Neurobehavioral Assessment

NeurobehavioralAssessment

Daniel I. Kaufer, MD, FAAN

ABSTRACTPurpose of Review: This article presents a multidimensional, integrative approachto clinical assessment and management of neurobehavioral disorders.Recent Findings: Behavioral neurology and neuropsychiatry has grown as a subspecialtyalongwith increased recognition of two common brain disorders: dementia and traumaticbrain injury. Alzheimer disease is a highly prevalent dementia and a prototypical mem-ory disorder, which has led to a primary focus on cognitive screening and assessment.By contrast, recent attention concerning possible long-term sequelae of repetitive trau-matic brain injury has emphasized aberrant behavior (eg, depression, impulsivity, aggres-sion). Clinical phenotyping across cognitive and behavioral dimensions, in conjunctionwith advancements in structural and functional neuroimaging, brain electrophysiologictechniques, and molecular genetics, is essential to improve diagnostic precision andtherapeutic targeting along the spectrum of CNS disorders.Summary: All neurologists benefit from honing their clinical skills in neurobehavioralassessment. A systematic approach to cognitive and behavioral assessment increasesdifferential diagnostic specificity, helps focus appropriate therapeutic interventions,and improves the quality of life for patients and their families. This article highlightspractical approaches to neurobehavioral assessment in support of differential diagnosisand therapeutic monitoring in general neurology practice.

Continuum (Minneap Minn) 2015;21(3):597–612.

INTRODUCTIONThe seeds of contemporary cognitiveand behavioral neurology arose abouta half-century ago in the fertile soil ofBoston led by Norman Geschwind. Thisrenaissance in behavioral neurologyadvanced work from the middle to late19th century, first in aphasiology (Brocaand Wernicke) and later in dementia (ie,Pick and Alzheimer). The necessity of adetailed neurologic and neurobehavioralexamination accrued from a forced de-pendence on inferential data in the ab-sence of direct visualization of the brain.Over the last several decades, brain imag-ing has revolutionized the daily practiceof neurology and is on the cusp of advanc-ing structural, functional, and moleculardiagnostic tools that will marry clin-ical diagnostic assessment with objec-

tive biomarker data in dementia, traumaticbrain injury, and other neuropsychiatricdisorders. In current neurology practice,cognitive, functional, and behavioral as-sessment is far from standardized. In atertiary memory disorder clinical practicesetting, there is much greater diagnosticyield from obtaining a detailed and com-prehensive history than from ordering abattery of esoteric tests. Accordingly, thisarticle focuses on the basic elements of acomprehensive neurobehavioral assess-ment that are amenable to general neu-rology practice settings.

HISTORYThe primary focus of clinical neurobe-havioral assessment is a change from aprevious level of functioning, which in-cludes cognitive and functional abilities,

Address correspondence to DrDaniel I. Kaufer, CB 7025,3129 POB, University ofNorth Carolina at Chapel Hill,Chapel Hill, NC 27599,[email protected].

Relationship Disclosure:Dr Kaufer serves on the boardof Alzheimers North Carolinaand the scientific advisorycouncil of the Lewy BodyDementia Association, Inc;served as a symposium directorfor theAmericanNeuropsychiatricAssociation’s Annual Meeting;provides study design supportfor Johnson & JohnsonServices, Inc; and providedindependent medical reviewand deposition for HensonFuerst.

Unlabeled Useof Products/InvestigationalUse Disclosure:Dr Kaufer reports no disclosure.

* 2015, American Academyof Neurology.

Supplemental digital content:Direct URL citations appear intheprinted text and areprovidedin the HTML, PDF, and app ver-sions of this article.

597Continuum (Minneap Minn) 2015;21(3):597–612 www.ContinuumJournal.com

Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

mood, emotional responsiveness, andsocial behavior. The clinical history isoften the most critical data source for aneurobehavioral evaluation and typicallyrequires an informant who knows the pa-tient well in order to ensure an accuraterendering. Knowing the reason for theevaluation helps determine strategy re-garding how to engage the patient andinformant. For example, a patient who isunaware that he or she is being evaluatedfor amemory problem needs to be inter-viewed (and debriefed) differently fromone who is concerned about his or herown memory functioning. In the formercase, it is often helpful to speak with theinformant separately or, alternatively, al-low the informant an opportunity todiscretely communicate sensitive infor-mation. Although informants generallyprovide a reliable history, at times theirfrustration and distress may lead to theiroverstating symptom severity in patients.In such circumstances it is often produc-tive to focus attention on helping themcope with caregiving demands. Rarely,informants may have nefarious financialmotives for exaggerating clinical symp-toms and associated disability in orderto obtain guardianship. Conversely, pa-tients with either depression or morbidanxiety may be hypercritical of their self-perceived cognitive status and exagger-ate cognitive changes.

