMORRHAGE ).

75. Small-vessel disease
• Damage to the microvasculature in the brain.
• There are two cardinal features of small-vessel
disease:
(i) white matter lesions (WMLs), which may be
apparent as periventricular lucency (also
known as leucoaraiosis) or as deep white
matter hyperintensities; and
(ii) central grey matter lacunae

76. • CT scan in multi-infarct
dementia. The ventricles
are normal in size, but there
are patchy radiolucencies
throughout the white matter.
These indicate the presence
of demyelinated patches,
which result from multiple
small infarcts in the brain.
Vascular dementia

78. Characteristics Alzheimer’s Disease Vascular Dementia
Sex Women Men
Age Generally over age 75 years Generally over age 60 years
Onset & progression Gradually progressive Stuttering or episodic, with
stepwise deterioration
History of hypertension Less common Common
History of
stroke(s),transient ischemic
attack(s),or other focal
neurological symptoms
Less common Common
Hypertension Less common Common
Focal neurological signs Uncommon Common
Emotional lability Less common More common
Cognitive deficits Uniform patchy
Alzheimer’s Disease Vs Vascular Dementia

79. Comorbidity
Major or mild NCD due to Alzheimer's disease
commonly co-occurs with major or mild vascular
NCD, in which case both diagnoses should be
made. Major or mild vascular NCD and
depression frequently co-occur.

80. • It is a dementia associated with degenerative atrophy of frontal and
temporal lobes.
• Often begins with marked behavioral disturbances, unlike AD
Fronto-temporal dementia

81. PREVALENCE
• Major or mild frontotemporal NCD is a common
cause of early-onset NCD in individuals younger
than 65 years.
• In all FTD variants the onset is usually in the
presenile period, with a range from 45 to 70
years
• Approximately 20%-25% of cases of
frontotemporal NCD occur in individuals older
than 65 years.

82. Major or Mild Frontotemporal
Neurocognitive Disorder
• A. The criteria are met for major or mild
neurocognitive disorder.
• B. The disturbance has insidious onset
and gradual progression.

83. • C. Either (1) or (2);
• 1. Behavioral variant;
• a. Three or more of the following behavioral
symptoms:
• i. Behavioral disinhibition.
• ii. Apathy or inertia.
• iii. Loss of sympathy or empathy.
• iv. Perseverative, stereotyped or
compulsive/ritualistic behavior.
• v. Hyperorality and dietary changes.
• b. Prominent decline in social cognition and/or
executive abilities.

84. 2. Language variant:
a. Prominent decline in language ability, in the form of
speech production, word finding, object naming,
grammar, or word comprehension.
D. Relative sparing of learning and memory and
perceptual-motor function.
E. The disturbance is not better explained by
cerebrovascular disease, another neurodegenerative
disease, the effects of a substance, or another mental,
neurological, or systemic disorder.

85. • Probable frontotemporal neurocognitive disorder
is diagnosed if either of the following is present;
otherwise, possible frontotemporal
neurocognitive disorder should be diagnosed:
1. Evidence of a causative frontotemporal
neurocognitive disorder genetic mutation, from
either family history or genetic testing.
2. Evidence of disproportionate frontal and/or
temporal lobe involvement from neuroimaging.
Possible frontotemporal neurocognitive disorder is
diagnosed if there is no evidence of a genetic
mutation, and neuroimaging has not been
performed.

86. CLINICAL FEATURES
• PATIENTS loose interest in socialization,
selfcare, and personal responsibilities, or
display socially inappropriate behaviors.
• Individuals may develop changes in social
style, and in religious and political beliefs, with
repetitive movements, hoarding, changes in
eating behavior, and hyperorality.
• In later stages, loss of sphincter control may
occur.

