Memory Loss, Alzheimer’s

Disease, and Dementia

A Practical Guide for Clinicians

WHY DIAGNOSE AND TREAT MEMORY LOSS, ALZHEIMER’S DISEASE, AND

DEMENTIA :
• Current treatments can help improve or maintain the patient’s cognitive and functional status by
“turning back the clock” on memory loss.
• Families and other caregivers are helped by treatments that maintain or improve functional status
and neuropsychiatric symptoms.
• Using current treatments saves money, as shown by pharmaco-economic studies.
• New, disease-modifying treatments are being developed and may be available soon.
• Accurate diagnosis helps define prognosis, facilitating future planning.
• Improving the quality (not quantity) of life is the goal.

EVALUATING THE PATIENT WITH MEMORY LOSS OR DEMENTIA :

1. A history of present illness
2. Medical history and Family history, including a history of late-life memory problems even if
considered normal for age at that time
3. Current and relevant past medications and Allergies to medications
4. Social history including education, occupation, and any possible learning disabilities
5. Physical and neurological examination
6. Cognitive examination
7. Laboratory studies
8. Neuroimaging studies.

1. A history of present illness

Talking with the family (or other caregivers)

Ideally, family or other caregivers are interviewed separately from the patient

MEMORY LOSS
The hippocampus and other medial temporal lobe structures
Episodic memory because it is memory for a specific episode of your life
Common symptoms of this memory loss include asking the same questions repeatedly, repeating the
same stories, forgetting important appointments, and leaving the stove on.
Anterograde amnesia or difficulty learning new information
Retrograde amnesia or difficulty retrieving previously learned information
Typically demonstrate preserved memory for remote information. Thus, a patient may report, “I’ve
got short-term memory problems—I cannot remember what I did yesterday but I can still remember
things from thirty years ago.”
Distortions of memory and false memories
Combine two memories together, or think that an event that happened long ago occurred recently.
Sometimes a false memory can be confused with a psychotic delusion or hallucination
WORD-FINDING
There is evidence to suggest that the lower, lateral portion of the temporal lobes is involved in the
representations of words and their meanings
The frontal lobes, by contrast, are thought to be involved in the selection or choice of the particular
word that is searched for
Both are affected by the pathology of Alzheimer’s disease
Patients will substitute a simpler word for a more complex one; later they may be unable to
complete sentences. Sometimes there will be circumlocutions, in which patients will describe the
word because they cannot retrieve it
Family members become accustomed to filling in missing words.
As the disease progresses, word substitutions (often referred to as paraphasic errors) occur. These
word substitutions are typically not random, but instead are usually related to the word by meaning
(often referred to as semantic paraphasic errors) or sound (often referred to as phonemic paraphasic
errors).
Sometimes the speech is fluent, but is relatively uninformative (often called “empty speech”)

GETTING LOST
The parietal lobe is involved in spatial function, and is particularly important for real-time spatial
navigation
Difficulty learning a new route
Becomes confused or lost in familiar places

REASONING AND JUDGMENT

Prefrontal cortex: problem solving, abstraction, reasoning, and judgment. These cognitive abilities
are sometimes collectively referred to as executive function
The frontal lobes are also critical for attention, concentration, and working memory—the ability to
temporarily maintain and manipulate information

BEHAVIOR ISSUES
The frontal lobes are involved in the control of behavior, as well as personality and affect
Apathy is the most common behavioral change early in the disease, followed by irritability. As the
disease progresses many patients show an exacerbation of their previous personality characteristics
Suspiciousness and paranoia: The usual scenario is that the patient puts his or her valuables away in
a safe place so that they cannot be stolen, forgets where they were put, and then is certain that they
were stolen—only to be found later.

DEPRESSION AND ANXIETY

It has long been thought that depression is a common cause of memory problems.
More likely that patients with memory complaints in addition to depression or anxiety will have an
underlying primary memory disorder such as Alzheimer’s disease.

INSIGHT
Commonly, patients in the very early stages of Alzheimer’s disease dementia—and those with the
pre-dementia stage of mild cognitive impairment (MCI) (see Chapters 3 and 8 for details)—show
insight into their memory deficits

FUNCTION
Part of the definition of dementia is that the patient has had a noticeable decline from their prior
level of functioning,
2. Medical history and Family history, including a history of late-life memory problems even if
considered normal for age at that time

Ask about whether the following have ever occurred:

• A significant brain infection such as meningitis or encephalitis
• A significant head injury in which the patient lost consciousness
• Repetitive mild head injuries from football, other sports, or other causes
• A stroke or a transient ischemic attack
• A seizure
• Fluctuating levels of alertness or periods of being relatively unresponsive
• Visual hallucinations of people or animals
• A disturbance of gait
• Falls
• A tremor
• Rigidity and other signs of parkinsonism
• A dramatic change in personality such that the patient seems like a different person
• Any major psychiatric problems earlier in life, such as major depression or bipolar disease
• Any weakness or numbness in the face or of an arm or a leg
• Problems with fevers, chills, or night sweats
• Problems with nausea, vomiting, or diarrhea
• Problems with chest pain or shortness of breath
• Any incontinence of bowel or bladder
• Problems going to sleep (insomnia), staying asleep, or early morning awakening; any naps?
• Acting out dreams during sleep or other abnormal movements while sleeping
• Difficulty distinguishing dreams from reality when transitioning to and from sleep

• Hypertension
• Hypercholesterolemia
• Coronary artery disease
• Atrial fibrillation and other cardiac arrhythmias
• Obstructive sleep apnea.

Family history of Alzheimer’s disease, but also to ask whether there is a history of memory loss,
senility, or dementia late in life.

3. Current and relevant past medications and Allergies to medications

First, are there medications that caused significant confusion or agitation when administered?
Susceptibility to confusion from medications may be present prior to the clinical onset of
Alzheimer’s disease or other dementia.
Second, are there reactions to medications used to treat Alzheimer’s disease? If so, are these true
allergic reactions to the medications, common side effects, or rare and unusual problems?

