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Neuropsychological Neurology

The Neurocognitive Impairments ofNeurological Disorders

Second Edition

NeuropsychologicalNeurologyThe NeurocognitiveImpairments of NeurologicalDisorders

Second Edition

A. J. LarnerConsultant Neurologist

Cognitive Function Clinic

Walton Centre for Neurology and Neurosurgery

Liverpool, UK

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Larner, A. J.

Neuropsychological neurology : the neurocognitive impairments

of neurological disorders / A.J. Larner. 2nd ed.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-107-60760-6 (pbk.)

I. Title.

[DNLM: 1. Nervous System Diseases complications. 2. Cognition Disorders

physiopathology. 3. Neuropsychology methods. WL 140]

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To Thomas and Elizabeth

Disorders of intellect . . . happen much moreoften than superficial observers will easilybelieve.Samuel Johnson: The History of Rasselas, Prince

of Abyssinia (1759)

Contents

Foreword Professor TD Griffiths page xiPreface to the second edition xiiiAcknowledgments xv

1 Cognitive function,neuropsychological evaluation, andsyndromes of cognitive impairment 11.1 Domains of cognitive function 11.2 Neuropsychological assessment 111.3 Syndromes of cognitive

impairment 12References 16

2 Neurodegenerative disorders 232.1 Alzheimers disease (AD) 242.2 Frontotemporal lobar

degenerations (FTLD) 292.3 Motor neuron disorders 402.4 Parkinsonian syndromes 442.5 Prion diseases 51References 54

3 Cerebrovascular disease: vasculardementia and vascular cognitiveimpairment 723.1 Vascular dementia (VaD);

vascular cognitive impairment(VCI) 73

3.2 Strategic infarct dementia;strategic strokes 77

3.3 Subarachnoid hemorrhage (SAH) 793.4 Intracranial vascular

malformations 813.5 Vasculopathies 82

vii

viii Contents

3.6 Other disorders of possiblevascular etiology 87

References 88

4 The epilepsies 974.1 Epilepsy and cognitive

impairment 974.2 Cognitive decline and epilepsy:

shared etiopathogenesis 984.3 Epileptic seizures causing

acquired cognitive impairment 1024.4 Antiepileptic drug therapy

causing cognitive impairment 1034.5 Treatment of cognitive problems

in epilepsy 104References 104

5 Neurogenetic disorders 1105.1 Hereditary dementias 1115.2 Hereditary ataxias 1165.3 Hereditary spastic paraplegia

(HSP) 1205.4 Hereditary movement disorders 1205.5 Hereditary metabolic disorders 1255.6 Hereditary neurocutaneous

syndromes (phakomatoses) 1325.7 Sex chromosome aneuploidies 133References 133

6 Inflammatory, immune-mediated,and systemic disorders 1456.1 Multiple sclerosis (MS) 1456.2 Acute disseminated

encephalomyelitis (ADEM) 1506.3 Neuromyelitis optica (NMO) 1506.4 Neurosarcoidosis 1506.5 Systemic lupus erythematosus

(SLE) 1516.6 Sjogrens syndrome 1526.7 Neuro-Behcets disease 1536.8 Rheumatoid arthritis (RhA) 1546.9 Systemic sclerosis, scleroderma 1546.10 Relapsing polychondritis 1546.11 Cerebral vasculitides 1546.12 Limbic encephalitides 156

6.13 Hashimotos encephalopathy(HE) 157

6.14 Sydenhams chorea; pediatricautoimmune neuropsychiatricdisorders associated withstreptococcal infections(PANDAS) 157

6.15 Histiocytosis 1586.16 Bilateral vestibulopathy 1586.17 Chronic inflammatory

demyelinating polyneuropathy(CIDP) 158

References 158

7 Structural brain lesions 1667.1 Brain tumors and their treatment 1667.2 Hydrocephalic dementias 1697.3 Other structural lesions 172References 173

8 Endocrine, metabolic, andtoxin-related disorders 1778.1 Endocrine disorders 1778.2 Metabolic disorders 1818.3 Toxin-related disorders 184References 187

