SECTION D Clinical Neurosciences
43 Neuropsychology
Benjamin D. Hill, Justin J.F. O’Rourke, Leigh Beglinger, Jane S. Paulsen
CHAPTER OUTLINE
GOALS OF NEUROPSYCHOLOGY
NEUROPSYCHOLOGICAL EVALUATION
Test Administration
Test Interpretation
BRIEF MENTAL STATUS EXAMINATION
Montreal Cognitive Assessment
Telephone Interview for Cognitive Status—Modified
Mini-Mental State Examination
Modified Mini-Mental State Examination
NEUROPSYCHOLOGICAL CHARACTERISTICS OF
NEUROLOGICAL DISEASE
Mild Cognitive Impairment
Alzheimer Disease
Vascular Dementia
Mixed Dementia
Frontotemporal Dementia
Parkinson Disease with Dementia and Dementia with
Lewy Bodies
Huntington Disease
Multiple Sclerosis
Epilepsy
Traumatic Brain Injury
Neuropsychology is the scientific study of neural correlates for
cognition and behavior, with a specific clinical interest in
patients presenting with a range of medical, neurological, and
psychiatric illnesses. Neuropsychologists are specialized clini-
cians who receive extended fellowship training (with available
board certification) in functional neuroanatomy, neurobiol-
ogy, psychopharmacology, neurological illness or injury,
neuroimaging, psychometric and statistical principles of neu-
rocognitive measures, and clinical psychology. Neuropsycho-
logical evaluation refines neuroimaging and neurological
examinations by operating from a biopsychosocial framework
to determine the extent to which cognition and behavior are
affected by brain dysfunction. Neuropsychologists aim to
characterize and objectively quantify abilities ranging from
simple sensory and motor functions to complex “higher
cognitive abilities” that include cognitive processing speed,
attention, language, visuoperception/construction, memory,
executive functioning (behavioral, cognitive, and motivational
aspects), and emotional/personality functioning.
In this chapter, we begin by explaining the goals and
utility of neuropsychology and describing the neuropsycho-
logical evaluation. Guidelines are then suggested for brief
cognitive screenings that may be useful for neurologists in
clinical settings. Finally, the typical patterns of cognitive
impairments associated with major neurological disorders
are discussed.
GOALS OF NEUROPSYCHOLOGY
When neural damage is present or cognitive changes are
observed, a neuropsychological evaluation is appropriate. The
prominent neuropsychologist Arthur Benton (1975) best
described neuropsychology as “a refinement of clinical neuro-
logical observation [that] serves the function of enhancing
clinical observation [and] is closely allied to clinical neuro-
logical evaluation and in fact can be considered to be a special
form of it” (p. 68). Neuropsychological assessment aims to
extend the neurological exam by: (1) providing important
information for differential diagnosis and prognosis; (2) iden-
tifying the cognitive, emotional, and behavioral deficits of
disease or injury and characterizing their severity; (3) guiding
treatment by using test results to select effective rehabilitation
strategies, determining functional capacity and decision-
making abilities for level-of-care decisions, driving and work
capacity, assessing medication cognitive side effects, and estab-
lishing candidacy for surgical procedures; and (4) monitoring
cognitive changes and treatment effectiveness across time.
Neuropsychological assessment is also frequently used in
forensic settings and for neuroscience research, but discussion
on these topics is beyond the clinical focus of this chapter
(Schoenberg et al., 2011).
Before the advent of neuroimaging in the 1970s and 1980s,
one of the main goals of neuropsychology was lesion localiza-
tion. Today, neuropsychology has shifted toward differential
diagnosis when lesions may not be evident or in conditions
with no clear biomarkers. For example, neuropsychologists
assist in the early identification of various dementias since
they are primarily diagnosed based on patterns of clear cogni-
tive declines and behavioral disturbances (see Table 43.1 for
a comparison of cortical versus subcortical dementias as an
example). Neuropsychological testing is also useful for diag-
nosing “non-neurological” conditions that can affect cognitive
functioning or masquerade as neurocognitive disease, such as
dementia of depression or somatoform disorders. Exaggerated
and manufactured symptoms can also be clearly identified
through the use of stand-alone and embedded measures of
valid test performances and symptom reports.
Another goal of neuropsychology is to accurately describe
cognitive deficits and their severity. Even when the cause of
cognitive dysfunction is clear (e.g., traumatic brain injury)
or lesions are evident on imaging, the cognitive and behavio-
ral manifestations of neural damage can be heterogeneous.
The interaction between symptom onset, etiology, and patient
characteristics results in a wide range of individual variability
in cognitive deficits. For instance, the neuropsychological
profiles of stroke and tumor patients can be very dissimilar
even after matching for lesion location (tumor patients
show notably less severe language deficits in the left hemi-
sphere, presumably due to the acute versus chronic etiologies;
511
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TABLE 43.1 Neuropsychological Characteristics of Cortical versus make legal, financial, and healthcare decisions, provide super-
Subcortical Dementia Using Alzheimer Disease and Huntington vision, live independently, and return to work (Demakis,
Disease as Examples 2012). Neurocognitive assessments may also be used to guide
Huntington disease
treatment plans by identifying cognitive deficits for specific
Alzheimer disease (subcortical rehabilitation strategies. For example, patients with behavioral
(cortical dementia) dementia) disinhibition and poor emotional regulation due to lesions in
the orbitofrontal cortex can be targeted for behavioral modi-
LEARNING AND MEMORY
fication strategies and training in self-monitoring (Sohlberg
Episodic memory Impaired encoding/ Impaired information and Turkstra, 2011). Neuropsychological assessments are also
consolidation retrieval useful for evaluating patients’ candidacy for certain surgical
Poor delayed recall and Recognition memory procedures. Neurosurgeons considering a temporal lobectomy
recognition memory is better than for refractory epilepsy often call on neuropsychologists to
delayed recall
conduct Wada testing to localize language, memory, or motor
Retrograde Severe, temporally Mild, nongraded, functioning in order to minimize postoperative cognitive
amnesia graded, retrograde retrograde losses. Neuropsychological assessment is also used prior to the
amnesia amnesia placement of a deep brain stimulator to help predict post-
Priming Impaired Preserved surgical outcomes.
Implicit Preserved Impaired
Lastly, neurocognitive testing is useful for monitoring treat-
procedural/ ment effectiveness and patients’ recovery from acquired brain
motor learning injuries. For instance, neuropsychologists use their expertise to
determine whether a coma patient has progressed into a veg-
Implicit cognitive Preserved Impaired
etative or minimally conscious state (Giacino and Whyte,
skill learning
2005). Accurate monitoring is vital given the differences in
Attention/ Relatively preserved Poor auditory and clinical outcomes for each level of consciousness and the
concentration visual attention danger of making erroneous decisions regarding the with-
Processing Relatively intact Very slow drawal of treatment. Treatment effectiveness can also be moni-
speed tored using repeat assessments to determine whether medical,
EXECUTIVE FUNCTIONING
pharmacological, and rehabilitation interventions are having
their desired cognitive effects. Monitoring treatment effective-
Set shifting Better able to shift Difficulty with ness leads to more efficient utilization of resources by updat-
focus perseveration ing treatment plans as necessary.
Working memory Mild deficits in ability Early notable deficits
to manipulate in phonological
information, but loop, visuospatial NEUROPSYCHOLOGICAL EVALUATION
preserved sketchpad, and Depending on the referral question and clinical setting, neu-
phonological loop ability to
ropsychological assessments can range from quick bedside
and visuospatial manipulate
sketchpad information
assessments to extended evaluations that include formal
standardized testing and a comprehensive clinical interview.
LANGUAGE AND SEMANTIC KNOWLEDGE A complete neuropsychological interview covers the onset and
Speech Preserved Dysarthric and slow course of the patient’s cognitive and mood problems, current
functional capacity, developmental background, medical and
Fluency More impaired Severe and equal
semantic fluency impairment in
psychiatric history, family medical history, academic perform-
than phonemic phonemic and ance, vocational achievements, and social background. Infor-
fluency semantic fluency mation obtained from collateral sources such as caregivers or
spouses about the patient’s medical and psychosocial history
Naming Impaired; more Relatively preserved;
can also be critical because many patients lack insight into
semantic errors (e.g., more perceptual
calling a lion “an errors (e.g., calling
their deficits. Besides gathering patient reported information,
animal”) a bucket “a cup”) the goals of the neuropsychological interview are to develop
hypotheses about the patient’s cognitive status and to estab-
Structure of Tend to focus on Able to focus on lish rapport that will elicit their best performance on testing.
semantic concrete perceptual abstract
Behavioral observations made during the interview and testing
knowledge information conceptual
knowledge are also an important source of information that can influence
test selection and interpretation. After a clinical interview is
Adapted from Salmon, D.P., Filoteo, J.V., 2007. Neuropsychology of completed, the following cognitive domains are assessed:
cortical versus subcortical dementia syndromes. Semin Neurol 27, sensory, motor, intellectual functioning, processing speed,
7–21.
attention, language, visuoperception/construction, memory,
executive functioning (behavioral, cognitive, and motivational
aspects), functional capacity, and emotional/personality
functioning.
Anderson et al., 1990). Repeated neuropsychological evalua-
tions are also useful for monitoring the decline of neurode-
generative diseases over time given the potential for varying
Test Administration
degrees of disease progression across patients. Two major approaches to neuropsychological evaluation cur-
In addition to offering information regarding the diagnosis rently dominate the field: the fixed battery approach and the
and clinical manifestation of neuroanatomical dysfunction, flexible battery approach (Barr, 2008).
neuropsychological assessment is unique in its ability to guide The fixed battery approach requires that the same tests are
treatment needs. Neuropsychologists are capable of utilizing administered to every patient in a standardized manner.
objective test data to thoroughly assess patients’ abilities to One example of a fixed battery is the Halstead–Reitan battery