4. Social history including education, occupation, and any possible learning disabilities

HABITS
Cigarette smoking, whether past or present, is of course a risk factor for cerebrovascular disease.
Alcohol use
Use or abuse of prescription medications and other drugs should also be elicited
EDUCATION AND OCCUPATION
SOCIAL SUPPORTS

5. Physical and neurological examination

The neurological examination: signs of focal brain lesions, signs of other neurodegenerative
disorders, and frontal release signs (Snout, Grasp, Palmomental reflex).
The cardiovascular examination

6. Cognitive examination

MENTAL STATUS SCREENING TESTS

The Mini-Mental State Examination
The Blessed Dementia Scale
The Montreal Cognitive Assessment (MoCA)

SINGLE NEUROPSYCHOLOGICAL TESTS

Clock Drawing Test
Category Fluency
Delayed Word Recall
Trailmaking A and B

SCREENING INSTRUMENTS THAT COMBINE SINGLE TESTS

The Mini-Cog
The 7 Minute Screen

CAREGIVER-COMPLETED QUESTIONNAIRES
IQCODE
Alzheimer’s Disease Caregiver Questionnaire
AD8 Dementia Screening Interview

RECOMMENDATIONS FOR IN-OFFICE SCREENING

The 7 Minute Screen and the Alzheimer’s Disease Caregiver Questionnaire (ADCQ)
The Montreal Cognitive Assessment (MoCA) and the AD8 Dementia Screening Interview (AD8)

NEUROPSYCHOLOGICAL EVALUATION

SCREENING FOR DEPRESSION

The Geriatric Depression Scale
Neuropsychiatric Inventory (NPI)

EVALUATING FUNCTION
Functional Activities Questionnaire

7. Laboratory studies
Vitamin B12 deficiency
Vitamin D
Thyroid disorders
Lyme disease should be considered in the appropriate clinical context
Neurosyphilis if the patient is immunocompromised

8. Neuroimaging studies.
MRI VERSUS CT
MRI scans do not show an acute hemorrhage of almost any type as effectively as CT scans
If a patient is claustrophobic or agitated (as can often be the case in Alzheimer’s disease dementia
after the early stages), a CT scan is easier to obtain than an MRI scan.
First in Alzheimer’s disease there is typically atrophy of bilateral hippocampi, anterior temporal
lobes, and parietal lobes. Note that the atrophy is often asymmetric, for unknown reasons.
Second, how extensive is the small vessel ischemic disease? Is the amount of these tiny small vessel
strokes average for the patient’s age, less, or more? Has the small vessel disease affected critical
areas of the brain such as the thalamus, where even a small stroke can cause memory loss?
Third, is there any other pathology present?

Functional Imaging Studies

We would also strongly recommend either a functional imaging study or a test that suggests
Alzheimer’s disease (see below) for a young person aged less than 66 years with dementia, even if
the evaluation appears straightforward.
SPECT VERSUS PET
SPECT (single photon emission computed tomography) and PET (positron emission tomography).
In both cases a small amount of a radiolabeled dye (usually technetium-99 for SPECT and
fluorodeoxyglucose for PET)
Before an area of the brain becomes atrophic, it is likely that it first becomes metabolically less
active. Thus, functional imaging scans are typically more sensitive to early brain dysfunction than
structural imaging scans
In Alzheimer’s disease the pattern is one of bilateral temporal and parietal hypometabolism
Note that these functional imaging studies are more likely than structural imaging studies to show
significant changes over relatively brief periods of time, such as 6–12 months

Tests That Suggest Alzheimer’s Disease

We would recommend obtaining one of these tests, however, if the patient appears to have a
straightforward case of Alzheimer’s disease dementia or mild cognitive impairment due to the
Alzheimer’s disease pathophysiologic process, but is younger than 66 years old
CEREBROSPINAL FLUID (CSF) Aβ AND TAU

AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) SCAN

APPROACH TO THE PATIENT WITH MEMORY LOSS, MILD COGNITIVE
IMPAIRMENT, OR DEMENTIA

A Two-Step Approach
(1) determining if mild cognitive impairment or dementia is present, and (2) determining the disease
or diseases that are the cause.

Is dementia present?
DSM-5 CRITERIA FOR MAJOR NEUROCOGNITIVE DISORDER
A. Evidence of significant cognitive decline from a previous level of performance in one or more
cognitive domains (complex 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.
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).

Is Mild Cognitive Impairment (MCI) Present?

DSM-5 CRITERIA FOR MILD NEUROCOGNITIVE DISORDER
A. Evidence of modest cognitive decline from a previous level of performance in one or more
cognitive domains (complex 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 independence in everyday activities (i.e., the patient
perseveres in performing complex instrumental activities of daily living such as paying bills or
managing medications, but greater effort, compensatory strategies, or accommodation may be
required).
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).
What is the Cause of the Dementia or Mild Cognitive Impairment?
ALZHEIMER’S DISEASE

Prevalence

Alzheimer’s Pathology
Atrophy of the temporal, parietal, and frontal lobes, as well as the hippocampus

Selective loss of neurons and synapses, and an increase in the number and activation of astrocytes

Senile plaques are extracellular structures that are composed of a specific type of amyloid (Up to
50% of the Aβ found in plaques is Aβ42), dystrophic neuritic processes (axons and dendrites),
astrocytes and their processes, and microglial cells.

Neurofibrillary tangles appear to be composed primarily of a hyperphosphorylated form of the

microtubuleassociated protein tau. Microtubules are one of the three major constituents of the
neuronal cytoskeleton.
Although neurofibrillary tangles begin as intracytoplasmic structures, they may remain behind after
the neuron dies, forming “ghost” or “tombstone” tangles in the neuropil.

A deficit in acetylcholine, norepinephrine, serotonin, glutamate, and dopamine.

Risk Factors
Age is the primary risk factor for Alzheimer’s disease

Specific mutations on chromosomes 21, 14, and 1 have been associated with early-onset familial
Alzheimer’s disease in their 40s and 50’s.
The strongest genetic risk factor for late-onset Alzheimer’s disease is the APOE allele. having an
APOE ε4 allele are at increased risk of developing Alzheimer’s disease.
A family history of Alzheimer’s disease in a first-degree relative increases the risk of developing
Alzheimer’s disease between twofold and fourfold.

Women have been found to be at greater risk for Alzheimer’s disease than men

An increased number of years of education may reduce the risk of Alzheimer’s disease.

Traumatic head injury associated with loss of consciousness or post-traumatic amnesia has been
shown to be a risk factor for Alzheimer’s disease.