A marked discrepancy between a pa-tient’s and informant’s portrayal of clin-ical cognitive changes sets the stage forclinical hypothesis testing based on thedegree of agreement with formal cog-nitive testing. For example, if aninformant’s report of the patient’s deficitsis supported by cognitive testing and thedeficits reported are greater than the pa-tient’s self-report, it is reasonable to inferthat the patient has impaired awarenessof his or her deficits. This finding is sug-gestive of a neurodegenerative disordersuch as Alzheimer disease or traumaticbrain injury, where deficit awareness is

often compromised.1 Impaired aware-ness of cognitive deficits is difficult tomeasure clinically but has important im-plications for a patient’s ability to complywith appropriate restrictions on drivingor accept supervision for activities suchas managing finances. Conversely, a pa-tientmay report a greater cognitive symp-tom burden than a reliable informant,with cognitive testing aligning morewith the latter’s assessment. This profileis more likely to be associated with amood disturbance, anxiety symptoms,or elevated level of stress. Although theterm ‘‘worried well’’ is sometimes usedin this context, in certain cases it may beappropriate to pursue a more in-depthneuropsychological evaluation to en-sure that early signs of a neurocognitivedisorder are not being missed. This isparticularly true in highly educated indi-viduals, where ‘‘normal’’ performance onstandard cognitive screening tests maybe misleading.

Other historical data may help elab-orate a differential diagnosis, includingtemporal onset and course, hereditaryfactors, and comorbid medical condi-tions (Table 1-1). A positive family his-tory deserves close attention, particularlyif autosomal dominant inheritance issuspected. Within a given family, a widerange of phenotypic variability may beseenwith autosomal dominantmutations.For example, an autosomal dominantmu-tation on chromosome 9 associated withthe expansion of a hexanucleotide repeat(chromosome 9 open reading frame 72[c9orf72]) is the most common causeof both familial ALS and familial fronto-temporal degeneration.2 Affected mem-bers within a family can exhibit clinicalfeatures on a spectrum between thesetwo disorders. Sleep disturbances suchas insomnia, restless leg syndrome, andsleep apnea are common comorbiditiesin neurobehavioral disorders, and rapideye movement (REM) behavior disor-der is a hallmark of synucleinopathies.3

KEY POINTS

h The primary focus ofclinical neurobehavioralassessment is achange from a previouslevel of functioning,which includes cognitiveand functional abilities,mood, emotionalresponsiveness, andsocial behavior.

h A marked discrepancybetween a patient’s andinformant’s portrayal ofclinical cognitive changessets the stage for clinicalhypothesis testingbased on the degreeof agreement withformal cognitive testing.

h Impaired awareness ofcognitive deficits isdifficult to measureclinically but hasimportant implicationsfor how challengingcomplying withappropriate restrictionsor supervision foractivities, such as drivingand managing finances,can be for the patient.

598 www.ContinuumJournal.com June 2015

Neurobehavioral Assessment


A history of mild repetitive traumaticbrain injury or concussions draws scru-tiny as a risk factor for a later-developingdementia syndrome: chronic traumaticencephalopathy.4 Head injuries associ-ated with falls, automobile or bicycleaccidents, recreational activities (eg, skiing,sledding), military activities, sports-relatedinjuries, and other home- or work-relatedaccidents may cause or exacerbate neu-rologic disorders such as headaches orseizures. Documenting a careful historyof head injuries and their associated acute(eg, alteration or loss of consciousness)and chronic (eg, headaches, vertigo) ac-

companiments will likely play an increas-ing role in understanding complexrelationships betweenmechanical braininjury and neurodegenerative disorders,such as frontotemporal degenerationand ALS.