BOX 43.1 Heaton Adaptation of Halstead–Reitan
Neuropsychological Test Battery
Tactual performance test
Finger oscillation test
Category test
Seashore rhythm test
Speech sounds perception test
Aphasia screening test
Sensory-perceptual examination
Grip strength test
Tactile form recognition test
Wechsler adult intelligence scale—revised
Wechsler memory scale—revised
Adapted from Heaton, R.K., Grant, I., Matthews, C.G., 1991.
Comprehensive Norms for Expanded Halstead-Reitan Battery:
Demographic Corrections, Research Findings, and Clinical Applications.
Psychological Assessment Resources, Odessa, Florida.
(Box 43.1), for which comprehensive norms have been pub-
lished by Heaton and colleagues (Heaton et al., 1991). An
advantage to the fixed battery approach is that the information
gathered is comprehensive and systematically assesses multi-
ple domains of cognitive functioning. Additionally, if repeated
assessments are available, test scores can be directly compared
with baseline information, and tests are well validated and
normed. Drawbacks of the fixed battery approach include its
length (up to 8 hours), because it may be too long for some
patients to tolerate and is difficult to afford with the limited
reimbursement schedules in managed care. Furthermore, an
extended assessment may not be necessary to address the refer-
ral question.
In contrast to the fixed battery approach, the flexible battery
(or hypothesis-driven) approach allows neuropsychologists to
develop a test battery based on the referral question, patient’s
history, and clinical interview. In the flexible battery approach,
a brief set of basic tests is initially administered, and addi-
tional tests of more specific abilities are used to conduct
in-depth follow-up assessments based on each particular
patient’s needs. For example, clinicians using the Iowa–Benton
method (Tranel, 2008) specifically tailor testing to each patient
based on their presenting concern by administering the appro-
priate portions of a core battery, which are then followed up
with tests that assess suspected impairments in more detail
(Fig. 43.1). Considerations when selecting tests include age,
primary language, level of education, ethnicity/cultural factors,
reading level, expected level of global cognitive impairment
(to avoid ceiling or floor effects in testing), and physical dis-
abilities (Smith et al., 2008). Although this approach is more
tailored to the individual needs of the patient (and is therefore
briefer), it can be less comprehensive than the fixed battery
approach. Most neuropsychologists’ approaches fall some-
where between the use of a set battery and a completely indi-
vidualized examination.
Test Interpretation
The interpretation of cognitive test results is central to the role
of the neuropsychologist and differentiates neuropsychology
from all other disciplines. Accurate interpretation of neuropsy-
chological test results depends on a comprehensive under-
standing of the neuroanatomical correlates of cognition,
neurological disease processes, and psychometric testing prin-
ciples. One cannot simply administer a test, look at the score,
and declare that the score indicates intact/impaired cognitive
Neuropsychology 513
functioning. Test interpretation requires an understanding
of test validity and reliability, sensitivity and specificity, 43
likelihood ratios, and score distributions to avoid over- or
underdiagnosing cognitive deficits. Substantial intraindividual
differences exist in cognitive abilities and a certain number of
poor test performances is common among the general popula-
tion. Cognitive test performances are also impacted by extra-
neurological factors such as the number of tests administered,
where cut scores are placed, the probability of certain test
scores occurring, and the demographic characteristics of the
patient (Iverson and Brooks, 2011). Proper test interpretation
requires that all of these variables are considered and that
conclusions are based on recognizable patterns of test results
rather than the interpretation of test scores in isolation.
Neuropsychological test interpretation is also dependent
on an understanding of the scientific and theoretical concepts
that underlie cognitive tests. No cognitive test measures a
single isolated aspect of cognitive functioning. Most neuropsy-
chological tests engage multiple cognitive abilities simultane-
ously. To illustrate, verbal memory tests (e.g., word list memory
tasks) assess memory functioning but they are also dependent
on the patient’s attention, processing speed, and executive
functioning. Therefore, an impaired score on a verbal memory
task does not necessarily indicate a primary memory impair-
ment. It is the neuropsychologist’s task to determine which
cognitive deficits are actually causing impaired test perform-
ances by analyzing the patient’s overall pattern of results
across the test battery and by comparing the neuropsychologi-
cal profile to known patterns of disease. If a score on a verbal
memory test does reflect a primary memory deficit, then the
neuropsychologist determines whether the impairment is due
to a deficit in encoding, storage, or retrieval since the type of
memory impairment may be indicative of different disease
processes or lesion locations. Neuropsychologists use a similar
method of analysis when assessing performances in other cog-
nitive domains.
Test interpretation also requires the integration of neu-
ropsychological test scores with findings from the clinical
interview, the patient’s history, the neurological examination,
neurophysiology and neuroimaging data, and relevant lit-
erature. Raw test scores must be compared to an appropriate
reference standard. Several reference standards are used in
interpreting neuropsychological test scores, including the use
of normative data, cut scores, and comparisons with an indi-
vidual’s own prior testing results.
Inferences about individual patients’ neuropsychological
test scores are often derived by comparing test scores to nor-
mative data that are typically collected by test developers as a
standardization sample. Normative data are useful for account-
ing for variables that are likely to influence test performance
(e.g., demographic factors) so that accurate and appropriate
conclusions are drawn. Confounding variables are accounted
for by stratifying test scores according to gender, age, and/or
level of education. An individual’s raw score is compared
with the distribution of scores from his or her peer group to
determine where it falls within the range of expected perform-
ances. Figure 43.2 and Table 43.2 show a normal distribution
and interpretive guidelines for use in neuropsychological
interpretation. The usefulness of normative data depends
strongly on the size and representativeness of the standardiza-
tion sample. Clinical interpretation can also be greatly affected
by the goodness-of-fit between the individual patient and the
standardization sample. Furthermore, it is important to use
the most recent norms available, because cohort effects may
lead to differences between current patients and those from
whom data were collected years ago. When appropriate norms
are not available, there is a danger of over- or underdiagnosis
of cognitive impairment.
514 PART II Neurological Investigations and Related Clinical Neurosciences

CORE BATTERY FOLLOW-UP TESTS

Wechsler memory scale-III

Memory
Iowa famous faces test

• Interview Category fluency test

• Orientation to time, person, and Language
place Boston naming test
• Recall of recent presidents
Judgement of
• Information subtest (WAIS-III) line orientation
Perception and
• Complex figure test attention
Hooper visual
• Auditory verbal learning test organization test

• Draw a clock
Draw a house, flower, bicycle
• Arithmetic subtest (WAIS-III)
Visuoconstruction
• Block design subtest (WAIS-III) Three-dimensional block
construction
• Digit span subtest (WAIS-III)

• Similarities (WAIS-III) Grooved pegboard test

Psychomotor and
• Trail-making test psychosensory
Line cancellation test
• Digit symbol subtest (WAIS-III)

• Controlled oral word association Wisconsin card sorting test

Executive
• Benton visual retention test functions
Stroop color-word test
• Benton facial discrimination test

• Picture arrangement subtest Minnesota multiphasic

(WAIS-III) personality inventory-2
Personality and
• Geschwind-Oldfield handedness affect
questionnaire Iowa rating scales of
personality change
• Beck depression inventory-II
Test of memory and
malingering
Symptom validity
testing
Rey 15 item test

Fig. 43.1 Example of a flexible battery approach. (Adapted from Tranel, D., 2008. Theories of clinical neuropsychology and brain–behavior
relationships, in: Morgan, J.E., Ricker, J.H. (Eds), Textbook of Clinical Neuropsychology. Taylor & Francis, New York, pp. 25–37.)

Another approach to test interpretation is through the use
of cut scores. Tests that rely on cut scores often measure per-
formances with low base rates or deficits very few healthy
people demonstrate. Some tests are fairly straightforward in
their capability to measure abilities that are largely intact in
normal subjects but impaired in disordered patients. For
example, most people are able to bisect a line without diffi-
culty, but patients with left-sided visuospatial neglect typi-
cally identify the midpoint of the line to be to the right of
center. Other tests, however, are more complex and require
more sophisticated analyses to develop valid cut scores. Smith
et al. (2008) provide an excellent explanation for how cut
scores are useful individual statistics that allow inferences
about which diagnostic group a patient is likely to belong to
(e.g., AD versus mild cognitive impairment versus healthy).
Test validation studies commonly use sensitivity and specifi-
city data with base rate information to calculate likelihood
ratios and positive predictive values for individual tests. Like-
lihood ratios and positive predictive values are differing
expressions of the probability that a patient has a particular
condition given his or her test score. Smith et al. (2008) put
these concepts another way by saying, “the positive predictive
value allows for statements such as: ‘Based on the patient
having earned a score of y on test z, the probability that this
patient has the condition of interest is x’ ” (p. 47). A common
example of the application of cut scores can be found in the
use of screening instruments to quickly identify potential
impairments.
 Neuropsychology 515

43

Standard deviations –4 –3 –2 –1 0 +1 +2 +3 +4
Cumulative 0.1% 2.3% 15.9% 50% 84.1% 97.7% 99.9%
percentages
Percentiles 1 5 10 20 30 40 50 60 70 80 90 95 99
Z scores –4.0 –3.0 –2.0 –1.0 0 +1.0 +2.0 +3.0 +4.0
T scores 20 30 40 50 60 70 80
Standard nine 1 2 3 4 5 6 7 8 9
(stanines)
Percentage 4% 7% 12% 17% 20% 17% 12% 7% 4%
in stanine
Fig. 43.2 The normal curve and its relationship to derived scores.