Cerebrovascular disease can turn an individual with asymptomatic Alzheimer’s pathology into a
patient with Alzheimer’s disease dementia.

Diagnostic Criteria
DSM-5 CRITERIA FOR MAJOR OR MILD NEUROCOGNITIVE DISORDER DUE TO
ALZHEIMER’S DISEASE
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).
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).
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
PUTATIVE BIOMARKERS FOR THE AD PATHOPHYSIOLOGICAL PROCESS CURRENTLY
BEING USED
Markers of Amyloid-β (Aβ) Protein Deposition in the Brain
• Low CSF Aβ42
• Positive PET amyloid imaging
Markers of Downstream Neurodegeneration
• Elevated CSF tau (total and phosphorylated)
• Decreased metabolism in temporal and parietal cortex on 18fluorodeoxyglucose PET
• Atrophy on MRI in temporal (medial, basal, and lateral) and medial parietal cortex

Common Signs, Symptoms, and Stages

Pattern of Impairment on Cognitive Tests
Memory, language, reasoning and judgment, visuospatial function, and attention may all be
impaired in Alzheimer’s disease.

Laboratory Studies
There are no routine laboratory studies that support the diagnosis of Alzheimer’s disease.
Tests of cerebrospinal fluid measuring Aβ42 and tau should be considered in certain circumstances,
such as when the patient appears to have a straightforward case of Alzheimer’s disease dementia or
mild cognitive impairment due to Alzheimer’s disease but is younger than 66 years old.

Structural Imaging Studies

Alzheimer’s disease cannot be either ruled in or ruled out by the pattern of atrophy observable on a
structural imaging scan, or the lack of such atrophy.
The primary purpose in obtaining a structural imaging study is to identify or rule out other
etiologies that may cause dementia.
Structural imaging studies are also invaluable for showing the extent of small vessel ischemic
disease that a patient has. Because almost every patient aged 70 years or older has some small
vessel ischemic disease, the question for the clinician is whether the extent of the small vessel
ischemic disease is a minor, major, or (rarely) the sole factor in the patient’s memory loss.
Functional Imaging Studies
When the patient is 65 years old or less, we recommend supporting the diagnosis with an amyloid-
PET scan even if the rest of the work-up strongly suggests a case of Alzheimer’s disease. The
prevalence of Alzheimer’s is much less likely in someone so young.

Treatments
Cholinesterase inhibitors should be initiated as soon as the diagnosis is established, and continued
until the goal of treatment is only hospice; that is, until the goal of treatment is to help the patient
die with care, comfort, and dignity.

In addition to treatment with cholinesterase inhibitors, we also recommend treatment with

memantine (Namenda) in patients with moderate and severe Alzheimer’s disease dementia.
Memantine (Namenda) tends to improve functional and neuropsychiatric symptoms in patients with
Alzheimer’s disease.

Selective serotonin reuptake inhibitor medication, sertraline (Zoloft, available as generic),

citalopram (Celexa, available as generic), or escitalopram (Lexapro) work best because they work
well to treat both depression and anxiety, and because they are well tolerated with few side effects
in the patient with memory loss and/or dementia.
DEMENTIA WITH LEWY BODIES (INCLUDING PARKINSON’S DISEASE DEMENTIA)

Prevalence
Autopsy studies have suggested that dementia with Lewy bodies accounts for up to 20% of cases of
dementia.
Most patients with dementia with Lewy bodies do progress more rapidly than those with
Alzheimer’s disease.
A subset of patients with dementia with Lewy bodies also meet clinical and pathological criteria for
Alzheimer’s disease.

Risk Factors, Pathology, and Pathophysiology

Other than age (mean of approximately 75 years) and male sex there are no known risk factors for
dementia with Lewy bodies.
Abnormal alphasynuclein metabolism and formation of Lewy bodies and Lewy neurites in various
brain regions.
The pathophysiology is attributable not only to the direct loss of neurons but also to neuronal loss in
brainstem centers that produce neurotransmitters (dopamine, acetylcholine).

Criteria and Diagnosis

True hallucinations, memory distortions, confabulations, and delusions— will often improve, at
least partly, with cholinesterase inhibitors.

Although we are all normally paralyzed during rapideye movement (REM) sleep, those with REM
sleep behavior disorder are not, and these individuals act out their dreams while sleeping.
Probably the most common sign of this disorder is that the sleeping partner complains that the
patient has begun kicking them at night, and frequently by the time the history is taken the spouse
has sought refuge by sleeping in another bed! For patients who sleep alone, a telltale sign is often
covers and pillows on the floor in the morning.

Common Signs, Symptoms, and Stages

Those patients who initially have more Lewy bodies in their brainstem will present with the motor
symptoms of Parkinson’s disease.
Those patients who present with Lewy bodies more evenly distributed throughout the brainstem,
basal forebrain, limbic regions, and neocortical regions usually present with both cognitive
impairment and Parkinsonism.
And those patients who present with mainly cortical Lewy bodies present with cognitive
impairment.

Each of these patients can demonstrate mild, moderate, or severe magnitude of motor and cognitive
symptoms.

Above 20–25% of autopsy-proven patients with dementia with Lewy bodies never develop
Parkinsonism.

Pattern of Impairment on Cognitive Tests

In patients with pure dementia with Lewy bodies, cognitive impairment is prominent on measures
of attention, visuospatial, and executive function with relative sparing of memory.

However, in the common scenario in which there is an underlying mixed dementia with
Alzheimer’s pathology as well.

Laboratory Studies
None

Structural Imaging Studies

There are no features of dementia with Lewy bodies that can be observed on structural imaging

Functional Imaging Studies

Occipital hypoperfusion on SPECT imaging (HMPAO).
Occipital hypometabolism on PET imaging (18 FDG).

Functional imaging of the dopamine transporter by either SPECT or PET using specialized tracers
is the imaging “gold standard” but is not widely available.

When the diagnosis of dementia with Lewy bodies is relatively straightforward there is no reason to
obtain a functional imaging study.
Differential Diagnosis
Parkinson’s disease dementia (PDD), diagnosed when extrapyramidal motor features are present for
more than a year prior to the onset of dementia.

