This document summarizes various types of dementia and their characteristics. It discusses Alzheimer's disease and other dementias such as vascular dementia, frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease dementia, and prion diseases. For each type, it describes clinical presentation, risk factors, neuropathology, diagnosis, and treatment options. The document provides a comprehensive overview of the classification, causes, symptoms, evaluations, and management strategies for the major forms of acquired cognitive impairment and dementia.
2. It is a syndrome of acquired global or
multifocal impairment of cognitive function
involving decline in intellect, memory or
personality in the presence of normal
consciousness
3. VITAMIN DEFICIENCIES
◦ B DEF- WERNICKES ENCEPH.
◦ B12 DEF- PERINICIOUS ANEMIA
◦ NIACIN- PELLAGRA
ENDOCRINE AND OTHER ORGAN FAILURE
◦ HYPOTHYROID
◦ HYPO & HYPER PARATHYROID
◦ ADRENAL INSUFF AND CUSHINGS
◦ LIVER FAILURE
◦ RENAL FAILURE
◦ PULMO FAILURE
7. The most important risk factors for AD are old age and a positive
family history.
The prevalence of AD increases with each decade of adult life,
reaching 20–40% of the population over the age of 85.
autosomal dominant inheritance occurs in only 2% of patients.
Female sex is a risk factor independent of the greater
women who carry an Apo ε4 allele are more susceptible than are
male ε4 carriers.
A history of head trauma with concussion increases the risk for
AD.
AD is more common in groups with low educational attainment,
8. environmental factors, including aluminum,
mercury, and viruses
nonsteroidal antiinflammatory agents is
associated with a decreased risk of AD.
Vascular disease,to lower the threshold for the
clinical expression of AD.
Also, in many patients with AD, amyloid
angiopathy can lead to microhemorrhages, large
lobar hemorrhages, ischemic infarctions most
often in the subcortical white matter, or in rare
cases an inflammatory leukoencephalopathy.
Diabetes increases the risk of AD threefold.
Elevated homocysteine and cholesterol levels;
hypertension; diminished serum levels of folic
acid; low dietary intake of fruits, vegetables, and
red wine; and low levels of exercise
9. At autopsy, the earliest and most severe
degeneration is usually found in the medial
temporal lobe (entorhinal/perirhinal cortex
and hippocampus), lateral temporal cortex,
and nucleus basalis of Meynert.
The characteristic microscopic findings are
neuritic plaques and NFTs
10.
11.
12. soluble amyloid species called oligomers may
cause cellular dysfunction and represent the
early toxic molecule in AD. Eventually, further
amyloid polymerization and fibril formation
lead to neuritic plaques, which contain a
central core of amyloid, proteoglycans, Apo
ε4, α-antichymotrypsin, and other proteins.
Aβ is a protein of 39–42 amino acids that is
derived proteolytically from a larger
transmembrane protein, amyloid precursor
protein (APP), when APP is cleaved by β and γ
secretases
13. The accumulation of Aβ in cerebral arterioles is
termed amyloid angiopathy.
NFTs are composed of silver-staining neuronal
cytoplasmic fibrils composed of abnormally
phosphorylated tau protein; they appear as paired
helical filaments by electron microscopy.
Tau binds to and stabilizes microtubules,
supporting axonal transport of organelles,
glycoproteins, neurotransmitters, and other
important cargoes throughout the neuron.
14. AD is associated with a decrease in the cortical levels of
acetylcholine, its synthetic enzyme choline
acetyltransferase, and nicotinic cholinergic receptors.
Reduction of acetylcholine reflects degeneration of
cholinergic neurons in the nucleus basalis of Meynert that
project throughout the cortex.
There is also noradrenergic and serotonergic depletion
due to degeneration of brainstem nuclei such as the locus
coeruleus and dorsal raphe, where tau-immunoreactive
neuronal cytoplasmic inclusions can be identified even in
individuals lacking entorhinal cortex NFTs.
15.
16. DOWN SYNDROME
APP GENE ON CHROMOSOME 21
PRESENILIS 1 ON CHROMOSOME 14 -protein
called S182. Mutations in this gene cause an
early-age-of-onset AD
PRESENELIS 2 ON CHROMOSOME 1- encodes
a protein called STM2.