TABLE 43.2 Descriptive Terms Associated with Performance within treatment recommendations, is communicated to the referring
Various Ranges of the Normal Distribution physician and the patient. Some form of written report is
typical in neuropsychological evaluations, and these tend to
Standard
deviation
vary in length and level of detail (e.g., <1 to 15 pages). A
score (i.e. Percentile common structure for neuropsychological report includes sec-
Qualitative terms z-score) T-score rank tions summarizing the patient interview, collateral interview,
medications, medical history, social background, behavioral
Severely impaired <−2.20 <29 <2
observations, neuropsychological battery, neuropsychological
Moderately impaired −2.20 to −1.60 29–34 2–5 test results and interpretation, final diagnostic impressions,
Mildly impaired −1.59 to −1.33 35–37 6–9 and treatment recommendations.
Below average −1.32 to −0.68 38–42 10–24
Average −0.67 to +0.67 43–57 25–75
BRIEF MENTAL STATUS EXAMINATION
Above average +0.68 to +1.59 58–66 76–94
Before referring a patient for a neuropsychological evaluation,
the neurologist typically has either clinical or historical evi-
Superior +1.60 to +2.20 67–72 95–98 dence of cognitive concerns. This might come from patient
Very superior >+2.20 >72 >98 self-report or collateral report, an informal mental status
examination, or a brief objective screening measure of mental
Note: The patient’s educational history and premorbid level of
status. Although many mental status examinations are con-
functioning should be taken into consideration in applying any
qualitative label.
ducted in a nonstandard manner, neurologists are encouraged
to use formal cognitive screening measures to develop a stand-
ardized method of mental status examination so comparisons
across time and patients can be reliably made. The purpose of
The comparison of current performance with past test cognitive screening measures is to determine the need for a
scores is another important component of test interpretation, more extended evaluation of neuropsychological functioning.
especially if cognitive decline is suspected. Rarely, however, do Given the limited scope of cognitive screening measures and
individuals have previous test data available for these com- the psychometric considerations noted earlier, it is not recom-
parisons. When no previous test scores are available, evidence mended that cognitive screening measures are routinely used
of the patient’s premorbid intellectual functioning is esti- as a final summation of a patient’s neuropsychological status.
mated. Several techniques are available for estimating premor- Scores from cognitive screeners must be considered in con-
bid intellect, including regression equations that utilize junction with clinical observation and judgment to determine
demographic variables as predictors of IQ (e.g., the Barona whether a referral for neuropsychological evaluation is neces-
formula; Barona et al., 1984), irregular-word reading tests that sary, since many patients may pass a cognitive screen but still
are correlated with IQ (e.g., the North American Adult Reading have suspected deficits that warrant more sensitive neuropsy-
Test; Blair and Spreen, 1989), and “hold” subtests from intel- chological testing. A few suggested objective screening meas-
ligence measures that are frequently used as proxies for pre- ures of cognitive functioning that may be useful for neurologists
morbid functioning (e.g., see Lezak et al., 2012, for review). to administer are briefly described in the following.
Most contemporary neuropsychologists use a combination of
these strategies, either formally (e.g., Oklahoma Premorbid
Intelligence Estimate-3, Schoenberg et al., 2002; Test of Pre-
Montreal Cognitive Assessment
morbid Functioning, Pearson, 2009) or informally. The Montreal Cognitive Assessment (MoCA) was originally
Ultimately, feedback about the results of the neuropsycho- developed as a screening tool to correct the shortcomings of
logical evaluation, along with diagnostic impressions and the widely used Mini-Mental State Examination (MMSE; see
516 PART II Neurological Investigations and Related Clinical Neurosciences

description in self-titled section), which demonstrated an
insensitivity to mild cognitive impairment (Nasreddine et al.,
2005). The MoCA also improved upon the MMSE by probing
more cognitive domains, including executive functioning,
immediate and delayed memory, visuospatial abilities, atten-
tion, working memory, language, and orientation to time and
place (see Figure 43.3 for example). Including more cognitive
domains reduces the likelihood that impairments or disorders
will be overlooked (e.g., executive dysfunction, a hallmark
symptom of vascular dementia). The total score ranges from
0 to 30 points, and a cut score of 26 has demonstrated very
good specificity (by correctly identifying 87% of healthy

Fig. 43.3 Montreal Cognitive Assessment. (Reprinted with permission from Nasreddine, Z.S., Phillips, N.A., Bedirian, V., et al., 2005. The
Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53, 695–699.)
 Neuropsychology 517

TABLE 43.3 Montreal Cognitive Assessment (MoCA) score by age and education
43
Years of education
<12 12 >12 Total by age
Age group (years) NO. MEAD (SD) MEDIAN NO. MEAN (SD) MEDIAN NO. MEAN (SD) MEDIAN NO. MEAN (SD) MEDIAN

<35 20 22.80 (3.38) 23 65 24.46 (3.49) 25 122 25.93 (2.48) 26 207 25.16 (3.08) 26
30–40 37 22.84 (3.18) 23 106 23.99 (2.93) 24 264 25.81 (2.64) 26 408 25.07 (2.95) 25
35–45 55 22.11 (3.33) 23 177 23.02 (3.67) 24 355 25.38 (3.05) 26 588 24.37 (3.51) 25
40–50 77 21.36 (3.73) 22 227 22.26 (3.94) 23 418 25.09 (3.16) 26 723 23.80 (3.80) 24
45–55 77 20.75 (3.80) 21 216 21.87 (3.95) 22 461 24.70 (3.24) 25 755 23.48 (3.84) 24
50–60 62 19.94 (4.34) 20 172 22.25 (3.46) 22 424 24.34 (3.38) 25 659 23.37 (3.78) 24
55–65 60 19.60 (4.14) 20 143 21.58 (3.93) 22 369 24.43 (3.31) 25 573 23.20 (3.96) 23
60–70 57 19.30 (3.79) 19 113 20.89 (4.50) 21 246 24.32 (3.04) 25 418 22.69 (4.12) 23
65–75 38 18.37 (3.87) 19 67 20.57 (4.79) 21 122 24.00 (3.35) 24 228 22.05 (4.48) 23
70–80 14 16.07 (3.17) 17 23 20.35 (4.91) 20 42 23.06 (3.47) 24 79 21.32 (4.78) 22
Total by education 230 20.55 (4.04) 21 608 22.34 (3.97) 23 1,306 24.81 (3.20) 25 2,148 23.65 (3.84) 24
Adapted from Rossetti, H.C., Lacritz, L.H., Cullum, C.M. & Weiner, M.F., 2011. Normative data for the Montreal Cognitive Assessment (MoCA) in a
population-based sample. Neurology 77, 1272–5

participants) and excellent sensitivity when differentiating
mild cognitive impairment (MCI) (90%) and AD (100%) from
healthy comparisons. More importantly, the positive predic-
tive value of the MoCA was 89% for both MCI and AD. Since
its inception as a screening measure for MCI, other studies
have found the MoCA to outperform the MMSE in screening
for general cognitive impairment in Parkinson disease (PD)
(Hoops et al., 2009; Nazem et al., 2009), vascular dementia
after acute stroke (Dong et al., 2010), and HD (Videnovic
et al., 2010) as a measure sensitive to early stages of different
types of dementia.
Although the MoCA has demonstrated its utility as a cogni-
tive screener, there are a few caveats worth noting. First, some
studies have demonstrated that its reliability is notably low in
nonclinical populations (Bernstein et al., 2011), which indi-
cates that it should primarily be used only to detect suspected
cognitive impairment in clinical patients. Additionally, the
original cut score of 26 used to identify impairment was devel-
oped without fully accounting for other variables that affect
test performance (e.g., age, education, gender, and race) and
the score has also been shown to identify a high number of
false positives in certain populations. Rossetti and colleagues
(2011) attempted to correct these problems by conducting a
normative study of the MoCA in an ethnically diverse sample
of healthy participants as presented in Table 43.3. They found
that 66% of their sample fell below the cut score of 26, indi-
cating “impairment,” and that many of the MoCA items had
high failure rates.
The MoCA is free to clinicians (http://www.mocatest.org)
and has been translated into 31 different languages and
dialects.
Telephone Interview for Cognitive
Status—Modified
The Telephone Interview for Cognitive Status—Modified
(mTICS) is a relatively brief screening instrument designed to
quickly and accurately assess cognition over the telephone,
although it can also be used in face-to-face settings. This
13-item measure is heavily weighted toward immediate and
delayed free recall, which might make it particularly useful in
detecting mild impairments (Duff et al., 2009; Lines et al.,
2003) such as amnestic MCI (Fig. 43.4). Age-, education-,
gender-, and race-corrected normative data are available
(Hogervorst et al., 2004).
Mini-Mental State Examination
One of the most widely used mental status examinations is
the MMSE (Folstein et al., 1975), a 30-point standardized
screening tool for assessing orientation, attention, short-
term recall, naming, repetition, simple verbal and written
commands, writing, and construction (Fig. 43.5). The MMSE
has been used in a variety of settings (e.g., community, institu-
tions, general hospital, specialty clinics), with many different
neurological and psychiatric conditions (e.g., dementia, stroke,
depression), across age ranges, and with different cultural and
ethnic subgroups. Demographic variables such as age and edu-
cation have been shown to systematically influence MMSE
scores, so normative data or cut scores should account for
these variables. One example of appropriate norms comes
from the Epidemiologic Catchment Area study (Crum et al.,
1993); these are presented in Table 43.4. Whereas many intact
individuals achieve total scores near 30, a cut score of 23 on
the MMSE has been shown to have adequate sensitivity and
specificity (86% and 91%, respectively) for detecting dementia
in community samples (Cullen et al., 2005). However, when
working with highly educated patients (i.e., ≥16 years of
formal education) a cut score of 27 is recommended (O’Bryant
et al., 2008).
Despite its widespread use, the MMSE has some drawbacks.
First, it only assesses a limited number of cognitive functions.
Second, a potential threat to the test’s internal validity is the
nonstandardized administration of some of the items. Exam-
ples of these frequent adaptations of the MMSE include the
use of nonorthogonal (i.e., semantically related) word stimuli
for registration and recall, nonstandard scoring of serial 7’s,
and nonstandard inclusion of spelling world backward.
Another drawback of the MMSE is that it has “ceiling effects”
that can miss cognitive impairments in high-functioning indi-
viduals. The MMSE also has difficulty differentiating individu-
als with MCI from controls and those with dementia ( Mitchell,
2009). Finally, because this test relies on a single total score,
partial administration of the measure (e.g., due to sensory
518 PART II Neurological Investigations and Related Clinical Neurosciences