9 Infective disorders 1939.1 Encephalitides and

meningoencephalitides 1949.2 Meningitides 1979.3 Human immunodeficiency virus

(HIV) and related conditions 1979.4 Other disorders of infective

etiology 199References 201

10 Neuromuscular disorders 20610.1 Myotonic dystrophy 20610.2 Limb-girdle muscular dystrophy

(LGMD) 20710.3 Oculopharyngeal muscular

dystrophy (OPMD) 20810.4 Spinal and bulbar muscular

atrophy (Kennedys syndrome) 208

Contents ix

10.5 McArdles disease 20810.6 Myasthenia gravis 208References 209

11 Sleep-related disorders 21211.1 Sleep-related breathing disorders 21211.2 Central hypersomnias 21511.3 Circadian rhythm sleep disorders 21511.4 Parasomnias 21611.5 Sleep-related movement

disorders 216References 216

12 Psychiatric disorders in the cognitivefunction clinic 21912.1 Delirium 21912.2 Schizophrenia 22012.3 Mood disorders 22012.4 Anxiety disorders 22112.5 Dissociative disorders 22212.6 Disorders of uncertain etiology 222References 223

Index 226

Foreword

Timothy D. GriffithsProfessor of Cognitive Neurology,

Newcastle University, UK

This impressive single-author work sets out the psy-chological features of all of the common (and anumber of not-so-common) neurological and med-ical disorders.Neurologists often regard the psychological

examination as a bit of a black art. However, thepsychological examination can be regarded as asimilar tool to the standard neurological examina-tion as ameans to establish profiles of deficits thatimplicate particular parts of the nervous system.I see the principal utility of this work as being thedemystification of cognitive profiles to enable neu-rologists to have an idea of what to expect and whatnot to expect in a large number of disorders. Thebook includes both conventional cognitive disor-ders, such as acute and chronic memory disorders,and also neurological disorders in which cognitivedeficits are not the most striking manifestations,in which it will serve as a useful reference. If yousurvey patients and their families that suffer fromcognitive symptoms, what they appreciate mostin the cognitive clinic is a clear explanation ofthe nature and effect of their disorder. This workprovides a basis for such explanation.Neuropsychological neurology is by definition a

two-way street that requires a close collaborationbetween neurology and neuropsychology. A num-ber of cognitive clinics in the UK, including myown, are run as joint clinics that cross between thetwo disciplines. Many neurologists, however, do nothave the luxury of spending time with neuropsy-chology colleagues and this work will help them

xi

xii Foreword

to know what to ask neuropsychology colleaguesabout in given disorders. This book will also behelpful to neuropsychologists who might need todemystify, for example, peculiar genetic conditionswith ack-ack names and understand what cognitivedeficits should be expected and sought. If the bookhelps neurologists and neuropsychologists to talk toeach other more usefully that will be a valuable out-come in itself.

Preface to the second edition

The aim of the second edition of this book remainsthe same as in the first, namely to review what isknown about the neuropsychological or neurocog-nitive impairments that occur in neurological dis-orders and in some general medical conditions thatmay be seen by neurologists. A phenomenologicalperspective is presented, using an etiological clas-sification of neurological disorders (in the absenceof a comprehensive pathogenic/molecular classifi-cation), an approach which at least has the advan-tage of being familiar to practising neurologists. Thevolume may be seen as the theoretical compan-ion to a prior, practical volume that attempted tosummarize the authors clinical experience of work-ing in a cognitive disorders clinic over more than adecade [1].There are two major changes from the first edi-

tion, one omission and one addition. The omis-sion is the long section devoted to Bedside neu-ropsychological test instruments (first edition, Sec-tion 1.8, pp. 2232), because these issues have sincebeen covered in greater detail elsewhere [1,2]. Theaddition has been two further chapters, devotedto sleep-related disorders (Chapter 11) and psy-chiatric disorders (Chapter 12), respectively, bothof which may be encountered in cognitive dis-orders clinics. All the pre-existing chapters havebeen thoroughly revised and updated, and therehas been some reordering to make the text morelogical.As in the first edition, detailed discussions of the

neurological features of the disorders covered and ofneurological signs are not included, further concise

xiii

xiv Preface to the second edition

information on which may be obtained elsewhere[3,4].

REFERENCES

[1] Larner AJ. Dementia in Clinical Practice: A Neurologi-

cal Perspective. Studies in the Dementia Clinic. London:

Springer, 2012.

[2] Larner AJ (ed.).Cognitive Screening Instruments. A Prac-

tical Approach. London: Springer, 2013.