After Alzheimer’s disease, the main differential diagnosis of dementia with Lewy bodies is vascular
dementia and atypical Parkinsonian syndromes including progressive supranuclear palsy (Chapter
9), multiple system atrophy, and corticobasal degeneration (Chapter 10). Jakob-Creutzfeldt disease
(JCD, Chapter 12) should also be considered, although the pace of the dementia will usually
distinguish between these disorders.

Treatments
Anticholinergic medications should be avoided

The FDA has approved the rivastigmine (Exelon) patch to treat Parkinson’s disease dementia,
which, as discussed above, is the same pathological entity as dementia with Lewy bodies.

Memantine (Namenda), enhances dopamine in addition to any effects on glutamate at the N-methyl-
D-aspartic (NMDA) acid receptor. Thus, like levodopa, memantine has the potential to be useful but
it could also make things worse.

The motor symptoms of Parkinsonism are generally best treated with levodopa (along with
carbidopa, usually referred to as Sinemet) in low dose.
Side effects, however, in patients with dementia with Lewy bodies can include confusion and
worsening of (or causing) visual hallucinations.

Successfully treating hallucinations is difficult, and pharmacological treatment should be initiated

when hallucinations become threatening or otherwise problematic. Only atypical antipsychotics
should be used, such as quetiapine (Seroquel) at bedtime.

If symptom of depression is present a selective serotonin reuptake inhibitor such as sertraline

(Zoloft).
VASCULAR DEMENTIA AND VASCULAR COGNITIVE IMPAIRMENT

Prevalence
Order of 5–10% of all dementias.

If the patient shows no signs of any other etiology of his or her cognitive impairment, we would
describe him or her as having a “pure vascular dementia” (or “pure vascular cognitive impairment,”
if not demented).
If the patient has a neurodegenerative disease (such as Alzheimer’s) and he or she has the average
amount of cerebrovascular disease that a nondemented, non-cognitively impaired older adult has,
we would describe him or her as simply having that neurodegenerative disease (such as
Alzheimer’s).
If the patient has a neurodegenerative disease (such as Alzheimer’s) and he or she has a greater than
average amount of cerebrovascular disease—such that it is highly likely that the cerebrovascular
disease is making a significant contribution to the patient’s dementia— then we would describe him
or her as having a “mixed dementia,” and would then further specify, for example, “a mixed
dementia of Alzheimer’s disease plus vascular dementia”.

Risk Factors, Pathology, and Pathophysiology

SMALL VESSEL ISCHEMIC DISEASE (SUBCORTICAL ISCHEMIC VASCULAR DISEASE)

Is thought to be attributable to two processes: lipohyalinosis and microembolis.

By itself, a small amount of small vessel ischemic disease does not typically cause noticeable
cognitive impairment or dementia.
MULTI-INFARCT DEMENTIA (ALSO KNOWN AS CORTICAL VASCULAR DEMENTIA
AND POST-STROKE DEMENTIA)
Multi-infarct dementia occurs when the patient suffers a number of cortical strokes.

STRATEGIC INFARCT DEMENTIA

When a focal lesion, often quite small, damages a brain region that is critical for cognitive brain
function.

Are typically lacunar infarcts or embolic strokes, although hypertensive hemorrhages can also
damage these regions.

CEREBRAL AMYLOID ANGIOPATHY

Deposits of β-amyloid, predominantly Aβ40, in the media of small- to medium-sized arteries in the
leptomeninges and superficial cortex, particularly in the parietooccipital, temporoparietal, and
sometimes frontal regions.

OTHER
Hypoperfusion
Hemorrhages due to hypertension may occur in strategic areas such as the thalamus
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy), which is due to mutation of the Notch3 gene at the chromosome locus 19p13

Criteria
Common Signs, Symptoms, and Stages
SMALL VESSEL ISCHEMIC DISEASE
Because most of the brain’s white matter is involved in transferring information to or from the
frontal lobes, patients with large amounts of small vessel ischemic disease often show signs and
symptoms of frontal subcortical dysfunction.

Difficulty focusing and maintaining attention

Gait is often affected leading to a “frontal” or “magnetic gait” (called by the French the “marche à
petits pas,” walk of little steps), in which patients describe their feet feeling like they are stuck on
the floor

Incontinence is common

Pseudobulbar affect:
The term “pseudobulbar affect” is often used to indicate the loss of cortical control of emotions,
such as when patients show inappropriate laughing and crying. Usually these signs of emotion come
out with minimal provocation (may cry when they hear about items on a news broadcast that are
sad, but not the sort of thing that would have caused them to come to tears in the past ).

Note that small vessel ischemic disease is the only form of cerebrovascular disease that does not
typically cause a stepwise progression

Pattern of Impairment on Cognitive Tests

The two aspects of neuropsychological function that are impaired in most patients with
cerebrovascular disease are frontal/executive function and the speed of cognition

Attention is generally impaired in vascular dementia.

Word-finding difficulties are extremely common in all types of vascular dementia.

Episodic memory shows a “frontal pattern”: encoding is often impaired, as is free recall, whereas
relative preservation is typically seen when tasks that assist in retrieval are used, such as cued recall,
multiple choice, and yes/no recognition.

Reasoning and judgment are typically impaired

Visuospatial function is typically intact with small vessel ischemic disease, but can be quite
impaired with multi-infarct and strategic infarct dementia.

Laboratory Studies
There are no laboratory studies that are useful in either confirming or ruling out vascular dementia.
Structural Imaging Studies
CT or MRI
Functional Imaging Studies
Functional imaging studies are useful in excluding neurodegenerative diseases such as Alzheimer’s
disease or frontotemporal dementia.

Treatments
No FDA-approved treatments

It is our experience that the majority of patients with a pure vascular dementia and resultant
memory problems show improvement in their memory with cholinesterase inhibitors.

Memantine is also often helpful when problems such as apathy occur.

Pseudobulbar affect can be treated with the combination pill dextromethorphan/quinidine

(Nuedexta)

Lastly, the underlying cause of the cerebrovascular disease must also be evaluated and treated.