Modified Telephone Interview for Cognitive Status (mTICS) impairments of the patient) provides no information about
cognitive status. This same limitation is true for the MoCA.
1. What is your name? /2

2. What is your telephone number? /2

Modified Mini-Mental State Examination
3. What is today’s date (month, date, year, season, day)? (5 points maximum,
1 point per correct response) Some of the criticisms of the MMSE led to the development
Month: /1 of the Modified Mini-Mental State Examination (3MS) (Teng
Date: /1 and Chui, 1987), a 15-item extension of the MMSE that
Year: /1 assesses orientation (self, time, place), attention (simple
Season: /1 and complex), memory (recall and recognition), language
Day: /1 /5
(naming, verbal fluency, repetition, following commands,
4. I’m going to read you a list of 10 words. Please listen carefully and try to writing), construction, and executive functioning (similari-
remember them. When I am done, tell me as many as you can in any order. ties). It remains relatively brief to administer (10 minutes),
Ready? (10 points maximum, 1 point per correctly recalled word)
and age- and education-corrected normative data are available
Cabin (Tschanz et al., 2002). Regression-based prediction formulas
Pipe for the 3MS allow for more accurate assessments of change
Elephant across time (Tombaugh, 2005). The broader scoring range (0
Chest
to 100) has been shown to be more sensitive than that of the
MMSE in identifying dementia (McDowell et al., 1997;
Silk
Tschanz et al., 2002) and other cognitive disorders (Bland and
Theatre
Newman, 2001) in large community samples. A cut score for
Watch
cognitive impairment is typically 77 (Bland and Newman,
Whip 2001; McDowell et al., 1997), and a change of 5 points over
Pillow the course of 5 to 10 years indicates the presence of clinically
Giant meaningful decline (Andrew and Rockwood, 2008).
TOTAL /10
5. Please count backwards from 20 to 1. /2 NEUROPSYCHOLOGICAL CHARACTERISTICS OF
20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
6. Please take 7 away from 100. Now continue to take away 7 from what you
NEUROLOGICAL DISEASE
have left over until I ask you to stop. (5 points maximum, 1 point per correct
response) In this section we briefly address the neurocognitive sequelae
93: /1 of some of the major neurological disorders. Although many
86: /1 of these disorders have psychiatric characteristics as well, these
79: /1 will only be briefly discussed. Please see Chapter 9, Behavior
72: /1 and Personality Disturbances, for a more comprehensive dis-
65: /1 /5 cussion on the psychiatric aspects of neurological disorders.
7. What do people usually use to cut paper? /2

8. What is the prickly green plant found in the desert? /2 Mild Cognitive Impairment
9. Who is president of the United States now? /2 A major focus of dementia research has been detecting pro-
10. Who is the vice president of the United States now? /2 dromes of cognitive impairment associated with neurodegen-
erative diseases, with a particular emphasis on characterizing
11. What word is opposite of east? /2
the incipient stages of Alzheimer disease. The diagnostic term
12. Please say this: “Methodist Episcopal” /2 mild cognitive impairment was initially defined by Petersen
Correct response (circle one): YES NO and colleagues (1999) as the presence of subjective memory
13. Please tap your finger 5 times on the part of the phone you speak into. complaints, a measured deficit in a cognitive domain of
(2 points if they tap 5 times, 1 point if they tap more or less than 5 times) /2 approximately 1.5 standard deviations below normative
14. Please repeat the list of 10 words I read earlier. means, otherwise intact cognition, no functional impair-
Cabin ments, and the absence of dementia.
Pipe
This became known as the Petersen criteria and requires
the utilization of neuropsychological tests to quantify the
Elephant
deficit using normative data. While MCI originally focused on
Chest
memory impairment, the concept has evolved to include other
Silk cognitive domains. Currently, MCI is typically categorized as
Theatre either amnestic or nonamnestic with some also specifying
Watch whether the cognitive impairment is single- or multi-domain.
Whip Both amnestic MCI and nonamnestic MCI are considered to
Pillow
be risk factors for Alzheimer disease with nonamnestic MCI
being viewed as a risk factor for other dementias as well. The
Giant
new DSM-V (APA, 2013) diagnosis of mild neurocognitive
TOTAL
/10 disorder is essentially MCI (Petersen et al., 2009). Amnestic
TOTAL: /50 MCI is associated with smaller hippocampal and larger infe-
rior lateral ventricle volumes similar to those of Alzheimer
Fig. 43.4 Modified Telephone Interview for Cognitive Status. (Data neuropathology (England et al., 2014) and approximately half
from Welsh, K.A., Breitner, J.C.S., Magruder-Habib, K.M., 1993. of these cases will convert to Alzheimer dementia (Ferman
Detection of dementia in the elderly using telephone screening of et al., 2013). However, MCI as a diagnostic concept is extremely
cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 6, heterogeneous, in terms of both cognitive profile and neu-
103–110.) ropathology (Stephan et al., 2012). Other MCI subtypes are
 Neuropsychology 519

1. “What is the year? 7. Read and obey /1 43

season?
date?
day of week? CLOSE YOUR EYES
month?
/5
8. Copy design /1
2. “Where are we? state?
county? (Must have 10 angles and
town? intersect)
hospital?
floor?
/5

3. Repeat 3 words:
(use list) 9. Write a sentence: /1
(Must have subject and verb make sense)
“Here are three words I want you to
remember.” Repeat up to 6 times.
# words on 1st trial
# repetitions
/3
4. Serial 7’s: 93 10. Repeat the following:
86
79 “no ifs, ands, or buts” /1
72
65 11. Follow a 3-stage command:
a. take a paper in your
/5
right hand
“Start with 100 and count backward b. fold it in half
by 7. For example: What is 100–7? c. put it on the floor
Keep subtracting 7. Stop after five /3
responses.”
“Now I will give you some directions to
Spell “world” backward: follow. Please listen carefully and do as I say.
D Take this paper in your right hand, fold it in
L half, and put it on the floor.”
R
O
W
/5

5. Recall 3 words:
(Set used in #3)

/3

6. Name a: Pencil
Watch TOTAL
/2 MAX = 30

Fig. 43.5 Mini-Mental State Examination. (Reprinted with permission from Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini-Mental
State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.)

hypothesized to progress to their own dementia outcomes. For
example, 20% of nonamnestic MCI cases with impairment in
either attention or visuospatial, or both domains have been
reported to convert to Lewy body dementia (Ferman et al.,
2013). Multi-domain MCI (e.g., deficits in executive functions
and processing speed) might be indicative of eventual vascular
dementia. Neuropsychological testing is essential for obtain-
ing the necessary information to differentiate MCI subtypes
and track their progression into the various forms of
dementia.
MCI has attracted so much attention because of its prog-
nostic value, with a 10-fold increase in the rate of dementia
for individuals with MCI (Petersen et al., 1999). Patients of
memory disorder clinics with MCI progress to dementia at a
rate of 10% to 15% per year (Farias et al., 2009), and com-
munity dwelling adults at an annual rate of 6% to 10% per
year (Petersen et al., 2009), but up to 25% may revert back to
normal cognitive baseline at follow-up. It is controversial
whether severity of MCI symptoms does not predict which
individuals will convert to dementia (Guo et al., 2013),
though impaired olfaction increases the risk of conversion by
four times (Conti et al., 2013). Using preclinical staging of AD
adds to the predictive validity of who demonstrates conver-
sion (Vos et al., 2013). Having a copy of APOE ε 4 also
increases the risk of developing MCI (Brainerd et al., 2013).
Individuals with MCI also experience global cognitive decline
at over twice the rate of what is observed in nonimpaired
individuals (Wilson et al., 2010). For cases that progress to
dementia, the average time they would be considered to have
MCI is 5.5 years, though they may not be diagnosed early in
the process (Wilson et al., 2012). Since not everyone with MCI
progresses to dementia, several predictors of the progression
from MCI have been identified. Bilingualism has been reported
to be a protective factor resulting in later onset of MCI (Bia-
lystok et al., 2014) as are more advanced education and
healthy lifestyle behaviors (Lojo-Seoane et al., 2014). Despite
 520

TABLE 43.4 Mini-Mental State Examination Score by Age and Educational Level, Number of Participants, Mean, Standard Deviation, and Selected Percentiles
Age (years) 18–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 ≥85 Total
EDUCATIONAL LEVEL
0–4 yr 17 23 41 33 36 28 34 49 88 126 139 112 105 61 892
Mean 22 25 25 23 23 23 23 22 23 22 22 21 20 19 22
SD 2.9 2.0 2.4 2.5 2.6 3.7 2.6 2.7 1.9 1.9 1.7 2.0 2.2 2.9 2.3
5–8 yr 94 83 74 101 100 121 154 208 310 633 533 437 241 134 3223
Mean 27 27 26 26 27 26 27 26 26 26 26 25 25 23 26
SD 2.7 2.5 1.8 2.8 1.8 2.5 2.4 2.9 2.3 1.7 1.8 2.1 1.9 3.3 22
9–12 yr or H.S. diploma 1326 958 822 668 489 423 462 525 626 814 550 315 163 99 8240
Mean 29 29 29 28 28 28 28 28 28 28 27 27 25 26 28
SD 2.2 1.3 1.3 1.8 1.9 2.4 2.2 2.2 1.7 1.4 1.6 1.5 2.3 2.0 1.9
College experience 783 1012 989 641 354+ 259 220 231 270 358 255 181 96 52 5701
PART II Neurological Investigations and Related Clinical Neurosciences

Mean 29 29 29 29 29 29 29 29 29 29 28 28 27 27 29
SD 1.3 0.9 1.0 1.0 1.7 1.6 1.9 1.5 1.3 1.0 1.6 1.6 0.9 1.3 1.3
Total 2220 2076 1926 1443 979 831 870 1013 1294 1931 1477 1045 605 346 18,056
Mean 29 29 29 29 28 28 28 28 28 27 27 26 25 24 28
SD 2.0 1.3 1.3 1.8 2.0 2.5 2.4 2.5 2.0 1.6 1.8 2.1 2.2 2.9 2.0
Data from the Epidemiologic Catchment Area household surveys in New Haven, CT; Baltimore, MD; St Louis, MO; Durham, NC; and Los Angeles, CA, between 1980 and 1984. The data are weighted
based on the 1980 U.S. population census by age, sex, and race. Adapted from Crum, R.M., Anthony, J.C., Bassett, S.S., et al., 1993. JAMA 269, 2386–2391.