87. • Cognitive decline is less prominent, and formal
testing may show relatively few deficits in the early
stages.
• Common neurocognitive symptoms are lack of
planning and organization, distractibility, and poor
judgment.
• Deficits in executive function, such as poor
performance on tests of mental flexibility, abstract
reasoning, and response inhibition, are present, but
learning and memory are relatively spared, and
perceptual motor abilities are almost always
preserved in the early stages.
• Primary progressive aphasia

88. • Hodges (2001) describes three distinctive
forms of FTD:
• Frontal variant FTD, 40 % each
• Semantic dementia and
• Progressive nonfluent aphasia. 20%

89. Frontal variant FTD presents with classical features of
loss of frontal lobe function
• Disinhibition, stereotypy, lack of impulse
control and antisocial behaviour. Apathy and
loss of executive function resulting in inability
to plan. Compulsive & repetitive behaviours or
speech patterns are common.
• Memory is relatively spared.
• Amnesia develops with time but even in
relatively advanced dementia, spatial memory
can be preserved.

90. Semantic dementia
• Temporal variant of FTD and presents with
complaints of loss of memory for words but is
usually accompanied by a receptive dysfunction
that the patient may be completely unaware of.
• The semantic loss is frequently accompanied by
prosopagnosia. i.e. loss of recognition and
naming of faces.
• Orientation is preserved.
• Interestingly, where there is memory impairment
it is predominantly remote rather than recent
memories that are most affected.

91. Non-fluent progressive aphasia
• Speech dysfluency and word-finding difficulties
often accompanied by deterioration in spelling

92. Features FTD AD
Personality change Early Late
Amnesia Late Early
Language disturbances Early Late
Stereotypes Early Mid or late
Apraxia, agnosia, alexia Late Variable
Kluver-Bucy syndrome Early Late
Visuospatial disorientation Rare Common
Age of risk Mean 50, up to 80yrs Risk increases with age
CT Scan Fronto-Temporal atrophy Widespread atrophy
Gross Pathology Anterior hemi. Atrophy, Posterior hemispheric
atrophy,
Histopathology pick’s body Neurofibrillary tangle
Length of illness 2-11 yrs 5-25 yrs

93. Course
• Individuals with major or mild frontotemporal NCD
commonly present in the sixth decade of life,
although the age at onset varies from the third to
the ninth decades. The disease is gradually
progressive, with median survival being 6-11 years
after symptom onset and 3-4 years after diagnosis.
Survival is shorter and decline is faster in major or
mild frontotemporal NCD than in typical
Alzheimer's disease.`

94. • Lewy bodies
– pathologic inclusions hallmark of Parkinson’s
disease when restricted to brain stem
• Patients have clinical parkinsonism with early and
prominent dementia
• Lewy bodies found in brain stem, limbic system, and
cortex
• Visual hallucinations and cognitive fluctuations
common
• Patients sensitive to adverse effects of neuroleptics.
Lewy body dementia

95. Major or Mild Neurocognitive Disorder
With Lewy Bodies
Diagnostic Criteria
• A. The criteria are met for major or mild neurocognitive
disorder.
• B. The disorder has an insidious onset and gradual
progression.
• C. The disorder meets a combination of core diagnostic
features and suggestive diagnostic features for either
probable or possible neurocognitive disorder with Lewy
bodies.
• For probable major or mild neurocognitive disorder with
Lewy bodies, the individual has two core features, or one
suggestive feature with one or more core features.
• For possible major or mild neurocognitive disorder with
Lewy bodies, the individual has only one core feature, or
one or more suggestive features.

96. 1. Core diagnostic features:
• a. Fluctuating cognition with pronounced variations in
attention and alertness.
• b. Recurrent visual hallucinations that are well formed and
detailed.
• c. Spontaneous features of parkinsonism, with onset
subsequent to the development of cognitive decline.
• 2. Suggestive diagnostic features;
• a. Meets criteria for rapid eye movement sleep behavior
disorder.
• b. Severe neuroleptic sensitivity.
• D. The disturbance is not better explained by
cerebrovascular disease, another neurodegenerative
disease, the effects of a substance, or another mental,
neurological, or systemic disorder.

97. Prevalence
• The few population-based prevalence estimates for
NCDLB available range from 0.1% to 5% of the
general elderly population, and from 1.7% to 30.5%
of all dementia cases. In brain bank (autopsy)
series, the pathological lesions known as Lewy
bodies are present in 20%-35% of cases of
dementia. The male-to-female ratio is
approximately 1.5:1.