CLINICAL ASSESSMENTA hallmark of neurobehavioral assess-ment is its multidimensional and inte-grative nature. Among dementias, thehigh prevalence of Alzheimer disease andits cardinal manifestations of short-termmemory and other cognitive disturbancesweight clinical assessment heavily toward

KEY POINTS

h Documenting a carefulhistory of head injuriesand their associatedacute (eg, alteration orloss of consciousness)and chronic (eg,headaches, vertigo)accompaniments willlikely play an increasingrole in understandingcomplex relationshipsbetween mechanicalbrain injury andneurodegenerativedisorders, such asfrontotemporaldegeneration and ALS.

h A hallmark ofneurobehavioralassessment is itsmultidimensional andintegrative nature.

TABLE 1-1 Diagnostic Elements in the Clinical History

b Initial/Concomitant Symptoms

Cognitive: Memory, language, visuospatial, executive (eg, judgment)

Functional: Work, managing finances, driving, shopping, household chores

Neuropsychiatric: Apathy, depression, anxiety, psychosis, impulsivity, disinhibition

Motor: Tremor, rigidity, incoordination, balance difficulty, dysarthria, weakness

b Temporal

Onset: Abrupt, subacute, insidious

Course: Static, progressive, fluctuating, improving

b Traumatic

Altered consciousness (eg, dazed, confused, groggy, ‘‘saw stars’’)

Loss of consciousness (duration)

Amnesia (retrograde/anterograde)

Neurologic sequelae (eg, headache, nausea, vertigo, vision change, sleep alteration)

b Individual

Age, gender, cultural background

Educational level, learning disability, premorbid personality

Social circumstances, financial resources, occupational activities

b Genetic

Family history suggesting autosomal dominant inheritance

Familial cases suggesting polymorphism association (eg, apolipoproteinE4 [APOE] in Alzheimer disease)

b General

Medical conditions (eg, hypothyroidism, vitamin deficiency, peripheralvascular disease)

Neurologic conditions (eg, transient ischemic attack, stroke, seizure,head trauma)

Sleep disturbances (eg, sleep apnea, insomnia, sleep-associatedmovement disorder)



cognitive symptoms. However, recentlyrevised diagnostic criteria for Alzheimerdisease now recognize noncognitive symp-toms such as depression and apathy asprimarydiseasemanifestations,5 and otherneuropsychiatric symptoms are often themost prominent changes in disorderssuch as dementia with Lewy bodies andfrontotemporal degeneration. Moreover,recent dementia quality measures devel-oped by the American Academy of Neu-rology (AAN) and other stakeholdershighlight a broad range of clinical param-eters that support comprehensive care toimprove clinical outcomes (Table 1-2).6

Among these 10 quality measures,which are used as part of Physician Qual-ity Reporting System (PQRS) and Mean-ingful Use (MU) requirements, numbers2 to 6 under Evaluation and TreatmentStrategies emphasize the multidimen-sional aspects of care. In addition to thestandard cognitive assessment, there isalso the provision for neuropsychiatricand functional assessments, as well as

screening for depression and managingneuropsychiatric disturbances. Moreover,other AAN quality measures for Parkinsondisease7 and ALS8 include provisions forcognitive and psychiatric symptom assess-ment. The former alsohighlights assessingsleep-wake disturbances such as REM be-havior disorder anddaytime somnolence ascommonassociated clinicalmanifestations.

Cognitive AssessmentTheexaminer can evaluate cognitive symp-toms both informally through a clinical in-terview and objectively by assessment withneurocognitive testing. The Ascertain De-mentia 8 (AD8), an 8-item measure ofinformant-reported changes in cognitivefunctioning, is a well-validated and widelyused historical cognitive screening instru-ment (Supplemental Digital Content 1-1,links.lww.com/CONT/A140).9

The AD8 was derived from semi-structured interviews involving a largeresearch data set and includes histo-rical features that were most strongly

TABLE 1-2 Dementia Quality Measures from the American Academyof Neurologya

b Evaluation and Treatment Strategies

Measure 1: Staging of Dementia

Measure 2: Cognitive Assessment

Measure 3: Functional Status Assessment

Measure 4: Neuropsychiatric Symptom Assessment

Measure 5: Management of Neuropsychiatric Symptoms

Measure 6: Screening for Depressive Symptoms

b Safety Issues

Measure 7: Counseling Regarding Safety Concerns

Measure 8: Counseling Regarding Risks of Driving

b Patient-Centered Care Strategies

Measure 9: Palliative Care Counseling and Advance Care Planning

Measure 10: Caregiver Education and Support

a Detailed information on these measures can be found atwww.aan.com/uploadedFiles/Website_Library_Assets/Documents/3.Practice_Management/2.Quality_Improvement/1.Quality_Measures/1.All_Measures/Dementia%20measure%20set%202014%20transition.pdf.