this growing research, no standard for predicting the MCI-to-
dementia conversion has yet been established.
Alzheimer Disease
Alzheimer disease-related dementia is the most common type,
with prevalence rates of 11% in those of 65 years and older
(Hebert et al., 2013) and 68% in memory disorder clinics
(Paulino Ramirez Diaz et al., 2005). Definitive diagnosis
requires postmortem neuropathological examination of brain
tissue for the hallmark signs of plaques and neurofibrillary
tangles in the hippocampal and entorhinal regions (Braak and
Braak, 1991); however, premortem diagnostic criteria are
widely employed in clinical and research settings. Recently,
DSM-V (APA, 2013) has changed the terminology for diagno-
sis of dementia in AD to major neurocognitive disorder due
to Alzheimer disease with specified criteria being evidence of
significant cognitive decline from a previously higher level of
functioning and the cognitive impairments interfering with
everyday functioning. The diagnosis is considered probable
Alzheimer disease if there is objective evidence of decline in
memory and one other cognitive domain, insidious onset and
gradual progression of symptoms, and no evidence of other
etiology. Evidence of a genetic mutation associated with Alzhei-
mer disease would also result in probable Alzheimer disease
diagnosis. However, autosomal dominant cases such as APP,
PSEN1, or PSEN2 are rare and account for less than 1% of
Alzheimer disease patients (Storandt et al., 2014). For research
purposes, the National Institute of Neurological and Com-
municative Disorders and Stroke Alzheimer’s Disease and
Related Disorders Association (NINCDS-ADRDA) criteria for
probable AD are the most commonly used. The National Insti-
tutes of Aging–Alzheimer’s Association workgroups (McKhann
et al., 2011) have recommended diagnosing probable Alzhei-
mer disease dementia when there is a change in cognition
that results in functional impairment and there is either an
amnestic presentation or a nonamnestic one in the domains
of language, visuospatial, or executive function with no evi-
dence of other likely etiologies. The workgroups recommend
a diagnosis of possible Alzheimer disease dementia if there is
an atypical course such as a lack of evidence of progressive
onset or mixed presentation that suggests comorbid etiologies.
They also recommend including the incorporation of biomar-
kers, neuroimaging, and genetic findings into the diagnostic
criteria but particularly emphasize the importance of measur-
able cognitive decline, especially for MCI. The presence of
biomarkers without cognitive decline is considered a preclini-
cal AD stage. However, the presence of biomarkers without
evidence of early cognitive decline is thought to convey lower
risk for dementia than if cognitive deficits are present (Jack
et al., 2013). Formal neuropsychological assessment for meas-
uring AD related declines has been demonstrated to have
better sensitivity than MRI for tracking disease progression
(Schmand et al., 2014). The brief bedside exams mentioned
earlier in this chapter also have some degree of utility in detect-
ing cognitive changes, but their comparatively limited scope,
low sensitivity, and susceptibility to ceiling effects make them
better suited for screening purposes.
Complaints about “memory problems” are what often lead
to a clinical evaluation of possible AD and cognitive decline
begins 7.5 years prior to diagnosis on average (Wilson et al.,
2012). Consistent with patient report and behavioral observa-
tions of rapid forgetting of new information, performances
across a comprehensive battery of neuropsychological assess-
ment measures are likely to identify stark memory deficits for
both verbally (e.g., lists, stories, paired associates) and visually
(e.g., concrete or abstract figures) mediated information,
including an atypical lack of a primacy effect for information
Neuropsychology 521
presented early in lists (Salmon and Bondi, 2009). Recogni-
tion memory is also likely to be significantly impaired and 43
intrusion errors are common (e.g., adding extra words to
delayed recall trials on word-list memory tasks). Other cog-
nitive deficits are seen in a number of other domains includ-
ing language functions (e.g., paraphasias, naming), semantic
knowledge, visuospatial abilities, and executive functions such
as motor planning (Weintraub et al., 2012). Impaired aware-
ness of their own cognitive deficits, known as anosognosia or
impaired metacognition, is also common (Rosen et al., 2014).
Even though impaired memory is a cardinal feature of AD, it
is important to keep in mind that other neurodegenerative
dementia syndromes can also result in memory decline and
that a nonmemory cognitive deficit may be the primary cogni-
tive presentation of AD, possibly reflecting posterior cortical
atrophy. Global cognitive functioning in AD declines at a rate
nearly four times faster than what is observed in cognitively
intact individuals of the same age (Wilson et al., 2010). Given
the pattern of deficits in AD, it is not surprising that measures
of semantic fluency, delayed free recall, and global cognitive
status demonstrate the highest levels of sensitivity and specifi-
city for detecting patients with early AD (Salmon et al., 2002).
Although memory deficits are usually glaring compared to
other deficits in AD, general and progressive cognitive decline
is common and shows an eightfold increase in rate of decline
approximately 3 years prior to death (Yu et al., 2013). As
dementia progresses to moderate stages, learning and memory
performances are likely to produce floor effects on many
standardized neuropsychological measures, and more pro-
found deficits are apparent in other cognitive domains. Defi-
cits in praxis also begin to develop. These pervasive declines
in late AD often make formal neuropsychological testing
unnecessary or impossible.
Vascular Dementia
Cerebrovascular disease frequently leads to cognitive impair-
ment and vascular factors have garnered significant attention
as a modifiable risk factor for dementia. So-called silent brain
infarcts, or asymptomatic vascular pathology, are found in up
to 35% of individuals with vascular disease (Slark et al., 2012)
and are known to double the risk of vascular dementia (VaD)
or major neurocognitive disorder due to vascular disease, as
described in the DSM-V. Extracerebellar lacunar, large vessel,
or strategically placed infarcts and hemorrhage lead to varying
degrees of cognitive impairment, and small vessel disease is
the most frequently observed vascular pathology that leads to
cognitive decline. Recently, the term vascular cognitive impair-
ment (VCI) has been introduced to encompass all cognitive
changes attributable to cerebrovascular pathology (i.e., from
mild cognitive impairment due to vascular events to VaD;
Rincon and Wright, 2013; Sachdev et al., 2014). Cognitive
changes can occur abruptly and in a stepwise pattern with
coinciding cerebrovascular accidents (CVAs), or they may fluc-
tuate or remain static. Neuroimaging is likely to detect lesions
that are a result of a CVA and enhance diagnostic certainty, but
imaging is not required to accurately identify dementia with
a vascular etiology. Neurological evidence of cerebrovascular
pathology (e.g., history of strokes, sensorimotor changes con-
sistent with stroke) in combination with cognitive changes is
considered indicative of VaD and the estimated prevalence is
8–12% (Jellinger, 2013).
The clinical presentation of VaD varies depending on the
number of infarcts, severity of neural damage following stroke,
and location of the CVA. Although many VaD patients may
acknowledge “memory problems,” which may lead to suspi-
cions of AD, further questioning reveals that these complaints
are quite different from those typically seen in AD. If VaD
522 PART II Neurological Investigations and Related Clinical Neurosciences
results from a discrete stroke, then the primary cognitive
impairment will likely be functionally related to the area of
infarct, resulting in focal deficits and a heterogeneous presen-
tation for VaD. Many patients do not experience a notable
stroke preceding the onset of VaD, and may not present to
memory disorder clinics because their primary symptoms are
often dysexecutive in nature (e.g., the patient “just can’t figure
things out anymore”) with accompanying apathy and/or
depression being common (Weintraub et al., 2012). Particu-
larly in the frontal regions, increasing lacunae are associated
with a higher probability of depression, apathy, atypical
behaviors, and other neuropsychiatric symptoms (Kim et al.,
2013). Impaired executive functioning is also strongly related
to the presence of metabolic syndrome, a significant risk factor
for VaD (Falkowski et al., 2014).
Classic dementia symptoms might be reported (e.g., diffi-
culty remembering names, appointments, medications) but
changes in instrumental activities of daily living that require
complex organizational and problem-solving skills (such as
managing finances or following directions) are likely more
prominent in a patient with VaD than in one with AD. Depres-
sion and apathy are hallmark symptoms and there is evidence
that vascular factors are etiologically linked to late life depres-
sion (Taylor et al., 2013). Upon first inspection, VaD may
initially be cognitively indistinguishable from other demen-
tias in many ways. However, a detailed neuropsychological
examination and behavioral observations are likely to reveal
a unique pattern of deficits in VaD referred to as the subcorti-
cal profile. VaD patients tend to have better long-term verbal
memory than their AD counterparts, worse executive func-
tioning, and slowed processing speed, particularly on motor
tasks. Impaired complex attention is also prominent (Benedet
et al., 2012) and VaD tends to have a rapid initial onset. Free
recall might occasionally appear similar in VaD and in AD,
but patients with VaD significantly outperform their AD coun-
terparts on tests of recognition memory (Tierney et al., 2001).
Better recognition memory suggests encoding processes are
relatively intact in VaD patients compared to AD patients,
but information retrieval is deficient. This retrieval deficit
appears to be quite common in subcortical dementias, with
which VaD appears to have several components in common.
Patients with VaD also perform more poorly on phonemic
fluency tasks relative to semantic fluency tasks, which suggests
greater executive dysfunction due to disruption of the frontal
subcortical circuitry rather than degeneration in the temporal
lobes.
Mixed Dementia
More common than AD and VaD in their pure forms is mixed
dementia. While mixed dementia typically refers to a patient
having both AD and cerebrovascular pathology, it concep-
tually can be any case which involves the coexistence of mul-
tiple neuropathologies (e.g., amyloid, small vessel ischemic
changes, Lewy bodies). For patients diagnosed with VaD, 30%
may have insignificant AD neuropathology as well (Lee et al.,
2011) and these patients tend to be older than pure VaD cases.
Across dementia autopsy studies, 21%–80% of cases had
mixed AD and vascular pathology (Jellinger, 2013; Wilson
et al., 2012). In older patients (>90 years), having both AD
and vascular pathology at autopsy was more likely if they had
been diagnosed with mixed dementia rather than AD alone
(James et al., 2012). The vast majority of mixed dementia
cases are AD and vascular pathology but 5% of cases are AD
and Lewy body disease. Persons with multiple pathologies are
three times more likely to develop dementia than others with
only one identifiable diagnosis (Schneider et al., 2007). There
is evidence that mixed dementia cases are more globally
impaired than similarly staged AD patients (Dong et al.,
2013). While this may result from interactive effects, there is
evidence that vascular and amyloid burden combine inde-
pendently to impact cognitive impairment (Park et al., 2013).
Frontotemporal Dementia
Frontotemporal dementia (FTD) is another common type of
dementia and is in fact the second most common in those
younger than age 65 (Arvanitakis, 2010). It is less common
in older adults and is frequently misdiagnosed as AD (Beber
and Chaves, 2013). The term frontotemporal lobar degeneration
(FTLD) is also frequently used in connection with FTD but
usually refers to the pathological aspects of FTD and not the
clinical entity (Hales and Hu, 2013). According to DSM-V
(APA, 2013) criteria, FTD has multiple clinical manifestations
that include behavioral and language variants. Behavioral
observations, neuropsychological testing, and neuroimaging
(e.g., frontal or temporal lobe atrophy on computed tomogra-
phy [CT] or magnetic resonance imaging [MRI], hypoperfusion
or hypometabolism on single-photon emission tomography
[SPECT] or positron emission tomography [PET]) are used in
combination to establish a clinically probable diagnosis of
FTD. A definitive diagnosis can be made with histopathologi-
cal evidence through biopsy or postmortem examination. The
latest consensus clinical diagnostic criteria (Rascovsky et al.,
2011) define possible FTD as the presence of progressive
behavioral and/or cognitive deterioration and three of the
following: behavioral disinhibition, apathy or inertia, loss of
empathy, perseverative or compulsive behaviors, hyperorality
or dietary change, and neuropsychological testing demonstrat-
ing executive impairments with intact memory and visuospa-
tial abilities. Probable FTD requires that the patient meet
criteria for possible FTD and also has evidence of functional
decline and neuroimaging consistent with frontal and anterior
temporal atrophy or dysfunction.
Although cognitive deficits are clearly evident on formal
testing, the earliest and most common complaints for the
behavioral variant of FTD are related to changes in personality
and behavior. Increases in impulsivity, poor judgment, stere-
otypic behaviors, lack of hygiene, and loss of appropriate
social behaviors are all prominent. Euphoria and disinhibi-
tion are particularly predictive of FTD compared to other
dementias (Perri et al., 2014) while apathy is a nonspecific
symptom that can occur in all dementias. A formerly mild-
mannered and conscientious patient who develops the behav-
ioral variant of FTD may present as overly frank, crass, and
uncaring. The patient is usually indifferent to their behavior,
but spouses and adult children are usually embarrassed by his
or her conduct. Many of these behavioral issues may have
underlying cognitive components. Impaired metacognition,
or a deficit in monitoring and appreciating behavior, is typical
and much more severe than is seen in AD (Rosen et al., 2014).
Social impairments likely reflect an inability to cognitively
recognize emotions or perspectives in others. Deficits on cog-
nitive testing typically involve impaired executive functions
such as mental flexibility, planning deficits, slowed word/
design generation, and multiple response errors. Phonemic
fluency also tends to be more impaired than semantic fluency.
As the disease progresses, even simple go/no go tasks are dif-
ficult. Despite the array of cognitive deficits in FTD, memory
and visuospatial functioning tend to be well preserved, and
some suggest that a lack of deficits in these domains might be
one of the best ways to differentiate FTD from other diseases
such as AD (Weintraub et al., 2012).
The language variants of FTD are different clinical entities
than the behavioral variant (Harciarek and Cosentino, 2013).
Confrontation naming, word finding, speech production,