98. The classical triad of symptoms of DLB comprises
• Fluctuating cognitive impairment,
• Parkinsonism
• and visual hallucinations .
Clinical Criteria

99. • ASSOCIATED features
Repeated falls
Syncope
Sensitivity to neuroleptics
Systematized delusions
Hallucinations in other modalities (e.g.
auditory, tactile)

100. –Rapid onset of dementia, transmissible: prion
protein.
– Prion disease may develop at any age in adults the
peak age for the sporadic CJD is approximately 67
years although it has been reported to occur in
individuals spanning the teenage years to late life.
– Both sexes appear to be equally affected, although a
female preponderance has sometimes been reported.
Dementia in Creutzfeldt- Jakob disease

101. Major or Mild Neurocognitive Disorder
Due to Prion Disease
Diagnostic Criteria
• A. The criteria are met for major or mild
neurocognitive disorder.
• B. There is insidious onset, and rapid
progression of impairment is common.
• C. There are motor features of prion disease,
such as myoclonus or ataxia, or biomarker
evidence.
• D. The neurocognitive disorder is not
attributable to another medical condition and is
not better expiated by another mental disorder.

102. CLINICAL FXX
• The patient complains of fatigue, insomnia, anxiety
and depression.
• Intellectual deterioration or neurological defects
soon become prominent.
• Myoclonic jerks are almost invariably seen.
• There may be ataxia of cerebellar type, spasticity of
limbs with progressive paralysis, extrapyramidal
rigidity, tremor or choreoathetoid movements,
• Atrophy of the small hand muscles, resembling
amyotrophic lateral sclerosis.

103. • Speech disturbances are common with dysphasia
and dysarthria, likewise parietal lobe symptoms
such as right–left disorientation, dyscalculia and
finger agnosia.
• Vision may be severely affected with rapidly
progressive cortical blindness.
• Brainstem involvement may lead to nystagmus,
dysphagia or bouts of uncontrollable laughing and
crying.
• Epileptic fits may occur.

104. • Both 14-3-3 protein and tau are elevated in CSF. and show
modest sensitivity and specificity in diagnosis
• CT may show cortical atrophy and ventricular enlargement
but this is rarely gross in degree. Indeed, CT can be
essentially normal when the dementia is well advanced, a
feature that was suggested to be of some importance in
differential diagnosis.
• The use of MRI has been of more value in diagnosis and
prognosis of CJD. Increased grey matter signal in sporadic
CJD is associated with shorter survival.
• Most notably, however, the MRI finding of a bilateral
pulvinar signal (the ‘pulvinar sign’) is very highly sensitive
and specific for CJD.

105. Electroencephalography is almost always
markedly Abnormal.
Initially there is some diffuse or focal
slowing. Later, paroxysmal sharp waves or
slow spike-and wave discharges appear;
these are bilaterally synchronous and may
accompany the myoclonic jerks. Ultimately,
a characteristic pattern emerges of
synchronous triphasic sharp wave complexes
at 1–2 Hz, superimposed on progressive
suppression of cortical background activity.

106. The course is much more rapid
than with most other primary
dementing illnesses, the great
majority of patients dying within 2
years. Death is usually preceded by
a period of deepening coma that
lasts for several weeks.

107. • Huntington's disease is classically associated with the development of
dementia.
• Sub-cortical type of dementia, characterized by more motor
abnormalities and fewer language abnormalities than in the cortical
type of dementia.
• The dementia of Huntington's disease exhibits psychomotor slowing
and difficulty with complex tasks, but memory, language, and insight
remain relatively intact in the early and middle stages of the illness.
Dementia in Huntington's disease

108. Dementia in Huntington's disease
• As the disease progresses, the dementia becomes
complete; the features distinguishing it from
dementia of the Alzheimer's type are the high
incidence of depression and psychosis, in addition
to the classic choreo-athetoid movement disorder.
• Usually have family history.
• DNA repeat expansion: HD mutation through
PCR to measure the number of CAG repeats in
the HD gene.

