2. • It is defined as an acquired deterioration in cognitive
abilities that impairs the successful performance of
activities of daily living. Memory is the most common
cognitive ability lost with dementia
• The single strongest risk factor for dementia is
increasing age
• AD is the most common cause of dementia ,
accounting for more than half of all patients. Vascular
disease is considered the second most frequent.
Dementias related to Parkinson's disease (PD) are
extremely common
5. Alzheimer's Disease (AD)
• Approximately 10% of all persons over the age of 70 have
significant memory loss, and in more than half the cause is AD
• AD most often presents with an insidious onset of memory loss
followed by a slowly progressive dementia over several years.
Pathologically, atrophy is distributed throughout the medial
temporal lobes, as well as lateral and medial parietal lobes and
lateral frontal cortex. Microscopically, there are neuritic plaques
containing A, neurofibrillary tangles (NFTs) composed of
hyperphosphorylated tau filaments, and accumulation of amyloid in
blood vessel walls in cortex and leptomeninges
• The most consistent neurotransmitter deficit in Alzheimer disease is
in cholinergic neurotransmission.
• Hippocampal atrophy is characteristic, and reductions in
hippocampal volumes may be observed on magnetic resonance
imaging
6. Clinical Manifestations
• The cognitive changes of AD tend to follow a
characteristic pattern, beginning with memory
impairment and spreading to language and
visuospatial deficits
• In the early stages of the disease, the memory
loss may go unrecognized or be ascribed to
benign forgetfulness.
7. • Slowly the cognitive problems begin to
interfere with daily activities, such as keeping
track of finances, following instructions on the
job, driving, shopping, and housekeeping.
Some patients are unaware of these
difficulties (anosognosia), while others remain
acutely attuned to their deficits. Changes in
environment (such as vacations or hospital
stays) may be disorienting, and the patient
may become lost on walks or while driving.
8. • In the middle stages of AD, the patient is unable to work, is easily
lost and confused, and requires daily supervision. Social graces,
routine behavior, and superficial conversation may be surprisingly
intact.
• Language becomes impaired—first naming, then comprehension,
and finally fluency. In some patients, aphasia is an early and
prominent feature.
• Word-finding difficulties and circumlocution may be a problem even
when formal testing demonstrates intact naming and fluency.
• 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 in parallel.
9. • In the late stages of the disease, some persons remain ambulatory
but wander aimlessly. Loss of judgment and reasoning is inevitable.
Delusions are common and usually simple, with common themes of
theft, infidelity, or misidentification. Approximately 10% of AD
patients develop Capgras' syndrome, believing that a caregiver has
been replaced by an impostor.
• Loss of inhibitions and aggression may occur and alternate with
passivity and withdrawal. Sleep-wake patterns are disrupted, and
nighttime wandering becomes disturbing to the household. Some
patients develop a shuffling gait with generalized muscle rigidity
associated with slowness and awkwardness of movement. Patients
often look parkinsonian (Chap. 372) but rarely have a high-
amplitude, rhythmic, resting tremor.
10. • In end-stage AD, patients become rigid, mute, incontinent,
and bedridden. 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. Generalized seizures may also
occur. 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 can range from 1 to 25 years. For
unknown reasons, some AD patients show a steady decline
in function, while others have prolonged plateaus without
major deterioration.
11. Epidemiology
• The most important risk factors for AD are old age and a positive family history.
• The frequency of AD increases with each decade of adult life, reaching 20–40% of
the population over the age of 85.
• A positive family history of dementia suggests a genetic cause of AD, although
autosomal dominant inheritance occurs in only 2% of patients with AD.
• Female sex may also be a risk factor independent of the greater longevity of
women. Some AD patients have a past history of head trauma with concussion.
• AD is more common in groups with low educational attainment, but education
influences test-taking ability, and it is clear that AD can affect persons of all
intellectual levels.
• One study found that the capacity to express complex written language in early
adulthood correlated with a decreased risk for AD.
• Numerous environmental factors, including aluminum, mercury, and viruses, have
been proposed as causes of AD, but none has been demonstrated to play a
significant role.
• Similarly, several studies suggest that the use of nonsteroidal anti-inflammatory
agents is associated with a decreased risk of AD, but this has not been confirmed
in large prospective studies.
12. • Vascular disease, and stroke in particular, seems 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,
or ischemic infarctions.
• 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 are all being explored as potential
risk factors for AD.
13. • The diagnosis of Alzheimer disease, like that of dementia itself, is
largely a clinical one based on the history and examination.
• The key elements in the history are a gradual onset and insidious
progression of cognitive impairment, especially anterograde
amnesia. The mental status examination should demonstrate
impairment in short-term memory and other cognitive deficits.
• Alzheimer disease should be thought of as a diagnosis of inclusion:
if the history and examination are compatible with Alzheimer
disease and if certain exclusions can be verified, the diagnosis can
be made with confidence.