comprehension, and/or syntax all gradually worsen over the
course of disease. Memory functioning and visuospatial skills
are relatively spared. The proposed DSM-V diagnostic criteria
suggest that the language variant of FTD be divided into four
subtypes: primary progressive aphasia (PPA), semantic variant,
nonfluent/agrammatic variant, and logopenic/phonologic
variant (APA, 2013). All of these variants except possibly the
semantic variant involve some aspect of anomia or impaired
object naming that is worse than AD (Reilly et al., 2011) but
have otherwise unique neuropsychological profiles. PPA is
characterized primarily by the insidious and gradual decom-
position of expressive language functions such as word finding,
object naming, grammar, and speech production that also
affects comprehension later in the disease process (Weintraub
et al., 2012). The semantic variant of FTD involves impaired
single-word comprehension, object and/or person knowledge,
and dyslexia in the presence of spared single-word repetition,
motor speech production, and syntax. These patients may
appear to have intact expressive and comprehension language
functions but are unable to define vocabulary words or con-
cepts. Nonfluent/agrammatic FTD results in impaired motor
speech production, grammatical errors, and comprehension
of complex sentences, with intact single-word comprehension
and object knowledge. Lastly, the logopenic/phonologic
variant presents with deficits in spontaneous word retrieval
and repetition of sentences and phrases, while single-word
comprehension, object knowledge, and motor speech and
grammar production are spared. Neuropsychological testing is
ideally suited for specifically characterizing deficits and parsing
out the complexity of FTD variants and their specific cognitive
profiles.
Parkinson Disease with Dementia and Dementia
with Lewy Bodies
Parkinson disease with dementia (PDD) and dementia with
Lewy bodies (DLB) have been collectively classified as Lewy
body dementias, given their shared α-synuclein pathology (Lim
et al., 2013). While it is believed that all patients with Parkin-
son disease would eventually develop a Lewy body dementia
with sufficient time, the incidence in patients with Parkinson
disease is only 12% for DLB and 8.5% for PDD (Savica et al,
2013). The Lewy body dementias are more common in women
under 80 years and significantly more common in men over
80 years. DLB accounts for 4.2% of all dementia cases in com-
munity settings and 7.5% of dementia diagnoses in specialty
clinics (Vann Jones and O’Brien, 2014). DLB is believed to be
commonly misdiagnosed, making the actual incidence rate
likely higher. Also, there is significant comorbidity with AD as
autopsy studies have reported that 27% of cases of likely AD
also had Lewy bodies present (Wilson et al., 2012). Incidence
peaks at 70–79 years and decreases after that (Savica et al.,
2013), making both PDD and DLB two of the young demen-
tias (along with FTD) that do not increase in prevalence with
advanced age. The neuropsychological findings in the two
disorders are largely similar, so they are often distinguished
by differences in the onset of signs and symptoms (Weintraub
et al., 2012). The cognitive symptoms of PDD often develop
at least 2 years after the onset of motor signs (e.g., bradyki-
nesia, gait instability, tremor, rigidity), while the cognitive
symptoms in DLB tend to precede motor features or occur
within 1 year of the manifestation of motor signs (Gealogo,
2013). Motor signs develop more quickly in DLB when com-
pared to the insidious onset of PDD signs and symptoms.
Although the time course of cognitive symptoms and motor
signs in DLB and PDD may serve as a helpful heuristic, caution
should be used when differentiating these dementias from
one another based on onset alone, since subtle cognitive
Neuropsychology 523
declines can be detected early in the course of PDD (Tröster,
2008). 43
The neuropsychological profiles of PDD and DLB are
similar. There is considerable heterogeneity in the presenta-
tion and progression of cognitive deficits, with some patients
displaying only minor cognitive slowing. Rapidly fluctuating
attention and level of alertness is a signature symptom (Lee
et al., 2012) along with abnormal REM-sleep behaviors and
anosmia. Overall, the neuropsychological profile of PDD
includes bradyphrenia and significant executive and visuospa-
tial impairments (Ballard et al., 2013). Executive dysfunction—
including impairments in decision-making and planning—may
be among the earliest signs of cognitive decline in PDD. Lan-
guage problems such as decreased verbal fluency, poor com-
prehension, and difficulty producing complex sentences can
occur frequently. Regardless of domain, patients with Parkin-
son disease generally perform better on neuropsychological
testing than Alzheimer patients. It has been noted that the
visuospatial deficits common in Parkinson disease may
account for some impairments observed on neuropsychologi-
cal testing (Toner et al., 2012). Psychiatric manifestations,
including mood disturbances, anxiety, apathy, and psychosis,
are also common in PDD (Ballard et al., 2013). Similar psy-
chiatric problems are also observed in patients with DLB, with
the most striking symptom in these patients being well-formed
visual hallucinations (Weintraub et al., 2012). These halluci-
nations are typically not frightening to the patient. They can
be any visual object but often take human or animal form.
Severity of visuospatial deficits predicts likelihood of visual
hallucinations (Perri et al., 2014). Importantly, both PDD and
DLB patients have strong adverse reactions to antipsychotic
medications that make their use contraindicated in this group.
In addition to characterizing the cognitive sequelae of PD
and the effects of pharmacological treatment, neuropsycholo-
gists are often called upon to evaluate candidates for deep
brain stimulation (DBS) of the subthalamic nucleus. DBS in
this region is known to result in potential global cognitive
decline (Witt et al., 2013) in preoperatively intact patients and
may be contraindicated in PDD or DLB patients who are
already cognitively impaired. Furthermore, older PD patients
with MCI prior to DBS may be at greater risk for postoperative
declines (Halpern et al., 2009).
Huntington Disease
The diagnosis of Huntington disease (HD) is dependent upon
the manifestation of an unequivocal extrapyramidal move-
ment disorder, although cognitive (Paulsen et al., 2014) and
behavioral deficits can be the most debilitating aspect of the
disease, place the greatest burden on HD families (Nehl and
Paulsen, 2004), and can be present in the absence of motor
dysfunction (Paulsen and Long, 2014) (see Fig. 43.6 and
Fig 43.7). HD is characterized by insidious and progressive
cognitive, emotional-behavioral, and motor symptoms. The
symptom presentation for any given individual can include
one or all of the HD domains. Cognitive symptoms can
include forgetfulness, inattention, executive dysfunction,
slowed psychomotor speed, negative emotion recognition,
and deficits in time discrimination and production. Emotional-
behavioral symptoms may include apathy, depression, aggres-
sion, disinhibition, anxiety, and obsessive and perseverative
behaviors. In response to findings illustrating the prominence
of cognitive outcomes in HD, Brooks and Dunnett (2013)
reviewed animal models of basal ganglia cognitive impair-
ments suggesting that translation of cognitive outcomes may
provide readouts that better track disease for interventional
studies. Additionally, readers are referred to new reviews that
provide excellent characterization of the human cognitive
524 PART II Neurological Investigations and Related Clinical Neurosciences