[3] Larner AJ, Coles AJ, Scolding NJ, Barker RA. A-Z of Neu-

rological Practice. A Guide to Clinical Neurology (2nd

edn.). London: Springer, 2011.

[4] Larner AJ. A Dictionary of Neurological Signs (3rd edn).

New York, NY: Springer, 2011.

Acknowledgments

Thanks are due to many colleagues with whom Ihave worked in Liverpool since the first edition ofthis book was published in 2008, including MarkDoran, Eric Ghadiali, Pavla Hancock, Atik Baborie,and Rhys Davies.Positive feedback on the first edition from two

clinical neuropsychologists, Ian Baker (Oxford) andRupert Noad (Plymouth), both encountered at thePractical Cognition Course inNewcastle, was greatlyappreciated. Thanks are due to Tim Griffiths, one ofthe organizers of this excellent annual course, whohas kindly agreed to write the foreword.I also thank colleagues and friends who have

offered either advice on particular topics in thebook or general encouragement, including AlasdairColes, Crispin Fisher, Anu Jacob, Alex Leff, Michaeland Sally Mansfield, Parashkev Nachev, and Sivaku-mar Sathasivam.At Cambridge University Press, I thank Nicholas

Dunton and Joanna Chamberlin for their continuedfaith in this project.My principal debt of gratitude remains to Sue, my

ever-supportive and endlessly forgiving partner.All errors or misconceptions that remain are

entirelymy ownwork. I shall be pleased to hear fromreaders who detect errors or omissions.

xv

1Cognitive function, neuropsychological evaluation, andsyndromes of cognitive impairment

1.1 Domains of cognitive function 11.1.1 Attention 21.1.2 General intelligence (IQ) 41.1.3 Memory 51.1.4 Language 71.1.5 Perception 81.1.6 Praxis 91.1.7 Executive function 10

1.2 Neuropsychological assessment 111.2.1 Formal neuropsychological assessment 111.2.2 Bedside neuropsychological assessment 11

1.3 Syndromes of cognitive impairment 121.3.1 Normal aging 121.3.2 Mild cognitive impairment (MCI) 131.3.3 Dementia 131.3.4 Disconnection syndromes; callosal dementia 15

References 16

1.1 Domains of cognitive function

Without necessarily subscribing to an explicitlymodular concept of cerebral function, it is nonethe-less convenient from the clinical standpoint to thinkin terms of cognitive domains or functional sys-tems (a congeries of mental faculties) in the brain,specifically attention, memory, language, percep-tion, praxis, and executive function. These sub-divisions, all working in concert not in isolationto produce in sum what we understand by con-sciousness, may direct a structured approach tothe clinical assessment of cognitive function. Nowa-days, a model of distributed neural networks with

nodal points more specialized for certain func-tions has supplanted the idea of particular braincenters [1].The neurocognitive domains may be described

as either localized, implying lateralization to onehemisphere or part thereof, focal damage to whichmay impair that specific function; or distributed,implying a nonlocalized function often involv-ing both hemispheres and/or subhemisphericstructures (basal ganglia, brainstem), widespreaddamage being required to impair these functions[2]. Furthermore, particular domains may besubdivided, or fractionated, into subsystems orspecific functions that may be selectively impaired,

1

2 1: Cognitive function

suggesting the existence of functionally distinctneuropsychological substrates.

1.1.1 Attention

It is surely redundant to point out that before anymeaningful assessment of higher cognitive func-tion can be made, it should be ascertained thatlower cognitive function is intact, assuming thatthe workings of the nervous system are hierarchical(in the Jacksonian sense) in their operation. Toindulge in reductio ad absurdum, it would notbe reasonable to expect a comatose patient, ora sleeping subject, to perform well on tests ofmemory, although memory function may be intactor impaired on recovery from coma or awakeningfrom sleep.The nature of consciousness is an area of great

interest to both neuroscientists and philosophers[37], but other than to assume that it is an emer-gent property of brain function, nothing furtherabout its possible neuroanatomical and neuro-physiological bases will be considered here, otherthan to note that dissociation between apparentpreservation of consciousness and absence of cog-nitive function may occur, as in vegetative states[8], although this has been questioned on the basisof neuroimaging [9] and electroencephalography(EEG) studies [10].Disturbance of consciousness may encompass