109. Major or Mild Neurocognitive Disorder
Due to Another Medical Condition
Diagnostic Criteria
• A. The criteria are met for major or mild
neurocognitive disorder.
• B. There is evidence from the history, physical
examination, or laboratory findings that the
neurocognitive disorder is the pathophysiological
consequence of another medical condition.
• C. The cognitive deficits are not better explained
by another mental disorder or another specific
neurocognitive disorder (e.g., Alzheimer’s
disease, HIV infection).

110. These conditions include
• structural lesions (e.g., primary or secondary brain tumors,
subdural hematoma, slowly progressive or normal-pressure
hydrocephalus),
• Hypoxia related to hypoperfusion from heart failure,
• Endocrine conditions (e.g., hypothyroidism, hypercalcemia,
hypoglycemia),
• Nutritional conditions (e.g., deficiencies of thiamine or niacin)
• Infectious conditions (e.g., neurosyphilis, cryptococcosis)
• Immune disorders (e.g., temporal arteritis, systemic lupus
erythematosus), hepatic or renal failure, metabolic conditions
and
• other neurological conditions (e.g., epilepsy, multiple sclerosis).
• Unusual causes of central nervous system injury, such as
electrical shock or intracranial radiation, are generally evident
from the history.

111.  Triad
1. Dementia: typically subcortical
2. Gait instability
3. Urinary incontinence
 Symptoms progress over weeks to months
 CT shows ventricular enlargement out of
proportion to cortical atrophy
Normal pressure hydrocephalus

112. Normal pressure hydrocephalus
Diagnosis is based on clinical picture plus CT scan/MRI
evidence of ventricular enlargement.
NPH must be differentiated from pts whose ventricular
enlargement is merely the result of shrinkage of the
surrounding brain, e.g. AD. These pts do not respond to CSF
shunting, whereas a proportion of NPH pts (but not all) show a
definitive improvement with ventriculo-peritoneal shunting.

113.  Most important test – therapeutic LP
1. Remove large amount of CSF
2. Examine gait and cognitive function
 Ventriculoperitoneal shunt may correct if:
◦ Patients improve within minutes to hours of
removal of 30 to 40 mL of spinal fluid
Normal pressure hydrocephalus

114. AIDS dementia complex
• Approximately two-thirds of persons with AIDS
develop dementia, mostly due to AIDS dementia
complex.
• In some patients HIV is found in the CNS at
postmortem. In others an immune mechanism or an
unidentified pathogen is blamed.
• Dementia is initially of a "subcortical " type.
• CT - atrophy; MRI - increased T2 signal from
white matter.
• Treatment with Zidovudine (AZT) halts and
partially revers neuropsychological deficit.

115. Major or Mild Neurocognitive Disorder
Due to HIV Infection
Diagnostic Criteria
• A. The criteria are met for major or mild
neurocognitive disorder.
• B. There is documented infection with human
immunodeficiency virus (HIV).
• C. The neurocognitive disorder is not better
explained by non-HIV conditions, including secondary
brain diseases such as progressive multifocal
leukoencephalopathy or cryptococcal meningitis.
• D. The neurocognitive disorder is not attributable to
another medical condition and is not better
explained by a mental disorder.

116. • Approximately one-third to over one-half of
HIV infected individuals have at least mild
neurocognitive disturbance, but some of
these disturbances may not meet the full
criteria for mild NCD.
• An estimated 25% of individuals with HIV will
have signs and symptoms that meet criteria
for mild NCD, and in fewer than 5% would
criteria for major NCD be met.

117. Trauma
• Reduction of intellectual function is common after
severe head injury.
• Chronic subdural haematoma can also present as
progressive dementia, especially in the elderly.
• Punch-drunk encephalopathy (dementia pugilistica) is
the cumulative result of repeated cerebral trauma. It
occurs in both amateur and professional boxers and it
manifests by dysarthria, ataxia and expy signs
associated with ’subcortical‘ dementia. There is no
treatment for this progressive syndrome.