60

55

Symbol Digit Modalities Test

Group
50
Control
Low
Medium
45 High

40

35
0 1 2 3 4 5 6 7 8 9 10
Year

330
320
310
300
290
Speeded Tapping

Group
280
Control
270 Low
Medium
260
High
250
240
230
220
210
0 1 2 3 4 5 6
Year
Fig. 43.6 The upper graph shows the fitted curves (based on a linear mixed effects regression fitted model) of the Symbol Digit Modalities Test
by year for progression groups (Control, Low probability of near-future diagnosis, Medium probability, High probability). The lower graph shows
the fitted curves for speeded tapping. (From Journal of Neurology, Neurosurgery & Psychiatry, Paulsen, J.S., Smith, M.M., Long, J.D.,
PREDICT-HD Investigators and Coordinators of the Huntington Study Group, 84, 1233–1239, 2013, with permission from BMJ Publishing
Group Ltd.)

profile of HD (Dumas et al., 2013; O’Callaghan et al., 2014).
Efforts to determine the best candidate biomarkers are
ongoing.
In a large study of over 1000 research participants with the
gene expansion for HD, longitudinal cognitive declines were
evident in every test examined (19 tests), with the earliest
declines in the Symbol Digit Modality Test, the Smell Identi-
fication Test, the Stroop Word Identification Test, and the Trail
Making Test evident in a subgroup decades before motor diag-
nosis (Paulsen et al., 2013, 2014). All cognitive measures
examined showed significant changes in the subgroup with
the greatest proximity to motor diagnosis, whereas nine of
ten cognitive measures showed significant change in the inter-
mediate group (7 to 15 years from motor diagnosis). The
cognitive profile of HD is characterized by bradyphrenia,
impairments in executive function, attention, working
memory, emotion recognition, smell identification, and the
perception and production of time (Paulsen et al., 2013, 2014;
Rowe et al., 2010). One author proposed that poor attention
in HD may be due to an inability to automatize task perform-
ance, which results in the diversion of cognitive resources
to tasks that are normally automatic in healthy people
(Thompson et al., 2010). This premise is consistent with the
well-known deficit HD patients have with procedural learning
and memory (Holl et al., 2012) as well as automated behavior
such as the Stroop reading task. Memory problems are also
frequently reported by patients with HD and their families.
Objective deficits in learning and memory have been widely
 Neuropsychology 525

10 TMS 43
9
8
7
6
CSF
5
4 DYS
3
SD

2 O-C
1
0
–1
–2
SDMT
–3 SMELL
–4 LOW MEDIUM HIGH TFC
PUTAMEN
–5
100 150 200 250 300 350 400 450 500 550 600
CAPD

Fig. 43.7 Data-derived model of premanifest Huntington disease. Scaled fitted spline curves of key variables plotted over CAPD (CAG-
corrected age). Blue colors indicate variables that decrease and red colors indicate variables that increase. Vertical axis is in standard deviation
(SD) units. TMS, Total motor score; CSF, cerebral spinal fluid; DYS, dysrhythmia; O-C, obsessive–compulsive; SDMT, Symbol Digit Modalities
Test; SMELL, University of Pennsylvania Smell Identification Test (UPSIT); TFC, total functional capacity. (From Paulsen, J.S., Long, J.D., Johnson,
H.J., et al., the PREDICT-HD Investigators and Coordinators of the Huntington Study Group, 2014, Clinical and biomarker changes in premanifest
Huntington disease show trial feasibility: a decade of the PREDICT-HD study. Front Aging Neurosci 6, 78.)

reported, with these patients displaying a typical subcortical
profile of reduced learning with difficulty in retrieval and
improvement with recognition cues. Additionally, emotion
recognition declines regardless of modality (i.e., facial expres-
sion, verbal intonation), especially for fear, anger, and disgust
(Brune et al., 2011; Eddy et al., 2011; 2012; Johnson et al.,
2007; Snowden et al., 2008). The cognitive processing retarda-
tion is a sensitive (but nonspecific) indicator of dysfunction
in most diseases of the basal ganglia and some recent authors
have attempted to disintegrate cognitive processing speed,
motor slowing, and executive abilities (Maroof et al., 2011;
O’Rourke et al., 2011). Similarly, efforts have been made to
separate the syntax deficits from working memory in HD
(Sambin et al., 2012) to determine whether difficulties in lan-
guage processing may be secondary to word retrieval, working
memory, or a direct syntactical role of the striatum.
Multiple Sclerosis
Estimates of the prevalence of cognitive disability in multiple
sclerosis (MS) range between 40% and 50% in community-
based samples (Amato et al., 2006; Jonsson et al., 2006) to
more than 55% in clinical settings (Feinstein, 2004). Slowed
processing speed is perhaps the most prominent neuropsycho-
logical deficit in MS (Parmenter et al., 2007; Rao et al., 1991).
A variety of other cognitive declines observed in MS include
working memory, cognitive flexibility, inhibition, problem
solving, attention, verbal fluency, and spatial reasoning. Con-
frontation naming and verbal comprehension are generally
not affected in MS, and dementia is uncommon (Rao et al.,
1991). Consistent correlations between brain lesion magni-
tude and severity of cognitive dysfunction have also been
reported (Benedict et al., 2002).
A distinct cognitive profile is difficult to establish in MS,
since individual differences in the microscopic and macro-
scopic pathology of the disease lead to tremendous variability
depending on the location of sclerotic plaques (e.g., subcorti-
cal white matter versus spinal cord). Furthermore, the cogni-
tive sequelae of MS are complicated by the fact that deficits
vary across the different subtypes of MS, with progressive sub-
types performing worse over time (Huijbregts et al., 2006).
Although deficits vary, the typical cognitive profile of MS has
been described as a subcortical one, similar to PD or HD,
given the deficits outlined above. Depression and other distur-
bances of emotional functioning occur in nearly half of these
patients (Siegert and Abernethy, 2005). Psychiatric distur-
bances have also been linked with additional cognitive disa-
bility (Feinstein, 2004). Depression in MS has also been found
to be related to cognitive deficits, particularly speeded atten-
tion and executive functioning (Arnett et al., 2002). Recent
updates in MS have indicated that subgroups may exist in MS
and that new measures may be beneficial to treatment assess-
ment, but neuropsychological assessment has not yet proven
effective (Filippi and Rocca, 2013; Rudick, 2012).
Epilepsy
Epilepsy, or seizure disorder, is well known to result in signifi-
cant psychiatric and cognitive comorbidities. Traditionally,
these comorbid issues were viewed as epiphenomena of epi-
lepsy but the emerging view is that there is a bidirectional
relationship (Helmstaedter et al., 2014). New evidence sug-
gests that neuropsychological deficits in epilepsy are likely
related to a variety of factors such as the cumulative effect on
the brain of seizure disorder over time or interictal activity, the
results of which have been called epileptic encephalopathies.
Many of the antiepileptic drugs (AEDs) are also known to have
negative cognitive side effects. Neuropsychological impair-
ments in epilepsy are generally underappreciated. The cogni-
tive effects of epilepsy are unique for each patient, because
there is no single cognitive profile associated with any
epilepsy subtype (e.g., partial seizures, complex partial,
526 PART II Neurological Investigations and Related Clinical Neurosciences
primary generalized). This is largely due to the fact that epi-
lepsy is not a single disease process but rather any number of
etiologies affecting different cortical substrates that result in
seizures (Korczyn et al., 2013). Earlier onset of seizures is
associated with increased risk of general cognitive decline and
significant discrepancies in intellectual functions (van Iterson
et al., 2014). Cognitive deficits also vary according to the loca-
tion of the seizure foci, frequency of seizures, duration of
seizure disorder, age of onset, and antiepileptic drug effects
(Jokeit and Schacher, 2004; Lee and Clason, 2008). Regardless
of whether a seizure is part of a single idiopathic event or a
chronic epileptic disorder, the abnormal electrical activity pro-
duced during the ictal period is usually associated with cogni-
tive and psychiatric changes. In chronic conditions, residual
interictal alterations in cognition and mood also occur. Given
the heterogeneity of cognitive deficits in epilepsy, neuropsy-
chological testing is particularly indicated to provide an accu-
rate characterization of patients’ unique cognitive deficits.
Memory deficits are one of the most common clinical
manifestations of cognitive impairment in epilepsy, likely due
to the high incidence of seizures originating in the medial
temporal lobes. There is general support for left temporal
lobe epilepsy (TLE) resulting in verbal memory impairment
(Brown et al., 2014), but there are mixed findings regarding
right TLE specifically resulting in visual memory impairments.
There is evidence that left TLE results in greater disruption of
cortical connective networks than right TLE and this may
support greater memory deficits in left TLE than right TLE
(Zulfi et al., 2014). In addition to memory, general intellectual
functioning can be impaired. More specifically, executive func-
tions and visuoconstructional abilities can be mildly impaired
in both left and right TLE compared to healthy individuals,
with earlier age of onset being associated with worse deficits,
but right TLE was specifically impaired for psychomotor speed
and higher level cognitive estimation abilities as well (Parente
et al., 2013) if the focus of seizure activity is in the language-
dominant hemisphere. Postictal language recovery is also
affected by seizure origin and generalization in frontal lobe
epilepsy patients. Patients with seizures originating in the left
frontal lobe and spreading to the language-dominant tempo-
ral lobe have a slower recovery than their counterparts with
either right frontal lobe seizures or seizures confined to the
frontal lobe only (Goldberg-Stern et al., 2004). Executive
functioning is primarily affected in frontal lobe epilepsy (FLE),
especially if seizures originate in the left frontal lobe. However,
executive dysfunction may not be specific to FLE, and TLE
patients can perform similarly on executive measures (Longo
et al., 2013). It should be noted that many forms of epilepsy
are thought to have little to no progressive effect on cognitive
functions such as benign rolandic, absence, and juvenile myo-
clonic epilepsies, to name just a few (Avanzini et al., 2013).
Neuropsychological evaluation is an integral part of neu-
rosurgical treatments for pharmaco-resistant epilepsy (Helm-
staedter, 2004). Preoperative evaluations and Wada testing
provide useful information about the localization and later-
alization of seizure-induced cognitive impairment. Assess-
ment of patients’ cognitive reserve can be useful for predicting
postoperative outcomes (e.g., better memory performance at
baseline usually means greater memory loss after resection).
Postoperative testing is also useful for treatment planning and
quality control following resection, and ultimately refines the
effectiveness of surgical procedures. It should be noted that
the evidence is mixed whether resective surgery significantly
improves cognitive functioning (Hallböök et al., 2013; Smith
et al., 2014). Neuropsychological test batteries for surgery
candidates are usually very extensive. Given the frequency of
temporal lobectomy surgery relative to other procedures,
most batteries are heavily focused on assessing memory and
language functioning given the deleterious effects these
areas can have on quality of life impairments, but executive
functioning, attention, cognitive efficiency, and visuospatial
abilities are also examined thoroughly. Wada testing is still
considered the gold standard for determining how the non-
epileptic hemisphere will function in isolation but fMRI is
gaining acceptance as an alternative for language mapping
(Barnett et al., 2014). Other indications include early seizure
onset (due to the increased potential for cortical reorganiza-
tion) and left-handedness. Ultimately, neuropsychological
assessment in Wada testing can help reduce the potential
for postsurgical disconnection syndromes, aphasia, and
functional loss due to unexpectedly poor contralateral
compensation.
In addition to the cognitive aspects of epilepsy, psychiatric
and behavioral disorders are prevalent (McCagh et al., 2009),
though they tend to not be severe. Depression is the most
common mood disorder, with 42% of epilepsy patients report-
ing symptoms (Helmstaedter and Witt, 2012). Rates of depres-
sion do not differ between TLE and FLE, though TLE patients
may be more neurotic and introverted. Symptoms of depres-
sion also appear to be associated with the future onset of
focal seizures in some patients. TLE patients with comorbid
depression or interictal psychosis have more complicated
courses and neuropathological differences than TLE patients
without psychiatric comorbidities (Kandratavicius et al., 2012).
Increased anxiety in patients does not appear to be directly
associated with the neuropathology of epilepsy, but rather the
unpredictability of seizures, social consequences of epilepsy,
and societal stigmatization (Mensah et al., 2007). There is also
the phenomenon known as forced normalization where the
successful pharmacological management of seizures results
in onset of psychotic symptoms. It is hypothesized that the
uncontrolled seizures acted as a type of electroconvulsive
therapy to suppress a pre-existing psychotic condition.
A complicating issue in identifying cognitive and behavio-
ral deficits associated with epilepsy is the independent effect
antiepileptic drugs (AEDs) commonly have on neuropsycho-
logical functioning (Carreno et al., 2008). Memory, executive
functioning, and processing are the most frequently affected
by both classic and new AEDs, with older drugs such as topira-
mate having worse cognitive side effects than newer medica-
tions (Helmstaedter and Witt, 2013). The varying effects these
medications have on cognition must be weighed against the
benefits of minimizing the frequency and severity of seizures.
An emerging area where neuropsychology is significantly con-
tributing is the diagnosis and treatment of psychogenic
nonepileptic seizure disorder (PNES). PNES is a conversion
disorder in which the patient has the behavioral manifesta-
tions of a seizure without any accompany epileptiform activ-
ity. The typical PNES case is a young adult female with lower
intellectual functioning, a history of trauma, and possibly
another psychogenic disorder that tends to experience psycho-
genic seizures when under stress. At least 10% of these patients
also have EEG diagnosed seizure disorder. While the gold
standard for diagnosing PNES is video electroencephalogra-
phy, this is not always available and neuropsychological
testing is recommended as part of a staged comprehensive
diagnostic process for PNES (LaFrance et al., 2013).
Traumatic Brain Injury
Traumatic brain injury (TBI) is one of the most common
forms of neurological damage in the United States, resulting
in more than 53,000 deaths a year, particularly in young males
(Coronado et al., 2011). In cases of moderate to severe
injury, impairments in several cognitive domains can occur,
depending on what caused the injury (i.e., blunt force
 Neuropsychology 527