If the patient has the common scenario of a mixed dementia of vascular dementia plus either
Alzheimer’s disease or dementia with Lewy bodies, treatment should proceed with medications
appropriate to those disorders, such as cholinesterase inhibitors and memantine.
PRIMARY PROGRESSIVE APHASIA AND APRAXIA OF SPEECH

Prevalence, Definition, and Pathology

Primary progressive aphasia is divided into three variants:
• Logopenic variant (often abbreviated to lvPPA).
• Semantic variant (also called semantic dementia or temporal variant frontotemporal
dementia; often abbreviated to svPPA or SD or tv-FTD).
• Non-fluent/agrammatic variant (also called progressive non-fluent aphasia; often
abbreviated to naPPA or agPPA or PNFA).
Primary progressive apraxia of speech is an impairment in the production of speech sounds in the
absence of language impairment (also called progressive apraxia of speech; often abbreviated to
PPAOS or PAOS).

Primary progressive aphasia and primary progressive apraxia of speech are not diseases they are
clinical syndromes that patients may manifest, with varying underlying neurodegenerative disease
etiologies

Criteria
Speech is hesitant, there is difficulty finding words and naming, there are often phonologic errors,
and there is difficulty repeating sentences. Grammar is preserved and there is no loss of
comprehension.
Could be described as a loss of memory for words. The disorder often starts as problems with word-
finding and naming difficulties (anomia), but progresses to include impaired word comprehension
and ultimately impaired comprehension of objects as well. The naming deficit in semantic variant
primary progressive aphasia is often referred to as a two-way naming deficit, because patients have
difficulty naming an object when shown its picture, and also describing an object when given its
name.

Effortful speech with errors in grammar and/or praxis of speech—the motor planning and
sequencing of the lips, tongue, and breath necessary for articulate speech. They often have
wordfinding difficulties, speak in short sentences, omit the articles (a, an, the), and show difficulty
in pronouncing words, similar to that of a patient with Broca’s aphasia. Comprehension is intact,
except for syntactically complex sentences
Impaired in the motor planning and sequencing of the lips, tongue, and breath necessary for
articulate speech. Speech is slow with articulatory groping, distorted articulation, sound
substitutions, false starts and restarts, segmentation of syllables

Language itself is not disordered; that is, although there is impaired speech output there is no
aphasia

Also different from dysarthria, in that the problem is not solely due to weakness of lips, tongue, and
other vocal apparatus

Pattern of Impairment on Cognitive Tests

Controlled Oral Word Fluency
Category Fluency
Boston Naming Test
the Boston Diagnostic Aphasia Battery,
the Western Aphasia Battery-revised,
part V of DeRenzi and Vignolo’s Token Test,
and the Pyramids and Palm Trees test.
To look for apraxia of speech, the features in Box 7-5 can be rated on a 0 to 4 scale

Structural and Functional Imaging Studies

Treatments
Treatment is supportive. Speech therapy can be helpful for some patients.
FRONTOTEMPORAL DEMENTIA

Prevalence, Prognosis, and Definition

The three common clinical presentations are:
• Behavioral (or frontal) variant frontotemporal dementia (often abbreviated to bvFTD or fvFTD)
• Semantic variant primary progressive aphasia (also called semantic dementia or temporal variant
frontotemporal dementia; often abbreviated svPPA, SD, or tvFTD)
• Non-fluent/agrammatic variant primary progressive aphasia (also called progressive non-fluent
aphasia; often abbreviated to naPPA, agPPA, nfvPPA, or PNFA)

Frontotemporal dementia is equally as common as Alzheimer’s disease in those with dementia aged
younger than 65.

Frontotemporal dementia has been found in 5–10% of cases.

Risk Factors, Pathology, and Pathophysiology

Other than family history there are no known risk factors for frontotemporal dementia.

Up to 40% of cases of frontotemporal dementia are familial, and about 10% have a clear autosomal
dominant pattern.

Many frontotemporal dementias show taupositive inclusions. These include classic Pick’s disease
which has tau- and ubiquitin-positive spherical cortical inclusions;

Criteria
Common Signs, Symptoms, and Stages
Although one might suspect that frontal release signs such as the snout, grasp, and palmomental
reflexes are more common in frontotemporal dementia, in our experience we have not found this to
be the case.

Pattern of Impairment on Cognitive Tests

The first point that should be noted is that in many cases of frontotemporal dementia the standard
cognitive testing may be normal until quite late in the disease.
This point is particularly true for the MiniMental State Examination (MMSE); the Montreal
Cognitive Assessment (MoCA) is more sensitive to frontotemporal dementia;

Helpful tests include the Wisconsin Card Sorting Test, verbal fluency to letters, the Trailmaking Test
Part B, the Delis–Kaplan Executive Function System (D-KEFS), and the Cambridge
Neuropsychological Test Automated Battery (CANTAB).

Although memory is often relatively spared, memory may be impaired secondary to problems with
attention, encoding, retrieval, source memory, memory distortions, and other frontal aspects of
memory.

Laboratory Studies
There are no routine laboratory studies to support or refute the diagnosis of frontotemporal
dementia.

Genetic testing for frontotemporal dementia with parkinsonism linked to chromosome 17 is

becoming more readily available, which may be helpful in evaluating a patient for possible
frontotemporal dementia who has a family history of either frontotemporal dementia or
parkinsonism.

Structural and Functional Imaging Studies

Although the structural imaging scan may be normal at the time of presentation, most cases of
frontotemporal dementia show frontal and anterior temporal lobe atrophy at some point in the
course of their disease.

Functional imaging studies such as SPECT and PET typically show decreased frontal hypofunction,
often several years prior to the atrophy being noted on a structural image.
Treatments
Patients with frontotemporal dementia show a significant deficit of serotonin, and it is therefore not
surprising that selective serotonin reuptake inhibitors are often of help.

Atypical antipsychotics are most often used as first-line medications to control these unwanted
behaviors.
Note: These medications are not approved by the United States Food and Drug Administration (US
FDA) for any dementia and have very serious side effects; see Chapter 24 for important additional
information prior to prescribing.
Risperidone (Risperdal) causes the least sedation of the three, and is often our first-line medication
for daytime agitation. Quetiapine (Seroquel) causes the most sedation, and is therefore particularly
useful for night-time agitation.

Other medications that may be useful include the sedating antidepressant trazodone.

Memantine : given the heterogeneity of the disorder we believe it is not unreasonable to try it.