118. Major or Mild Neurocognitive Disorder
Due to Traumatic Brain Injury
Diagnostic Criteria
• A. The criteria are met for major or mild neurocognitive disorder.
• B. There is evidence of a traumatic brain injury—that is, an impact to the
head or other mechanisms of rapid movement or displacement of the
brain within the skull, with one or more of the following:
• 1. Loss of consciousness.
• 2. Posttraumatic amnesia.
• 3. Disorientation and confusion.
• 4. Neurological signs (e.g., neuroimaging demonstrating injury; a new
onset of seizures; a marked worsening of a preexisting seizure disorder;
visual field cuts; anosmia; hemiparesis).
• C. The neurocognitive disorder presents immediately after the occurrence
of the traumatic brain injury or immediately after recovery of
consciousness and persists past the acute post-injury period.

119. • Neurobehavioral symptoms tend to be most
severe in the immediate aftermath of the TBI.
• Resolve within days to weeks after the injury
with complete resolution typical by 3 months.
• May potentially co-occur with the neurological
symptoms (e.g., depression, irritability, fatigue,
headache, photosensitivity, sleep disturbance)
also tend to resolve in the weeks following mild
TBI.

120. • With moderate and severe TBI, in addition to
persistence of neurocognitive deficits, there may be
associated neurophysiological, emotional, and
behavioral complications.
• These include seizures (particularly in the first year),
photosensitivity, hyperacusis, irritability, aggression,
depression, sleep disturbance, fatigue, apathy,
inability to resume occupational and social
functioning at pre-injury level, and deterioration in
interpersonal relationships.

121. Risk factors for traumatic brain injury.
• Traumatic brain injury rates vary by age, with
the highest prevalence among individuals
younger than 4 years, older adolescents, and
individuals older than 65 years.
• Falls are the most common cause of TBI, with
motor vehicle accidents being second.
• Sports concussions are frequent causes of TBI in
older children, teenagers, and young adults.

122. Risk factors for neurocognitive disorder after
traumatic brain injury.
• Repeated concussions can lead to persistent
NCD and neuropathological evidence of
traumatic encephalopathy.
• Co-occurring intoxication with a substance may
increase the severity of a TBI from a motor
vehicle accident, but whether intoxication at the
time of injury worsens neurocognitive outcome
is unknown.

123. • CT scanning may reveal petechial hemorrhages,
subarachnoid hemorrhage, or evidence of
contusion.
• Magnetic resonance image scanning may also
reveal hyperintensities suggestive of
microhemorrhages.

124. Diagnostic Work-Up
• This is done to
– (1) rule out disorders besides dementia (e.g. delirium)
– (2) to identify reversible/treatable dementias
• Routine Assessment: CBC with diff, serum electrolytes, Ca++,
glucose, BUN/CR, LFTs, TFTs, B12 & folate, U/A, kft, head imaging,
Neuropsychological Testing
• When indicated: Sed. rate, HIV, CXR, heavy metals, LP, EEG,
functional imaging, Lyme titers, endocrine studies,
rheumatologic studies,

125. Specialized Testing
• LP: Suspicion of metastatic CA, CNS infections,
neuropsyphilis, hydrocephalus, vasculitis. Also for
dementia <55 and rapidly progressive dementias
• Neuroimaging - consider in all new cases.
However without focal symptoms or signs, seizures
or gait disturbances in an individual over age 70 -
consider this optional
• Functional Imaging (SPECT, PET, MRS, fMRI):
to clarify type of dementia when necessary (and in
the future to track course of illness and response to
tx)
• EEG - can help distinguish delirium from dementia,
can help with seizure disorder and CJD

126. RISK FACTORS
• 1. Non-modifiable risk factors:
• Age, Genes, Family history of dementia, Down's
syndrome
• 2. Modifiable risk factors:
• Vascular risk factors:
• Vascular cognitive impairment (VCI) encompasses the
entire spectrum of cognitive disorders associated with
cerebrovascular insults. Other factors which contribute
to
• vascular risk include current smoking,
hypercholesterolemia, atherosclerosis, hypertension
especially midlife, obesity, etc.

127. • Diabetes:
• Diabetes seems to be a much stronger risk factor for vascular
dementia than for Alzheimer's disease, and cerebrovascular disease
is likely to be an important mediating mechanism.
• Researchers have discovered that even high blood sugar level, not
amounting to diabetes, may have an increased risk of developing
dementia compared with those who have a normal blood sugar
level.
• Metabolic syndrome:
• People with metabolic syndrome are found to have augmented risk
of cognitive decline and each vascular risk appears to be additive.
Possible mechanisms may include microvascular and macro-
vascular disease, inflammation, adiposity, and insulin resistance.
• Alcohol consumption:
• Although small amount of alcohol may reduce the risk of dementia
but heavy intake can cause cognitive impairment.