versus projectile), the severity of the injury, site of the lesion,
premorbid cognitive and personality factors, and treatment
received after the injury. Advances in knowledge regarding the
various cognitive sequelae of TBI have allowed for better diag-
nostic clarity. Beyond the established methods for staging the
severity of TBI (e.g., length of loss of consciousness or post-
traumatic amnesia, Glasgow Coma Scale [GCS]), neuropsy-
chological testing can be used to increase diagnostic accuracy
by measuring the classic cognitive deficits that result from
head injury.
Neuropsychological testing is frequently indicated in TBI,
because the range of deficits following parenchymal damage
can vary significantly. Damage to the frontal cortex is common
due to the morphology of the skull and frequency of anterior
impacts during falls and motor vehicle accidents. For example,
a circumscribed TBI involving the ventromedial prefrontal
cortex can produce changes in social cognition and emotion
recognition that result in behavioral issues (Spikman et al.,
2013) associated with misinterpretation of social cues or
lowered frustration tolerance. There is also evidence of a
general pattern of executive impairment following TBI result-
ing from disruption of white matter structural networks in the
brain (Caeyenberghs et al., 2014). This combination of social,
behavioral, and executive dysfunction is often called the
frontal lobe syndrome and is common in TBI. A less severe
TBI might only lead to subtle deficits in attention or process-
ing speed (Rackley et al., 2012). Lingering fatigue is also a
common comorbidity (Zgaljardic et al., 2014). Despite indi-
vidual clinical variability, several common neurobehavioral
sequelae of moderate to severe TBI can be identified (Table
43.5). Cognitive recovery is protracted for moderate to severe
TBIs, with most improvements occurring in the first year but
measurable recovery of cognitive functioning still occurring
several years after the injury. However, even after a prolonged
length of time, individuals do not necessarily return to prein-
jury levels.
In addition to moderate and severe TBI, the cognitive
sequelae of concussion or mild TBI (mTBI) have become a
major focus of research and public education campaigns with
particular emphasis on sports-related concussion and blast-
related mTBIs sustained by soldiers in Iraq and Afghanistan.
For mTBI, there are generally two categories: uncomplicated
with a recognized change in mental status generally less than
20 minutes and complicated where there is an acute change
in mental status and visible structural abnormalities on neu-
roimaging. While complicated mTBI has traditionally been
believed to result in worse outcomes, research has demon-
strated there is no real difference between complicated and
uncomplicated mTBI on measures of cognitive functioning
and self-reported symptoms at a month post-injury (Iverson
et al., 2012a; Lange et al., 2012). Additionally, though clinical
lore stipulates that there is increasing neurologic damage with
a history of multiple concussions, there is mixed evidence
supporting this proposition (Iverson et al, 2012b), though a
history of more severe TBI may negatively affect health out-
comes (Dams-O’Connor et al., 2013). The latest consensus
statement on treatment of concussion (McCrory et al., 2013)
states that 90% of adult mTBIs resolve within 10 days, that
TABLE 43.5 Common Neurocognitive Sequelae of Moderate to
Severe Traumatic Brain Injury 43
Cognitive domain Clinical manifestation of impairment
Attention Difficulty with sustained attention
Poor concentration
Psychomotor impersistence
Memory Problems with acquiring and retaining new
verbal or nonverbal information
Problems in retrieving verbal and nonverbal
memories
Speed of information Slowed sensorimotor skills and information
processing processing
Executive functioning Problems in convergent and divergent
reasoning
Poor judgment
Difficulty planning
Problems in self-monitoring and self-
correcting behavior
Awareness of Difficulty recognizing deficits
symptoms Unrealistic expectations concerning the
recovery of functions
Problems related to poor treatment
compliance
Language and Problems in word comprehension
communication Impaired reading, spelling, and writing ability
Tendency to become fragmented in free
speech
Integrative functions Problems in adequate or time-efficient
execution of various perceptual-motor-
spatial-sequential tasks
neuropsychological assessment is recommended to assist with
management, and that while acute rest is recommended fol-
lowing mTBI, there is limited research support for the efficacy
of this intervention. Comparing TBI to mTBI, executive func-
tioning, attention, processing speed, and memory are the most
common deficits while mTBI typically results in no lingering
deficits (Jamora et al., 2012; Vanderploeg et al., 2014; Winardi
et al., 2014). The vast majority of mTBI cases will make a full
recovery. Some individuals report a constellation of symptoms
following mTBI that include headaches, fatigue, irritability,
depression, and poor concentration. This is commonly
referred to as the postconcussion syndrome (PCS) and is asso-
ciated with pre-existing mood and anxiety symptoms, as well
as mood changes surrounding the injury, and negative beliefs
regarding cognitive effects of TBI (Kit et al., 2014; Lange et al.,
2014). Treatment for patients with persisting PCS frequently
involves education and setting factual expectations about the
normal course of recovery from their injury and prognosis,
with earlier education leading to generally better outcomes.
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