http://links.lww.com/CONT/A140

http://www.aan.com/uploadedFiles/Website_Library_Assets/Documents/3.Practice_Management/2.Quality_Improvement/1.Quality_Measures/1.All_Measures/Dementia%20measure%20set%202014%20transition.pdf



associated with Alzheimer disease. An in-formant typically completes the screeningquestions, although patients can self-report if no informant is available.10 TheAD8 content includes memory, orienta-tion, and other faculties, including exec-utive, motivation, praxis, and functionalability (eg, managing money). A score of2 or higher (out of 8 total items) on theAD8 is highly predictive of dementia (sen-sitivity 0.85, specificity 0.86). Inquiring aboutthe patient’s ability to manage financesdeserves special attention because fi-nancial capacity is often affected early inthe course of mild cognitive impairment(MCI), Alzheimerdisease, andother formsof dementia, and the potential conse-quences of poor financial managementcan be devastating.11

Performing cognitive testing in clin-ical practice is a challenge that varies inproportion to the length and complex-ity of required testing and availabletesting resources. The standard single-system neurologic examination generallycovers level of arousal, attention, orien-tation, speech, language, recent and remotememory, and general fund of knowledgeand is useful only for general screening.Thesedatashouldalsobesupplementedbyobservations regardingaffect (eg,blunted,expansive,pseudobulbar),moodstate (eg,hypomanic, sad, anxious), motivation(eg, apathetic, disinhibited), distractibil-ity, fidgetiness, restlessness, persever-ation, obsessive thinking, paranoid orpsychotic thinking, impulsivity, or otherbehavioral phenomena noted to be pres-ent. Beyond this, clinical cognitive assess-ment is used for a variety of purposes,ranging from screening for possible de-mentia using tests such as the Mini-Cog,12

to performing a comprehensive neuro-psychological evaluation. The latter typ-ically involves several hours of testingusing age- and education-adjusted nor-mative data, yielding a quantitative psy-chometric assessment. Behavior andpsychological rating scales are also often

included to evaluate for depression,anxiety, and effort (eg, malingering).

All screening cognitive tests havelimitations and require specific knowl-edge regarding test administration andscoring in order to be valid. More de-tailed and sophisticated cognitive testsgenerally require more training of theexaminer. A screening test such as theMini-Cog may yield a negative screenbased on the patient recalling all threewords, yet indicate a potential problemin a patient with, for example, Parkinsondisease, who may have difficulty draw-ing a clock. When administering cogni-tive tests, it is crucial to document anypotential confounds to the validity of thetest, such as hearing or vision problems,motor dysfunction, language barrier tounderstanding instructions, and psy-chological factors such as effort, moti-vation, depression, and anxiety.

A fundamental limitation regarding clin-ical cognitive testing is that it is generallynot reimbursable. One exception is toadminister a battery of cognitive tests andbill as a separate neurobehavioral statusexamination (Current Procedural Termi-nology [CPT] code 96116). This approachrequires a physician or advanced practicepractitioner to conduct most of the test-ing, which may not be feasible in manyclinical practice settings. Another alter-native is to have an office staff personsupervise testing the subject in a computer-administered test battery such as CNSVital Signs.13 This assessment consistsof seven neuropsychological tests thatyield five domain scores:memory, psycho-motor speed, reaction time, cognitiveflexibility, and complex attention, withscaled percentile performance indicesgenerated automatically. While this ap-proach collects data on a battery of testswith minimal supervision, lack of train-ing qualifications and clinical diagnosticstandards for data interpretation currentlylimit its utility. Computer-based test mate-rials offer the prospect of improving

KEY POINTS

h Inquiring about thepatient’s ability tomanage financesdeserves specialattention becausefinancial capacity isoften affected early inthe course of mildcognitive impairment,Alzheimer disease,and other forms ofdementia, and thepotential consequencescan be devastating.

h When administeringcognitive tests, it iscrucial to document anypotential confounds tothe validity of the test,such as hearing orvision problems, motordysfunction, languagebarrier to understandinginstructions, andpsychological factorssuch as effort, motivation,depression, and anxiety.



standardization and scoring of clinicalcognitive testing, which, combined withthe establishment of robust training andapplication criteria, may eventually sup-port higher levels of reimbursement.