We are quite cautious with cholinesterase inhibitors and stimulants as these classes of medications
can sometimes “activate” a patient with frontotemporal dementia and make behavior worse.
PROGRESSIVE SUPRANUCLEAR PALSY:
Prevalence, Prognosis, and Definition
It has a prevalence of 5–6 per 100,000.

Risk Factors, Pathology, and Pathophysiology

There are no known risk factors for developing progressive supranuclear palsy.

Accumulation of hyperphosphorylated tau protein isoforms in the brain.

Made up of a four-repeat tau, whereas in frontotemporal dementia the tau is predominantly

composed of a three-repeat tau

Atrophy of midbrain, pontine tegmentum, and globus pallidus is common in progressive

supranuclear palsy.

Criteria
Common Signs, Symptoms, and Stages
This type of palsy affects mainly voluntary eye movements, while involuntary movements are
relatively spared.

Testing for voluntary gaze may be easily accomplished by having the patient look rapidly between
two points (often called “saccades”), usually between the thumb on one hand and the index finger
on the other (“Look at my thumb, look at my finger,” and so on).

Testing for involuntary gaze is best performed by having the patient stare at a stationary point while
you gently move their head up and down and back and forth, thus moving their eyes in their head.

Pseudobulbar palsy typically exhibits slurred and otherwise abnormal speech (dysarthria), and
difficulty eating and swallowing (dysphagia)

It should be emphasized that, although there must be at least a slowing or disruption of vertical or
horizontal eye movements, an actual reduction in the degree of downward gaze is not necessary.
Other common ocular abnormalities include spontaneous involuntary eyelid closure, reduced
spontaneous blink rate.

Abnormalities of speech, gait, postural reflexes (often tested with the “pull test,”), axial rigidity,
snout, grasp, dystonia, and myoclonus. Apraxias are very common.

Pattern of Impairment on Cognitive Tests

The first thing that should be noted is that not all patients with progressive supranuclear palsy
demonstrate cognitive deficits.

First there is a slowing of mental processing, often termed “bradyphrenia.” This slowing will
obviously produce impairment on any timed test, including verbal fluency to letters and categories,
the Trailmaking Tests parts A and B, and others.

The second aspect of cognition that is impaired is executive function.

Laboratory Studies
There are no routine studies that are helpful.

Structural and Functional Imaging Studies

Atrophy of the midbrain in patients with progressive supranuclear palsy has been frequently
observed on MRI.

When viewed from a midline sagittal perspective, the shrunken midbrain with a relatively normal
pons leads to what has been called the “hummingbird” sign.

Patients with PSP had midbrain anterior–posterior diameters ranging from 11 to 15 mm (average
13.4 mm), much smaller than both controls (range 17–20 mm, average 18.2 mm) and patients with
Parkinson’s disease (range 17–19 mm, average 18.5 mm).
Treatments
There are no FDA-approved treatments for progressive supranuclear palsy.

Symptomatic treatments that are worth trying include levodopa/carbidopa (Sinemet), memantine,
and amantadine.

Botulinum toxin may be used to treat spasms and dystonia.

Atropine 1% eye drops can be administered sublingually to help reduce drooling.

Management of dysphagia to prevent choking and aspiration is critical.

CORTICOBASAL DEGENERATION

Prevalence, Prognosis, and Definition

Prevalence of about 2 per 100,000

The mean age of onset was 64 years, ranging from 45 to 77 years, with an average prognosis from
diagnosis to death of about 6.6 years, ranging from 2 to 12.5 years.

Risk Factors, Pathology, and Pathophysiology

There are no known risk factors.

The distribution of pathology and atrophy is asymmetric. Cortical regions affected are around the
main sulci of the brain: parasagittal, peri-Rolandic, and peri-Sylvian. Subcortical structures affected
include substantia nigra, and variably the globus pallidus, subthalamic nucleus, and thalamus.

The pathology consists of swollen achromatic neurons in amygdala and limbic structures, as well as
ballooned neocortical achromatic neurons in specific layers (III, V, and VI) in frontal and parietal
lobes.

Criteria
Common Signs, Symptoms, and Stages
Presenting and early symptoms may include the following:
• Alien limb (not common but pathognomonic when it occurs): The affected limb is described as
“having a mind of its own,” and patients report having little or no control over it. It may grasp,
grope, wander, or take hold of objects, clothes, and people. Occasionally it may interfere with the
function of the unaffected limb.
• Useless limb (common): The limb is not able to participate in functional activities, often due to
varying combinations of rigidity, akinesia, dystonia, myoclonus, and apraxia.
• Focal/limb apraxias: Inability to perform skilled and/or learned movements unexplained by
abnormalities such as weakness, incoordination, language difficulties, etc.
• Rigidity: An increase in muscle tone causing resistance to movement of the joint.
• Akinesia: An inability to initiate movement due to difficulty selecting and/or activating motor
programs.
• Dystonia: Occurs when sustained muscle contractions cause abnormal postures or movements.
• Asterixis: A sudden involuntary loss of tone in a muscle group.
• Myoclonus: A brief, involuntary twitching of a muscle group.
• A jerky postural tremor: A “tremor” typically due to frequent asterixis and myclonus
• Sensory symptoms: Includes numbness and tingling.
• Cortical sensory loss: Primary sensory abilities are normal, but there are deficits in the ability to
use this information to make appropriate judgments. Patients can feel a touch, distinguish sharp
from dull, warm from cold, etc., but they are unable to identify a coin by feeling it (stereognosis) or
a number when it is drawn in their hand (graphesthesia).
• Visuospatial deficits
• Neglect: Ignoring one side of space.
• Apraxia of speech
• Speech disturbance
• Executive dysfunction
• Behavioral disorder: Symptoms may include apathy, bizarre or antisocial behavior, personality
changes, irritability, disinhibition, and hypersexuality

Pattern of Impairment on Cognitive Tests

In corticobasal degeneration frontal and parietal dysfunction are common, thus leading to
difficulties with executive function, visuospatial function, language, and praxis.

Laboratory Studies
There are no laboratory, genetic, or cerebrospinal fluid studies that are helpful.

Structural and Functional Imaging Studies

There is no pathognomonic pattern of atrophy that can by itself distinguish corticobasal
degeneration from other types of dementia. Structural imaging of corticobasal degeneration does,
however, typically show much asymmetric posterior frontal and parietal atrophy.