17. APO E4 ON CHROMOSOME 19( SINGLE MOST
IP BIOLOGICAL MARKER)-increased risk of AD
in the general population, including sporadic
and late-age-of-onset familial forms
APO E2 ON CHROMOSOME 14( PROTECTIVE
FOR ALZHEIMER)
18. The cognitive changes begin with memory
impairment and progressing to language and
visuospatial deficits.
upstream visual processing dysfunction
(referred to as posterior cortical atrophy
syndrome) or a progressive “logopenic”
aphasia.
19. Some may present with an asymmetric
akineticrigid- dystonic (“corticobasal”)
syndrome or a dysexecutive “frontal variant”
of AD.
Once the memory loss becomes noticeable to
the patient and spouse and falls 1.5 standard
deviations below normal on standardized
memory tests, the term mild cognitive
impairment (MCI) is applied.
20. “prodromal AD” refers to a person with
biomarker evidence of AD (amyloid imaging
positive with positron emission tomography
or low cerebrospinal Aβ42 and mildly
elevated tau) in the absence of symptoms.
21. Some patients are unaware of these
difficulties (anosognosia), but most remain
acutely attuned to their deficits.
Changes in environment (travel, relocation,
hospitalization) tend to destabilize the
patient. Over time patients become lost on
walks or while driving.
22. the patient is unable to work, is easily lost and
confused, and requires daily supervision.
Language becomes impaired—first naming, then
comprehension, and finally fluency.
Word-finding difficulties and circumlocution can
be evident in the early stages
Apraxia emerges, and patients have trouble
performing learned sequential motor tasks.
Visuospatial deficits begin to interfere with
dressing, eating, or even walking, and patients
fail to solve simple puzzles or copy geometric
figures.
Simple calculations and clock reading become
difficult
23. In the late stages, some persons remain
ambulatory, wandering aimlessly. Loss of
judgment and reasoning is inevitable.
Delusions are common, usually simple, with
common themes of theft, infidelity, or
misidentification.
24. 10% of AD patients develop Capgras’
syndrome, believing that a caregiver has been
replaced by an impostor.
in AD this syndrome emerges late. (In
contrast to dementia with Lewy bodies (DLB),
where Capgras’ syndrome is an early feature)
25. Disinhibition.
Sleep-wake patterns are disrupted, and
nighttime wandering.
Some patients develop a shuffling gait with
generalized muscle rigidity associated with
slowness and awkwardness of movement.
Patients often look parkinsonian.
26. In the end stages, AD patients become rigid,
mute, incontinent, and bedridden, and help is
needed with eating, dressing, and toileting.
Hyperactive tendon reflexes and myoclonic
jerks (sudden brief contractions of various
muscles or the whole body) may occur
spontaneously or in response to physical or
auditory stimulation.
27.
28. Often death results from malnutrition,
secondary infections, pulmonary emboli,
heart disease, or, most commonly, aspiration.
The typical duration of AD is 8–10 years, but
the course ranges from 1 to 25 years.
29. As AD progresses, more distributed but
usually posterior-predominant cortical
atrophy becomes apparent, along with
atrophy of the medial temporal memory
structures
30.
31. Functional imaging studies, such as positron
emission tomography (PET), reveal
hypometabolism in the posterior temporal-
parietal cortex in AD
32. PET can also be used to detect the presence
of fibrillar amyloid in the brain and amyloid
PET positivity is becoming required for entry
into treatment trials for AD.
Electroencephalogram (EEG) is normal or
shows nonspecific slowing; prolonged EEG
can be used to seek out intermittent
nonconvulsive seizures.
Cerebrospinal fluid (CSF) Aβ42 level is
reduced, whereas the tau protein is elevated
33. Building rapport with the patient, family
members, and other caregivers.
In the early stages of AD, memory aids such
as notebooks and posted daily reminders can
be helpful.
Kitchens, bathrooms, stairways, and
bedrooms need to be made safe, and
eventually patients will need to stop driving.
35. The pharmacologic action of donepezil,
rivastigmine, and galantamine is inhibition of
the cholinesterases, primarily
acetylcholinesterase, with a resulting increase
in cerebral acetylcholine levels.