The prevailing standard for cognitiveassessment in neurologic practice is toadminister brief cognitive tests suchas the Mini-Mental State Examination(MMSE) or Montreal Cognitive Assess-ment (MoCA).14Y16 The primary aim ofsuch testing is to evaluate cognitive symp-toms reported to be present in dailyactivities, as opposed to screening forcognitive impairment.17 Although theMMSE is the historical gold standardfor clinical cognitive assessment, itwas copyright protected more than25 years after its initial publication andnow requires payment on a per-use basis(www.parinc.com).

Although the MMSE is fairly well suitedto screening for and tracking Alzheimerdisease over time, it is not particularlyuseful for identifying MCI or nonYAlzheimer dementias. However, in de-pressed or disinhibited patients, the con-tent of the sentence they compose (eg,‘‘I amdepressed’’ or ‘‘I love you’’)may, attimes, provide useful diagnostic data.

An extended 50-point version of theMMSE, the Mini-Mental State Examina-tion Extended (MMX), was developed,which requiresminimal additional time,yields standard MMSE scores, and issensitive to MCI and nonYAlzheimerdementias (Table 1-3).18 The additional20 points of the MMX test are derivedfrom a combination of alternate scor-ing criteria and some brief additions(Table 1-4). Alternate scoring involvesscoring the sumof serial 7s subtraction andWORLD backward scores (5 additionalpoints, 10 points total) and using a 4-pointscoring scheme for the intersecting pen-tagon figure (3 additional points, 4 pointstotal). Additional items include addingpen clip or pen holder and watchbandor watch strap to naming (2 additional

points), reproducing the intersectingpentagon figure from memory (4 addi-tional points), and long-delayed spon-taneous recall of the three words withmultiple-choice recognition for any thatare not recalled (6 additional points). Inthe MMX delayed recall/recognition test,2 points are given for each word that isrecalled, and for those that are not, 1 pointis given if correctly identified from amongthree choices. This test may also provideuseful qualitative information to help dis-criminateAlzheimerdiseaseandamnesticMCI from other types of cognitive im-pairment, as these patients also tend todopoorly onmultiple-choice recognitiontesting.

The MoCA is a comprehensive cog-nitive screening test with multiple alter-nate forms and an expanding normativedatabase (mocatest.org). The MoCA issensitive to detecting cognitive distur-bances in Parkinson disease and MCI.19,20

Studies in community samples suggestthat it may have lower specificity in less-educated subjects (ie, high false-positiverates), a trade-off to being sensitive toearly cognitive impairment. A dementiacutoff score lower than 26 may need tobe used in selected clinical populations.21

The five-word recall test is more chal-lenging than the three-word test on theMMSE and includes qualitative mea-sures for cued recall and multiple-choicerecognition. The MoCA represents adistillation of a neurobehavioral statusexamination battery and requires spe-cific training in test administration andscoring. Untrained examiners commonlyfail to instruct the test subject to rem-ember the five-word list after repeat-ing the list over two trials, as this scriptis not printed on the test form. Thisomission invalidates the test as it wasdesigned and may contribute to false-positive results.

The St. Louis University Mental Sta-tus (SLUMS) examination is a 30-pointcognitive screening test that includes a

KEY POINTS

h The Montreal CognitiveAssessment (MoCA)test is a comprehensivecognitive screening testwith multiple alternateforms and an expandingnormative database.

h The MoCA testrepresents a distillationof a neurobehavioralstatus examinationbattery and requiresspecific training intest administrationand scoring.




http://www.parinc.com

http://mocatest.org

five-word memory list and story recall,as well as fluency, orientation, clockdrawing, and other executive cognitivetasks.22 The SLUMS has been shown to

have similar characteristics to the MoCAwith respect to identifying MCI and de-mentia.23 The SLUMS includes a word-based arithmetic problem and paragraph

TABLE 1-3 Brief Cognitive Screening Instruments

Test Format and Content Comments

Mini-Mental StateExamination (MMSE)

30-point scale Old standard assessment forAlzheimer disease, not sensitive tomild cognitive impairment andnonYAlzheimer disease disorders,withdrawn from public domain

Orientation, memory, attention,praxis, language, constructions

Mini-Mental State ExaminationExtended (MMX)

50-point scale (MMSE withan additional 20 points)

Yields standard MMSE with littleeffort, sensitive to mild cognitiveimpairment and nonYAlzheimerdementia, MMSE forms arecopyright protected, requiringpay per use