128. Treatment

129. The treatment of dementia is basically directed towards the management of
cognitive, behavioural and the ADL symptoms of dementia. The standard
treatment goals are:
Early diagnosis
1) Detection of tiny, misfolded protein fragments Ab oligomers in cerebrospinal
fluid taken from patients.
2) The researchers report that combining MRI, FDG-PET, and CSF data with routine
clinical data (age, education, ApoE status, standard neuropsychological tests)
significantly increases the accuracy of predicting conversion to AD compared with
clinical data alone.
3) Patients presenting with sudden onset behavioural abnormality in late life
should be evaluated for dementia

130. Optimization of physical health, cognition, activity and wellbeing by
controlling the contributing risk factors.
Safeguarding the residual cognitive functioning of the brain:
1) This includes pharmacological treatment involving several drugs viz:
1a) Cholinesterase inhibitor: Donepezil, galantamine, Galantamine,
extended release rivastigmine, Rivastigmine transdermal patch
1b) NMDA-receptor antagonist: Memantine
2) Several agents have been associated with slowing of cognitive
decline in dementia
including: Vitamin E, NSAIDS, Gingko Biloba, Hormone replacement
therapy, MAO-B inhibitor, Ergoloids

131. Cholinesterase inhibitors
• These drugs stop the breakdown of
acetylcholine which is an important
neurotransmitter in memory and cognition
• All show modest improvement in cognition and
function, and behavioural symptoms
• Do not prevent progression of underlying
disease

132. Cholinesterase inhibitors
• Donepezil
given once daily, dosage of 5mg to 10mg
• Rivastigmine
given twice daily, dosages of 3mg to 12mg
• Galantamine
given once daily, dosages of 8mg to 24mg
(can also be given twice daily)

133. Use of cholinesterase inhibitors
• need specialist diagnosis of Alzheimers
Disease, and a MMSE score of 10 to 24.
• side effects - nausea, vomiting, diarrhoea,
dizziness, headache, muscle cramps
• use carefully if gastric ulcer, heart disease,
chronic lung disease

134. Cholinesterase Inhibitors
• Donepezil
– Precautions: Nausea, vomiting, diarrhea,
GI bleed, sick sinus syndrome, seizures
– Interactions: CYP2D6 (flecainide, metopropol,
codeine), used with NSAID risk for GI bleed

135. Cholinesterase Inhibitors
Galantamine
◦ Precautions: AV block, seizures, bladder
obstruction, renal and hepatic, GI bleed,
GI upset
◦ Interactions: CYP3A4 (cholinergic agonist -
bethanechol, ketoconazole, cimetidine,
erythromycin)

136. Cholinesterase Inhibitors
Rivastigmine ( Cap / 24 hour Patch)
◦ Precautions: Nausea, vomiting, anoxia,
GI bleed, sick sinus syndrome, seizures
◦ Interactions: CYP2D6 and CYP3A4, potentates
muscle relaxants, used with NSAID 3-4x risk for
GI bleed

137. NMDA [glutamate] antagonist
Memantine
◦ Precautions: Dizziness, headache, alkalinized
urine (ATN, UTI) seizures, GI upset
◦ Interactions: Other NMDA antagonists
(amantadine, dextromethorphan), decreased
by renally-excreted drugs

138. Memantine
• Glutamate is a transmitter in the brain that is
affected by Alzheimers Disease
• Memantine blocks the pathological effects of
abnormal glutamate release, and allows better
function of the impaired brain
• Indicated for moderate to severe AD
• Trials show slowing in cognitive and functional
decline and decrease in agitation in treated
group compared to placebo

139. Memantine
• can use with other AD medications
• side effects - headaches, dizziness
• do not use in kidney disease or seizure
disorders
• dosage: start with 5mg daily and increase
to10mg twice daily