Typically, the patient with corticobasal degeneration will show marked asymmetry of frontal and
parietal blood flow and metabolism on SPECT and FDG-PET imaging.

Treatments
Dystonia may be relieved with botulinum toxin.

Clonazepam may be helpful for myoclonus.

Physical and occupational therapy is important for range of motion in affected limbs so that
contractures do not develop.
NORMAL PRESSURE HYDROCEPHALUS

Prevalence, Prognosis, and Definition

Prevalence close to 1%.

Risk Factors, Pathology, and Pathophysiology

Normal pressure hydrocephalus is thought to result from low-grade scarring or obstruction of the
ventricular system or subarachnoid pathways.

Criteria
Should be suspected when the so-called “triad” of symptoms (cognitive impairment, gait disorder,
and urinary incontinence) is present in the setting of enlarged ventricles.
Common Signs, Symptoms, and Stages
The gait disturbance in normal pressure hydrocephalus is typically the most prominent symptom
and is usually the earliest in onset.
The gait disorder is of a frontal type, and has been described as a “magnetic gait” or a “marche à
petits pas” (walk of little steps), and is somewhat different from shuffling.
Some patients may complain of difficulty lifting their feet off the ground, feeling like their feet are
stuck to the floor.

Cognitive impairment generally presents next.

Because most of the brain’s white matter is involved in transferring information to or from the
frontal lobes, patients with normal pressure hydrocephalus often show signs and symptoms of
frontal subcortical dysfunction.
Most cognitive processes are slow.

Incontinence generally occurs late in normal pressure hydrocephalus.

Urge incontinence is usually seen, such that the patient only has a very short time between when he
or she feels the need to empty their bladder and when it empties.

Pattern of Impairment on Cognitive Tests

Cognition tends to be generally slow.
Attention is invariably impaired.
Working memory tasks, such as keeping information in mind and/or manipulating it, are also
commonly impaired.
Episodic memory performance shows a frontal pattern: encoding is often impaired, as is free recall,
whereas recognition is relatively preserved.
Word-finding difficulties are prominent, but true aphasia is not.
Visuospatial tasks may or may not be impaired.

Laboratory Studies
There are no laboratory studies to either support or rule out the diagnosis of normal pressure
hydrocephalus.

Structural and Functional Imaging Studies

The imaging study, either a CT or MRI, will invariably show enlargement of the ventricles,
rounding of the ventricular contours, the presence of periventricular abnormalities—particularly
around the frontal horns, and relatively normal-sized subarachnoid spaces.

The importance of relatively normal-sized subarachnoid spaces is to differentiate ex vacuo

dilatation of the ventricular system due to atrophy from true ventricular enlargement.
the ventricular enlargement in normal pressure hydrocephalus will be out of proportion to the
amount of cortical atrophy.
Lumbar Puncture
Measuring the opening pressure is important, as some patients with suspected normal pressure
hydrocephalus will actually have high-pressure hydrocephalus.

The next step is to withdraw a large volume of cerebrospinal fluid, between 30 and 50 mL, to see if
the gait improves after the fluid is withdrawn. Gait should be measured between two points on the
floor (around 30 feet apart), and a number of trials (around 3–10) should be undertaken, until a
reliable measurement is obtained. A video recording of the gait preand post-lumbar puncture
provides both a record of the timing and also a valuable way to evaluate other aspects of gait, such
as stride length, apraxia, and the like.

If there is no definite response from a single large-volume lumbar puncture, serial large-volume
lumbar punctures can be performed daily for several days. Improvement of gait after three days of
lumbar puncture also predicts a good response to shunting.

If the lumbar puncture tests are non-diagnostic, MRI has been used to measure the flow of
cerebrospinal fluid through the Sylvian aqueduct; increased flow has been reported in those who
ultimately had a good response to shunting.

Continuous pressure monitoring for 24–48 hours can be performed using a frontal ventricular
catheter, lumbarcatheter, or epidural transducer; elevated baseline cerebrospinal fluid pressure or
pressure waves also suggest a good response to shunting.

Differential Diagnosis
The differential diagnosis of normal pressure hydrocephalus is quite broad. Any disorder that
damages the periventricular frontal subcortical white matter tracts can lead to the clinical triad of
gait disorder, cognitive impairment, and urinary incontinence.

Vascular Dementia, Multiple sclerosis, Lyme disease, Parkinson Disease, Lewy bodies, progressive
suprani=uclear palsy, corticobasal degeneration, frontotemporal dementia, motor neuron disease
(amyotrophic lateral sclerosis), Huntington’s disease, …

Treatments
Shunt to help remove excess cerebrospinal fluid from the ventricular system. The most common
type shunts fluid from the lateral ventricle (usually on the right to avoid language centers on the
left) to the peritoneum.
JAKOB–CREUTZFELDT DISEASE

Prevalence, Prognosis, and Definition

Prion diseases, also called transmissible spongiform encephalopathies, are progressive
neurodegenerative diseases characterized by a specific neuropathology and a rapid cognitive decline
that can progress to akinetic mutism over weeks.

Sporadic Jakob– Creutzfeldt disease (making up 85–90% of prion diseases) has an incidence of
approximately 1 to 1.5 per million, with a usual age of onset from 45 to 75 years (average about 68
years).
Other forms of Jakob– Creutzfeldt disease include genetic (gJCD; 10–15% of prion diseases) and
acquired (1–3% of prion diseases).
Acquired forms include iatrogenic (iJCD) and variant (vJCD).

Risk Factors, Pathology, and Pathophysiology

Prions are unconventional agents that consist of proteinaceous infectious particles that produce
transmissible diseases characterized by spongiform change, neuronal death, astrocytosis, and
accumulation of a pathological protein (PrPSc) in the brain as well as other organs to a lesser extent.

Prion diseases are transmissible because an inoculation with the pathological protein can cause the
disease in another individual.

Iatrogenic cases have been attributed to transplantation of human brain tissues or human pituitary
hormones from individuals with unrecognized prion diseases.
Patients with familial Jakob–Creutzfeldt disease have been found to have mutations in the gene that
codes for the PrPSc protein.
Variant Jakob–Creutzfeldt disease is similar biochemically and histopathologically to bovine
spongiform encephalopathy attributed to ingesting beef contaminated with bovine spongiform
encephalopathy.
Other prion diseases have been described including kuru, Gerstmann–Straussler– Schenker disease,
and fatal familial insomnia.