Constructions, language,verbal/nonverbal memory

Montreal CognitiveAssessment (MoCA)

30-point scale Sensitive to mild cognitiveimpairment and nonYAlzheimerdementia, alternate forms; requirestraining; may see false-positiveresults in subjects with less thana college education

Memory, constructions, executive,visuospatial, language

St. Louis University MentalStatus (SLUMS) examination

30-point scale Word list and paragraph recall,emphasizes practical cognitive functions,belongs to the public domain, alternativeto MMSE

Memory attention, language,praxis, abstraction, calculations

TABLE 1-4 Mini-Mental State Examination (MMSE) Versus the Mini-Mental State ExaminationExtended (MMX)

MMSE (30 Points) MMX (50 Points) Added Points

Alternate scoringMental control WORLD backward or serial

7s subtraction (5 points)WORLD backward and serial7s subtraction (10 points)

+5

Figure copy 0Y1 Point 0Y4 Pointsa +3

AdditionsNaming Pen (1 point)

Watch (1 point)

Pen clip (holder) (1 point)

Watchband (strap) (1 point)

+2

Figure recall NA 0Y4 pointsa +4

Three-word delayedrecall/recognition

NA Spontaneous recall (2 points each)Multiple choiceb (1 point each)

+6

NA = not applicable.a One point for each pentagon, one point if there is any overlap, one point if the overlap is four-sided.b Used only for words not recalled (eg, carrot [choices: celery/carrot/cabbage], robin [choices: robin/sparrow/bluejay], hammer [choices:wrench/screwdriver/hammer]).



recall test that may better reflect real-world functioning (ie, ecological validity).

Single-domain cognitive testsmay beuseful as adjuncts to cognitive screeningor as part of a more comprehensiveneurocognitive evaluation. Clinical testsof attention, memory, language,visuoperceptual, and visuomotor (eg,figure copy) function are generally sen-sitive to corroborating reported deficitsin thesedomains. By contrast, executivedysfunction, which encompasses a widearray of cognitive/behavioral/motor pro-cesses such as working memory, plan-ning, sequencing, and abstract conceptualthinking, may be more challenging to de-monstrate. Fluency testing is a combinedlanguage and executive task that involvesasking subjects to name as many itemsfrom a given class or category as they canin 1 minute using stimuli such as animals(semantic) or a letter (S or D). Semanticfluency is often selectively impaired inAlzheimer disease or the semanticvariant of primary progressive aphasia,whereas selective impairment in letterfluency is more suggestive of frontalsubcortical network dysfunction as seen

in frontotemporal degeneration or de-mentia with Lewy bodies.24,25 For eithertest, unwitting repetitions provide a back-door view of memory function, and strat-egies the patient employs in wordgeneration may paint a portrait of otherhigher cognitive functions as well.

Short forms of the Boston NamingTest are also useful for aphasia screen-ing.26,27 Confrontational naming is usu-ally markedly impaired in the semanticvariant of primary progressive aphasia,where errors typically involve semanticrelatedness (eg, saying airplane forhelicopter). The Northwestern Nam-ing Battery is a more recently devel-oped naming assessment that includesboth verbs and nouns, assesses bothproduction and comprehension, andhas been developed for patients bothpoststroke and with primary progressiveaphasia.28 A brief summary of commonlyused single-domain cognitive tests isshown in Table 1-5.

Functional AssessmentThe assessment of functional abilitiesis indirectly related to specific cognitive

KEY POINT

h Single-domain cognitivetests may be useful asadjuncts to cognitivescreening or as part of amore comprehensiveneurocognitive evaluation.

TABLE 1-5 Single-Domain Cognitive Tests

Domain Test Description (approximate normal range)

Working memory Digit span forward (7 T 2)

Divided attention Digit span backward (6 T 2)

Months in reverse order (15Y20 sec)

Orientation Time (date, month, season, year)

Location (building, floor, city, state)

Fluency Category: number of animals named in 1 min (18 T 6)

Letter: number of S words named in 1 min (12 T 2)

Language (naming) 15-item Boston Naming Test

Constructions Copy cube or intersecting pentagons

Visuomotor Clock drawing (including drawing the hands as 10 minutesafter 11)

Executive Trails B (letter-number tracing), age-dependent

Verbal memory 3Y5 word list (spontaneous/cued recall)




domains and reflects the collective prac-tical impact of cognitive dysfunction.High-level daily functional abilities (instru-mental activities of daily living) includemanaging finances, shopping, operatinga motor vehicle, and performing house-hold chores. Whether or not cognitivesymptoms are clinically significant un-derscores the categorical distinction be-tween dementia and MCI, which can beambiguous at times. The Functional Ac-tivities Questionnaire (FAQ) is a briefinformant-rated 10-item measure of in-strumental activities of daily living thatis part of the uniform data set forAlzheimer disease research centers(Figure 1-1).29 Basic activities of dailyliving such as dressing, bathing, and toi-leting tend to be preserved early in thecourse of dementing disorders but, overtime, become important determinantsof overall care needs and disposition.