140. Neuroprotective Strategies
 Nerve Growth Factor
 Acetyl-carnitine
 Estrogen
 Homocysteine reduction( folate, B6, B12)
 Antioxidants (Vit E, Gingko,)
 ‘Statins’ (may lower abnormal amyloid levels)
 Rosiglitazone -anti-inflammatory, amyloid
processing modulation activities

141. Neuroprotective Strategies
• Vitamin E, vitamin D, Gingko (antioxidant)
 Nerve Growth Factor
 Acetyl-carnitine
 Estrogen
 Homocysteine reduction( folate, B6, B12)
 Antioxidants (Vit E, Gingko,)
 ‘Statins’ (may lower abnormal amyloid levels)
 Rosiglitazone -anti-inflammatory, amyloid
processing modulation activities

142. Vitamin E
 Potent antioxidant properties
 Recent study showed no difference from placebo in
preventing progression from MCI to AD over 3 yrs
 Doses used in recent studies: up to 1000 IU bid
 Consider 400-800 IU per day for prevention
 May work better if combined with Vitamin C

143. Ginkgo biloba
• extract from the ginkgo tree taken in doses
of 120mg to 240 mg daily
• anti-inflammatory, anti-oxidant properties
• trials show modest improvements in some
measures of function and memory
• reasonably safe and well tolerated, but
watch for bleeding

144. Estrogen
• At this point the summary of many studies
suggests that Hormone replacement therapy
(HRT) is questionably effective in slowing the
onset of AD in some women
• The earlier started, the better response

145. Statins
• Lovastatin(Mevacor), pravastatin(Pravachol),
simvastatin(Zocor), atorvastatin(Lipitor)
• May prevent aggregation of B-amyloid* in the brain by
preventing cholesterol build up. May activate alpha-
secretase.
*AKA amyloid-beta peptide or ABeta

146. RECENT ADVANCES
• Huperzine A (Chinese herbal medicine)
– cholinesterase inhibitor, antioxidant, possible
neuroprotection properties
– nutraceutical - 200 to 800 mcg daily
• Alzhemed
– prevents formation and deposition of amyloid in
the brain
• Phenserine (recent poor trial results)
– cholinesterase inhibitor and regulates formation of
amyloid in the brain

147. RECENT ADVANCES
• Huperzine A (Chinese herbal medicine)
– cholinesterase inhibitor, antioxidant, possible
neuroprotection properties
– nutraceutical - 200 to 800 mcg daily
• Alzhemed
– prevents formation and deposition of amyloid in
the brain
• Phenserine (recent poor trial results)
– cholinesterase inhibitor and regulates formation of
amyloid in the brain

148. NSAID Use & AD in Elderly Patients
• NSAID users had ~50% lower risk of being
affected by AD
• Aspirin trended this way but was not
significant
• Treatment studies have not shown any
consistent benefits.
Landi, et al, Am J Geriatric Psychiatry, March-April, 2003

149.  Vaccination Strategy: AN-1792 vaccine is in testing.
This is an amyloid B protein fragment which can
induce antibodies that bind to plaques and activate
microglial destruction processes.
 ‘Plaque busters’
 Alzhemed prevents Amyloid B fragments from forming fibrils
 Clioquinol - A metal-protein-attenuating compound (MPAC)
that inhibits zinc and copper ions from binding to beta-
amyloid, thereby helping to dissolve it and prevent it from
accumulating.
 Transthyretin shows promise at interfering with toxic effects
 Generate new tissue -
 neuroregeneration strategies (STEM cells)
 neurotransplantation strategies

150. • Tau protein modulators (to prevent abnormal
phosphorylated ‘tau’ protein
• Beta and gamma-secretase inhibitors
• Alpha secretase stimulators
• Bryostatin – CA drug that stimulates brain protein
production. Reduces B-amyloid levels in mice,
enhances memory and learning.
• New generation NSAIDS (flubiprofen) – testing in
humans looks promising
• Immune enhancers (immunoglobulin)

151. • Environmental modifications such as music,
Speak slowly, keep commands simple and
positive, use gestures, gentle touch
• Structured activities and use of schedules
• Massage, exercise
Non-pharmacological management
Rowe, Alfred 1999
Gerdner, Swanson 1993