Memantine appears to act by blocking
overexcited N-methyl-d-aspartate (NMDA)
glutamate receptors
36. Memantine, used in conjunction with
cholinesterase inhibitors or by itself, slows
cognitive deterioration and decreases
caregiver burden for patients with moderate
to severe AD but is not approved for mild AD.
an extract of Ginkgo biloba found modest
improvement in cognitive function in subjects
with AD and vascular dementia
37. Vaccination against Aβ42 efficacious in
mouse models. In human trials, this
approach led to lifethreatening
complications, including
meningoencephalitis, in a minority of
patients.
use of β and γ secretase inhibitors that
diminish the production of Aβ42, but the first
two placebo-controlled trials of γ secretase
inhibitors, tarenflurbil and semagacestat,
were negative, and semagacestat may have
accelerated cognitive decline compared to
placebo.
38. Medications that modify tau phosphorylation
and aggregation, including tau antibodies,
39. nonsteroidal antiinflammatory agents and 3-
hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase inhibitors (statins) may
have a protective effect on dementia if used
prior to the onset of disease but do not
influence clinically symptomatic AD.
40. Mild to moderate depression is common in
the early stages of AD and may respond to
antidepressants or cholinesterase inhibitors.
Selective serotonin reuptake inhibitors (SSRIs)
are commonly used
41. Seizures can be treated with levetiracetam unless
the patient had a different regimen that was
effective prior to the onset of AD.
Agitation, insomnia, hallucinations, and
belligerence are especially troublesome
characteristics of some AD patients, and these
behaviors can lead to nursing home placement.
The newer generation of atypical antipsychotics,
such as risperidone, quetiapine, and olanzapine,
are being used in low doses to treat these
neuropsychiatric symptoms
42. two general categories: multi-infarct dementia
and diffuse white matter disease (also called
leukoaraiosis, subcortical arteriosclerotic
leukoencephalopathy, or Binswanger’s disease)
Other rare causes of white matter disease also
present with dementia, such as adult
metachromatic leukodystrophy (arylsulfatase A
deficiency) and progressive multifocal
leukoencephalopathy .
A dominantly inherited form of white matter
disease is known as cerebral autosomal dominant
arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL),
43.
44.
45.
46.
47.
48. FTD most often begins in the fifth to seventh
decades.
In the behavioral variant (bvFTD), the most
common FTD syndrome, social and emotional
systems dysfunction manifests as apathy,
disinhibition, compulsivity, loss of empathy,
and overeating, often but not always
accompanied by deficits in executive control.
49. Two forms of primary progressive aphasia
(PPA), the semantic and
nonfluent/agrammatic variants, are
commonly due to FTLD.
In the semantic variant, patients slowly lose
the ability to decode word, object, person-
specific, and emotion meaning
patients with the nonfluent/agrammatic
variant develop profound inability to produce
words, often with prominent motor speech
impairment.
50.
51. Any of these three clinical syndromes, but
most often bvFTD, may be accompanied by
motor neuron disease (MND), in which case
the term FTD-MND is applied.
In addition, the corticobasal syndrome (CBS)
and progressive supranuclear palsy syndrome
(PSP-S) can be considered part of the FTLD
clinical spectrum.
52. Right hemisphere-predominant or symmetric
anterior cingulate/medial prefrontal, orbital,
and anterior insular degeneration predicts
bvFTD.
Patients with nonfluent/agrammatic PPA show
left (dominant) frontal opercular and
precentral gyrus degeneration, whereas left
anterior temporal atrophy presents with
semantic variant PPA.
53. The most common autosomal dominantly
inherited mutations causing FTD involve the
C9ORF72 (chromosome 9), GRN
(chromosome 17), and MAPT (chromosome
17) genes.
Progranulin is a growth factor that binds to
tumor necrosis factor (TNF) receptors and
participates in tissue repair and tumor
growth.
54.
55. The gross pathologic hallmark of FTLD is a
focal atrophy of frontal, insular, and/or
temporal cortex.
Loss of cortical serotonergic innervation is
seen in many patients. In contrast to AD, the
cholinergic system is relatively spared in FTD,
56. Pick’s disease a progressive degenerative
disorder characterized by selective
involvement of the anterior frontal and
temporal neocortex and pathologically by
intraneuronal cytoplasmic inclusions (Pick
bodies).
Classical Pick bodies are argyrophilic,
staining positively with the Bielschowsky
silver method (but not with the Gallyas
method) and also with immunostaining for
hyperphosphorylated tau.
57.
58. Progressive supranuclear palsy syndrome
(PSP-S; also known as Steele-Richardson-
Olszewski syndrome) is a degenerative
disorder that involves the brainstem, basal
ganglia, limbic structures, and selected areas
of cortex.
59.