Neuropsychiatric AssessmentNeuropsychiatric symptoms overlap withidiopathic psychiatric disorders in con-ditions such as depression, anxiety, andpsychosis, but differ in that they occurby definition in the setting of a neurologicdisorder. Other symptoms such as apa-thy, disinhibition, and agitation typi-cally accompany or are associated withneurobehavioral disorders such as de-mentia and traumatic brain injury. Mooddisturbance may be a primary manifes-tation of neuropsychiatric disorders andis a common comorbidity of neurologicconditions. The term pseudodementia,which refers to cognitive dysfunctionattributed to a mood disturbance, wasused historically as a counterpoint to‘‘true’’ dementia (eg, dementia versuspseudodementia). This wayward con-struct has given way to recent find-ings that depression is an independentrisk factor for dementia. From a clini-cal perspective, it is useful to thinkof depression as a multidimensionalsyndrome with variable features and

severity, as opposed to a conditionthat is either present or absent. Com-ponents of depression include he-donic state (eg, sadness), level of effort/motivation, neurovegetative changes(eg, sleep/appetite), and comorbiditiessuch as anxiety, irritability, and agita-tion. The Patient Health Questionnaire-9 (PHQ-9) (Figure 1-230) and 15-itemGeriatric Depression Scale (GDS-15)(Figure 1-331) are two of the morewidely used scales for clinically assess-ing depression. One recent studyshowed the GDS-15 to be more sen-sitive as a depression screen than thePHQ-9 in a cohort of subjects withParkinson disease.32

The Neuropsychiatric Inventory (NPI)developedbyCummings and colleagues33

is the gold-standard assessment for neu-ropsychiatric symptoms in dementia andhas been widely used as an outcomemeasure in Alzheimer disease clinicaltherapeutic trials. However, as aninformant-based interview, the test isnot well suited for standard clinicalpractice. A derivative clinical form ofthe NPI, the Neuropsychiatric InventoryQuestionnaire (NPI-Q),34 uses a ques-tionnaire format where caregivers rate10 behavioral domains, as well as eatingand sleep-related behaviors, in termsof symptom severity in the patientalong with associated caregiver distress(Supplemental Digital Content 1-2,links.lww.com/CONT/A141). The NPI-Qis also used in multicenter Alzheimerdisease research studies (administeredas an interview to increase data quality)and includes symptoms that aid in thedifferential diagnosis of frontotemporaldegeneration (eg, apathy, disinhibition,aberrant motor behavior, appetite oreating changes) and dementia with Lewybodies (eg, hallucinations, anxiety, andsleep disturbances) (Case 1-1). Neuro-psychiatric symptom burden in subjectswith MCI increases the risk of prog-ressing to Alzheimer disease.35

KEY POINT

h Froma clinical perspective,it is useful to think ofdepression as amultidimensionalsyndrome with variablefeatures and severity, asopposed to a conditionthat is either present orabsent. Componentsof depression includehedonic state (eg,sadness), level ofeffort/motivation,neurovegetative changes(eg, sleep/appetite),and comorbidities suchas anxiety, irritability,and agitation.



http://links.lww.com/CONT/A141

FIGURE 1-1 Functional Activities Questionnaire.

Reprinted with permission from Pfeffer RI, et al, J Gerontol.29

B 1982, Gerontological Society of America. geronj.oxfordjournals.org/content/37/3/323.short.




http://geronj.oxfordjournals.org/content/37/3/323.short

http://geronj.oxfordjournals.org/content/37/3/323.short

FIGURE 1-2 Patient Health Questionnaire-9 (PHQ-9).

Reprinted from Kroenke K, et al. J Gen Intern Med.30

link.springer.com/article/10.1046/j.1525-1497.2001.016009606.x.



http://link.springer.com/article/10.1046/j.1525-1497.2001.016009606.x

FIGURE 1-3 Geriatric Depression Scale: Short Form.