152. Non-pharmacological treatment
• Cognitive Enhancement
Reality orientation and memory training, reminiscence
therapy, Validation Therapy, music Therapy, Dance
Therapy, Massage Therapy, Exercise & Yoga , Art
Therapy, Family Therapy
• Individual and Group Therapy
– emotional orientated psychotherapy
– stimulation orientated therapy

153. Other Nonpharmacological
treatment
 Communication with family and caregiver,
psychoeducation of caregivers
 Tips to caregivers regarding how to avoid stress)
 Environmental Modifications
◦ moderate stimulation only
◦ memory measures
clocks, calendars, to-do lists
name tags, alert bracelets

154. Antipsychotics…
• Commonly prescribed in older patients with
dementia and behavioral problems (agitation,
sundowning, aggression)
• Choices:
– Haloperidol (0.5mg-1mg)
– Atypical agents:
• Risperidone
• Olanzapine
• Quetiapine

155. • Best choices are: risperidone, olanzapine,
quetiapine
• All have significant side-effects
- Risperidone: watch for EPS
- Olanzapine: sedation, anticholinergic SE, increased vascular
risk factors
- Quetiapine: hypotension, sedation, difficult to find
therapeutic dose
• ?increased risk of cerebro-vascular events
reported with both olanzapine & risperidone
Treatment of persistent psychotic
symptoms and aggression

156. Antipsychotics
• Concern with haloperidol for significant risk of EPS and TD
with prolonged use in elderly
• All of risk of sedation, orthostasis and varying amounts of
anticholinergic effects
• Studies show slight efficacy for behavioral problems in
dementia
• BUT NOT FDA approved for this
• AND INCREASED RISK OF DEATH AND CVA with use of atypical
agents…

157. Antidepressants
• Guidelines (American & UK Geriatric Society)
– treating all patients with dementia and signs of
depression/ anxiety with an SSRI or SNRI

158. • SSRI antidepressants are now first line treatment for
anxiety symptoms
- Will take a few weeks to work fully
- Watch for GI symptoms, headaches, hyponatremia
• May also consider Trazodone for its sedating effects
- Watch for hypotension, over-sedation, priapism
• If anxiety is specific to occasional situations, consider sos use of
lorazepam.
- May cause falls, worsening of disinhibited behaviour, confusion and memory
problems
Medications for anxiety symptoms

159. • If well established diagnosis of bipolar illness
prior to dementia, low dose lithium with
appropriated geriatric blood levels (0.4-0.6
mEq/L) may be best treatment but requires
close monitoring
• For new onset of manic-like symptoms,
consider valproic acid or carbamazepine
Treatment of manic-like symptoms (very
limited data)

160. Prevention
• Exercise •
• The researchers measured the fitness of 57 early-stage
AD patients, and a similar number of non-demented
subjects, during exercise on a treadmill, and
determined whole brain volume by MRI. Their results
indicate that subjects with AD had a modestly but
significantly reduced maximum oxygen consumption (a
measure of cardiorespiratory fitness) compared to non-
demented subjects. Fitness level correlated with brain
volume in the AD group, so that people with AD who
were in better shape had more brain tissue. There was
no such relationship in people without dementia, and
there was no correlation between brain volume and
cognitive measures after adjustment for age.

161. Prevention
• Diet – Mediterranean diet: high intake of fish,
low to moderate intake of saturated fatty acids.
low to moderate intake of dairy products and
meats .
– Associated with lower AD risk
– Associated with lower mortality in AD

162. Prevention
• Many studies have shown that a higher level of
education is protective against Alzheimer’s disease.
• This theory suggests that the brain's ability to
cope with Alzheimer's disease varies from person to
person, but the number of neurons and synapses
are likely to be more numerous in people who are
highly educated.
• Alternatively, even if the quantity of neurons and
synapses is no different, the synapses are likely to
be more efficient and/or the alternative circuitry is
likely to be operating in those who are highly
educated.

163. • Dementia causes a huge burden.
• Needs multidisciplinary approach to prevent,
diagnosis and management.
• Need further research in corresponding field.
Conclusion

164. THANK YOU