• The pathophysiology of Alzheimer disease in patients with mild
cognitive impairment or dementia can be assessed with
cerebrospinal fluid (CSF) protein markers (β-amyloid and tau) and
with brain imaging (structural MRI, 18fluoro-deoxyglucose PET,8
and amyloid positron emission tomography
14. Treatment: Alzheimer's Disease
• The management of AD is challenging and
gratifying, despite the absence of a cure or a
robust pharmacologic treatment.
• The primary focus is on long-term
amelioration of associated behavioral and
neurologic problems, as well as providing
caregiver support
15. • Building rapport with the patient, family members, and other
caregivers is essential to successful management. In the early stages
of AD, memory aids such as notebooks and posted daily reminders
can be helpful.
• Family members should emphasize activities that are pleasant and
curtail those that are unpleasant. In other words, practicing skills
that have become difficult, such as through memory games and
puzzles, will often frustrate and depress the patient without proven
benefits.
• Kitchens, bathrooms, stairways, and bedrooms need to be made
safe, and eventually patients must stop driving. Loss of
independence and change of environment may worsen confusion,
agitation, and anger.
• Communication and repeated calm reassurance are necessary.
16. • Donepezil (target dose, 10 mg daily), rivastigmine
(target dose, 6 mg twice daily or 9.5-mg patch daily),
galantamine (target dose 24 mg daily, extended-
release), memantine (target dose, 10 mg twice daily),
and tacrine are the drugs presently approved
• 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 due to their low
anticholinergic side effects (
17.
18.
19.
20.
21.
22.
23.
24.
25.
26. • Holoprosencephaly (HPE) is a malformation in
which the two cerebral hemispheres appear
fused in the midline, but is really a failure of
cleavage in the midsagittal plane of the
embryonic cerebral vesicle at 33 days' gestation
and thus a paramedian hypoplasia of the
forebrain. HPE has a frequency of 1 in 16,000
live births, but in 1 in 250 spontaneously
aborted fetuses in the first trimester; hence it is
among the most common of the major cerebral
malformations.
27.
28.
29.
30. • Traditionally, HPE was a single malformation
with three variants: alobar, semilobar, lobar.
Later, a fourth was added, the middle
interhemispheric variant
• six known defective genes together account for
only about 20% of cases
• After chromosomal defects, the most common
association of HPE is maternal diabetes mellitus;
sacral agenesis is another common
malformation in infants of diabetic mothers
31.
32. • Unenhanced computed
tomographic scan of a 6-year-
old boy with semilobar
holoprosencephaly. The lateral
ventricles are fused,
particularly frontally, but show
some division into two
occipital horns. A deep
abnormal sulcus is seen across
the fused frontal lobes
(arrowheads). This is one of
several radiological variants of
holoprosencephaly.
33. • Unenhanced computed tomographic
scan of a 6-year-old boy with
semilobar holoprosencephaly. The
lateral ventricles are fused,
particularly frontally, but show some
division into two occipital horns. A
deep abnormal sulcus is seen across
the fused frontal lobes
(arrowheads). This is one of several
radiological variants of
holoprosencephaly.
34. • The diagnosis of HPE often occurs at the time of delivery because 93% of
patients exhibit midline facial dysplasias. Midfacial hypoplasia is present
in most patients with HPE, but others have a normal face. The facial
dysmorphism ranges from mild hypotelorism and vomer bones to severe
forms including cebocephaly with a single nare, severe hypotelorism and
absence of the premaxilla and vomer bones to produce a midline cleft lip
and palate, or cyclopia with a midline proboscis dorsal to the single
median eye. The severity of the facial dysmorphism does not correlate as
well with the anatomical variant as originally expressed in the often-
cited statement “the face predicts the brain.” Midfacial hypoplasia does
correlate, however, with the rostrocaudal extent of the defective genetic
expression. If the gradient extends to the embryonic mesencephalic
neuromere and causes hypoplasia of the midbrain, neural crest
formation and migration are affected . The mesencephalic neural crest is
the most rostral origin of neural crest and this tissue forms not only
peripheral neural structures such as the ciliary ganglion, but also most of
the membranous bones of the face, globe of the eye (except the retina
and choroid), and much of the facial connective tissue.
35. • The characteristic clinical course of HPE is severe
developmental delay and a mixed pattern of seizures that
often are refractory to anticonvulsant medications
• Some patients develop hydrocephalus that requires a
ventriculoperitoneal shunt. This condition is paradoxically
more common in the less severe anatomical forms of the
malformation
• The treatment of HPE symptoms is directed toward the
complications, such as seizures, hydrocephalus, and
endocrine disturbances. Educational potential and needs
depend on the degree of mental retardation, speech, and
visual impairment