Reprinted from Sheikh JI, Yesavage JA, Clin Gerontol.31




Case 1-1A 68-year-old right-handed man developed cognitive, behavioral, and motor changes over a 1- to 2-yearperiod. His past medical history was notable for obstructive sleep apnea that had been diagnosedapproximately 15 years earlier, and he had used the continuous positive airway pressure (CPAP) machineregularly since then. However, he reported a history of loud snoring for 25 to 30 years prior to being diagnosedwith obstructive sleep apnea. Neuropsychiatric evaluation yielded the diagnoses of bipolar disorder andobsessive-compulsive disorder, which were treated with serial additions of clomipramine, valproic acid, andlamotrigine.Neurologic evaluation revealedgait disturbanceandbrainMRI showedprominent ventriculomegaly,raising the possibility of normal-pressure hydrocephalus (NPH) (Figure 1-4). However, he showed noresponse to either a high-volume lumbar puncture or a subsequent 48-hour lumbar drain procedure.Examination revealed the following: a Mini-Mental State Examination (MMSE) score of 25 out of 30(1 out of 3 recall, 3 out of 5 WORLD, poor pentagon copy), a Mini-Mental State Examination Extended(MMX) score of 38 out of 50, and verbal fluency: animals 17, F-words 7; clock drawing: intact. On theNeuropsychiatric Inventory Questionnaire (NPI-Q) completed by his daughter, the patient reportedlyexhibited moderate symptoms of apathy, euphoria, disinhibition, irritability, and appetite changes (cravingsweets). Neurologic examination was notable for hypomimia, intact extraocular movements, no dysarthria,stooped posture, decreased left arm swing with ambulation, and reduced stride length.

Over the next severalmonths, serialmedication changes includeddiscontinuing clomipramine, valproic acid,and lamotrigine and adding sertraline, resulting in significantly improved motor, behavioral, andcognitive symptoms. He exhibited some residual obsessive symptoms, but was able to resume livingindependently without any appreciable decline for several years.

Comment. This patient was variably diagnosed with a neuropsychiatric disturbance based onprominent changes in behavior and possible NPH based on motor and cognitive signs as well as brainimaging that was suggestive of this disorder. He was duly evaluated for NPH and failed to improve with alumbar drain. His overall presentationmet criteria for behavioral variant frontotemporal degeneration, withcongruent MRI findings. However, his motor dysfunction and cognitive symptoms improved dramaticallywith medication adjustments, suggesting an iatrogenic etiology. The conundrum of this case is why hisMRI appeared so abnormal, particularly suggestive of NPH.

It is noteworthy that obstructive sleep apnea and NPH may have a shared pathophysiologic substrate,with pressure waves associated with obstructive sleep apnea contributing to loss of ventricular complianceseen in NPH. Moreover, repeated episodes of hypoxia and hypercarbia associated with obstructive sleepapnea may cause oxidative stress that preferentially affects frontal and temporal lobe regions that regulatemood, motivation, and executive functions.36

FIGURE 1-4 Imagingof the patient inCase 1-1. Axial fluid-attenuated inversion recovery (FLAIR) MRI showingminimal frontal and temporal lobe atrophy. There is also subcortical atrophy, characterized byenlarged ventricles.



FIGURE 1-5 Neurobehavioral screen.




CONCLUSIONThis review has focused on delineatingthe various elements of a comprehensiveneurobehavioral assessment, including asystematic approach to history takingand involving clinical history assessmentsthat assay cognition, functional abilities,and behavior. An informant generallyprovides these data components due tothe limited reliability of a patient withimpaired memory and insight. The in-struments reviewed use a questionnaireformat that the caregiver can completein the waiting room or while the phy-sician is performing a cognitive assess-ment on thepatient. Conducted in parallel,a comprehensive screening history andgeneral cognitive assessment (which clinicstaff can administer) can be accomplishedin real time prior to, or in conjunctionwith, physician involvement. Althoughthis review covers domain-specific screen-ing questionnaires that are widely usedin research studies, an informal hybridform may be adequate to support clini-cal care (Figure 1-5).

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KEY POINT

h Conducted in parallel,a comprehensivescreening history andgeneral cognitiveassessment (which canoften be administeredby clinic staff) canbe accomplished inreal time prior to, orin conjunction with,physician involvement.



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