Criteria
Common Signs, Symptoms, and Stages
Rapid cognitive and motor decline that can progress to akinetic mutism within weeks. Myoclonus
and cerebellar signs (such as ataxia), as well as pyramidal abnormalities (such as weakness) may all
occur.
The vast majority of patients show a significant cognitive decline, including abnormalities of
memory and executive function in addition to depression and/or other changes in personality.
More variability is seen with visual disturbances and naming, with only some patients showing
impairment.

Laboratory Studies
Laboratory studies can play only a supportive role, the elevation of the 14-3-3 protein in the
cerebral spinal fluid is a nonspecific sign of rapid neuronal injury, but in a review of cases in which
there was a strong suspicion of Jakob–Creutzfeldt disease, the sensitivity was 92% and the
specificity was 80%. Cerebrospinal fluid total tau is another useful marker; when higher than 1150
pg/mL there is reported sensitivity and specificity of greater than 90%. Combining these markers
may increase their diagnostic accuracy.

Structural and Functional Imaging Studies

Characteristic abnormalities on the MRI scan are probably the most helpful noninvasive diagnostic
findings. Because neurons are rapidly dying, most cases show FLAIR and diffusion MRI
abnormalities in cortical and deep gray matter structures including basal ganglia (caudate and
putamen) and thalamic involvement.

Treatments
Treatment for Jakob–Creutzfeldt disease is supportive.
CHRONIC TRAUMATIC ENCEPHALOPATHY

Prevalence, Prognosis, and Definition

Repetitive head injury has been associated with chronic traumatic encephalopathy, a progressive
tauopathy.

Criteria

Common Signs, Symptoms, and Stages

There has also been the recognition that there are two common clinical presentations of chronic
traumatic encephalopathy :
• A Behavioral/Mood Variant whose initial features develop at a younger age with behavioral and/or
mood disturbance, and
• A Cognitive Variant whose initial features develop at an older age and involve more cognitive
impairment.

There are two main things to look for in the history of a patient who may have chronic traumatic
encephalopathy.
The first is a history of repetitive head trauma of some type, such as contact sports, military service,
domestic abuse, head banging, motor vehicle accidents, etc.
The second is the constellation of behavioral, mood, cognitive, and sometimes motor features that
are common with the disorder.

Some patient may have symptoms of parkinsonism.

Other patients can show frontal signs and symptoms indistinguishable from a frontotemporal
dementia.

Pattern of Impairment on Cognitive Tests

Tests that most often show abnormalities in patients with chronic traumatic encephalopathy include
those for memory, executive function, and simple and complex attention, followed by those for
language and visuospatial function.

Structural and Functional Imaging Studies

Enlarged cavum septum pellucidum and/or cavum vergae; these are anterior and posterior,
respectively, fluid-filled spaces between the leaflets of the septum pellucidum.
The second type of abnormality to look for on imaging studies is atrophy (on MRI or CT scans),
hypometabolism (on fluorodeoxyglucose [FDG] PET scans), and/or hypoperfusion (on technetium-
99 [99Tc] SPECT scans) of the cortex, particularly in medial temporal and frontal lobes.
Treatments
Treatment is supportive.
OTHER DISORDERS THAT CAUSE MEMORY LOSS OR DEMENTIA

Depression and Anxiety

In our experience it is much more likely that a patient who is over the age of 65 and presents with
both memory loss and depression has depression due to the memory loss, rather than the other way
around.

The history is one important clue to help determine whether the memory loss or the depression is
primary. It would be extremely unlikely that a 75-year-old patient without a prior history of major
depression would now develop a first episode of major depression severe enough to cause memory
problems.

Frontal/executive and speed of processing deficits are often found on neuropsychological testing.
Another pattern that is sometimes present in patients with depression is that they experience more
difficulty remembering things in the past than the present.

In treating a patient who has both memory loss and depression, we always recommend treating the
underlying disorder first.

Medication Side Effects

In our experience, attention is the most common cognitive function to become affected, followed by
memory, and then langage.
Disrupted Sleep
First, sleep is necessary for good attention. In order to encode or learn new information, being able
to focus and sustain attention is critical.
Second, there is increasing evidence that our consolidation of memory—memories going from
temporary to more long-term storage—requires sleep.

Disrupted sleep may be due to a sleep disorder such as insomnia, sleep apnea, periodic limb
movements of sleep, and restless leg syndrome.
Sleep may be disrupted by depression.
And sleep may be commonly disrupted by poor sleep hygiene—that is, poor scheduling or
management of sleep.

For the average individual who is best with 8–9 hours of sleep, one can often get away with 7 hours
without noticeable cognitive consequences. But trying to reduce sleep further often causes difficulty
with attention and memory.

Hormones?
Large randomized controlled trials have now shown no evidence for improvement and instead
worsening of cognition and increased risk for dementia with hormone replacement therapy.

Metabolic Disorders
Almost any medical disorder that makes a patient ill can cause memory loss and/or impair other
aspects of cognition.
Common disorders that impair cognition include renal failure, liver failure, congestive heart failure,
hypercapnia from chronic obstructive pulmonary disease, hypercalcemia, and many others.

The first clue is that dementias are progressive, whereas metabolic disorders tend to wax and wane.
The second clue that cognitive impairment is due to a metabolic disorder is that the impairment in
cognition is virtually always poor attention.
The last thing to note here is that a patient may have an incipient dementia that is made apparent by
a metabolic disorder—the so-called “unmasking effect.”

Diabetes
from cerebrovascular disease and hypoglycemia.

Hypoglycemia damages both gray and white matter, meaning that both neurons and myelinated
axons and dendrites suffer injury
Correlation between how tightly the glucose is trying to be maintained and how frequently episodes
of hypoglycemia and subsequent cognitive impairment occur.
Prevalence, Prognosis, and Definition

Risk Factors, Pathology, and Pathophysiology

Criteria

Common Signs, Symptoms, and Stages

Pattern of Impairment on Cognitive Tests

Laboratory Studies

Structural and Functional Imaging Studies

Treatments