60. Clinically, PSP-S begins with falls and
executive or subtle personality changes (such
as mental rigidity, impulsivity, or apathy).
Shortly thereafter, a progressive oculomotor
syndrome ensues that begins with square
wave jerks, followed by slowed saccades
(vertical worse than horizontal) before
resulting in progressive supranuclear
ophthalmoparesis.
Dysarthria, dysphagia, and symmetric axial
rigidity can be prominent features that
emerge at any point in the illness.
A stiff, unstable posture with hyperextension
of the neck and a slow, jerky, toppling gait
are characteristic.
61.
62. Some patients with a pathologic diagnosis of PSP begin
with a nonfluent aphasia or motor speech disorder and
progress to classical PSP-S. Response to l-dopa is limited
or absent; no other treatments exist.
In PSP, accumulation of hyperphosphorylated 4-repeat tau
is seen within neurons and glia. Neuronal inclusions often
take the form of NFTs be large, spherical (“globose”), and
coarse in brainstem, cerebellar dentate, and diencephalic
neurons. Tau deposition is most prominent in subcortical
structures
Death occurs within 5–10 years of onset.
63. PSP is associated with prominent tau-positive
glial pathologies, such as tufted astrocytes
(Fig. 448-5), thorny astrocytes, and coiled
oligodendroglial inclusions (“coiled bodies”).
Most patients with PSP-S show PSP at
autopsy, although small numbers will show
another tauopathy (corticobasal degeneration
[CBD] or Pick’s disease
64. Corticobasal syndrome (CBS) is a slowly
progressive dementiamovement disorder
associated with severe atrophy in perirolandic
cortex and basal ganglia (substantia nigra
and striatopallidum).
Patients typically present with asymmetric
onset of rigidity, dystonia, myoclonus, and
apraxia of one limb, at times associated with
alien limb phenomena in which the limb
exhibits unintended motor actions such as
grasping, groping, drifting, or undoing.
65. Eventually CBS becomes bilateral and leads to
dysarthria, slow gait, action tremor, and typically
a frontal-predominant dementia.
Whereas CBS refers to the clinical syndrome, CBD
refers to a specific histopathologic FTLD-tau
entity.
In CBD, the microscopic features include
ballooned, achromatic, tau-positive neurons;
astrocytic plaques; and other dystrophic glial tau
pathomorphologies that overlap with those seen
in PSP. Most specifically, CBD features a severe
tauopathy burden in the subcortical white matter
66. The DLB clinical syndrome is characterized by
visual hallucinations, parkinsonism,
fluctuating alertness, falls, and often rapid
eye movement (REM) sleep behavior disorder
(RBD).
Dementia can precede or follow the
appearance of parkinsonism.
67. dementia that is associated with visual
hallucinations and fluctuating alertness. When
this occurs after an established diagnosis of
PD, many use the term Parkinson’s disease
dementia (PDD).
Patients with PDD and DLB are highly
sensitive to metabolic perturbations, and in
some patients, the first manifestation of
illness is a delirium, often precipitated by an
infection, new medicine, or other systemic
disturbance.
68. The key neuropathologic feature in DLB is the
presence of Lewy bodies and Lewy neurites
throughout specific brainstem nuclei, substantia
nigra, amygdala, cingulate gyrus, and, ultimately,
the neocortex.
Lewy bodies are intraneuronal cytoplasmic
inclusions that stain with periodic acid–Schiff
(PAS) and ubiquitin but are now identified with
antibodies to the presynaptic protein, α-
synuclein.
69. Lewy bodies are composed of straight neurofilaments 7–20 nm
long with surrounding amorphous material and contain epitopes
recognized by antibodies against phosphorylated and
nonphosphorylated neurofilament proteins, ubiquitin, and α-
synuclein.
Lewy bodies are typically found in the substantia nigra of
patients with idiopathic PD, where they can be readily seen with
hematoxylin-and-eosin staining.
A profound cholinergic deficit, owing to basal forebrain and
pedunculopontine nucleus , is present in many patients with DLB
and may be a factor responsible for the fluctuations, inattention,
and visual hallucinations
70. CJD is a rapidly progressive disorder
associated with dementia, focal cortical signs,
rigidity, and myoclonus, causing death <1
year after first symptoms appear.
The markedly abnormal periodic complexes
on EEG and cortical ribboning and basal
ganglia hyperintensities on fluid-attenuate
inversion recovery MRI are diagnostic features
of CJD,