both a quantitative and a qualitative dimension.Hence, one may speak of a level of conscious-ness, perhaps in terms of arousal, alertness, or vigi-lance, forming a continuum from coma to theawake state; and an intensity or quality of con-sciousness, in terms of clarity of awareness of theenvironment, and ability to focus, sustain, or shiftattention. There are various clinical descriptors ofstates of impaired consciousness including coma[11], vegetative state [8], and minimally consciousstate [12]. Coma implies a state of unresponsivenessfrom which a patient cannot be roused by verbalor mechanical stimuli. Lesser degrees of impairedconsciousness, sometimes labeled clinically as

stupor, torpor, or obtundation (although theseterms lack precision, their meaning often vary-ing between different observers), may also inter-fere with cognitive assessment. These states maybe obvious clinically, such as drowsiness, or diffi-culty rousing the patient, but may also be occult,perhaps manifesting as increased distractibility.Impairments in level of consciousness are a sine quanon for the diagnosis of delirium, as enshrined inthe diagnostic criteria of the Diagnostic and Statis-ticalManual (DSM-IV) and the International Classi-fication of Diseases (ICD10), although these deficitsmay be subtle and not immediately obvious atthe bedside but yet sufficient to impair attentionalmechanisms. These attentional deficits may beresponsible for the impaired cognitive function thatis also a diagnostic feature of delirium (Section 12.1)[13,14].Attention, or concentration, is a nonuniform,

distributed cognitive function. It may be definedas that component of consciousness which dis-tributes awareness to particular sensory stimuli.The nervous system is bombarded with stimuliin multiple sensory domains, only some of whichreach awareness or salience while many perceptsare not consciously noticed. Attentional resources,which are finite, are devoted to some channelsbut not to others. Attention is thus effortful, selec-tive, and closely linked to intention. Distinctionmay be made between different types of attentionalmechanism: sustained attention implies devotion ofmost attentional resources to one particular stimu-lus, whereas selective attention is the directing ofattentional resources to one stimulus among many(the cocktail party phenomenon); divided atten-tion implies a division of attentional resourcesbetween competing stimuli. Various neuroanatom-ical structures are thought to be important in medi-ating attention, including the ascending reticularactivating system in the brainstem, the thalamus,and prefrontal cerebral cortex of multimodal asso-ciation type, particularly in the right hemisphere,as damage to any of these areas may result inimpairments of attention [15]. Dopaminergic andcholinergic tracts are thought to be the important

1.1 Domains of cognitive function 3

neurotransmitter pathways mediating attention[16].The term working memory is used by neuro-

psychologists to describe a limited capacity storefor retaining and manipulating information over ashort term, one to two minutes, and for onlinemanipulation of that information. This system hasa limited capacity wherein information rapidlydegrades unless continuously rehearsed (henceunstable, compared to longer-term memory).Working memory may be fractionated into a num-ber of subsystems: verbal (phonological or artic-ulatory loop) and visual (visuospatial sketch pad)components, governed by a supervisory centralexecutive, as well as a postulated episodic bufferthat acts as a multimodal temporary store tointerface with perception and long-term mem-ory [17]. Working memory function is dissociablefrom long-term memory function (Section 1.1.3);for example, in patients with amnesia as a con-sequence of WernickeKorsakoff syndrome, work-ing memory is preserved (Section 8.3.1.1). Workingmemory is perhaps better envisaged as a compo-nent of the selective attention system (the speciouspresent of William James), and is certainly notcongruent with the usage of the term short-termmemory by patients, which generally refers torecent long-termmemory. Grammatical complexity,for example in sentence construction, is associatedwith working memory capacity, which mediates theneed to keepmany elements in play and not lose thetrain of thought before completing the sentence.Another clinical phenomenon related to atten-

tional processes is neglect. Sometimes also knownas inattention, neglect is a failure to orient to,respond to, or report novel or meaningful stim-uli in the absence of sensory or motor deficits(such as hemiparesis or hemianopia), which couldexplain such behavior. Extinction, the failure torespond to a novel or meaningful sensory stimuluson one side when a homologous stimulus is givensimultaneously to the contralateral side (i.e., dou-ble simultaneous stimulation), sometimes calledsuppression, may be a lesser degree of neglect. Inthe visual domain, neglect may be categorized as

a disorder of spatial attention, which is more com-mon after right-sided rather than left-sided braindamage, usually of vascular origin. This observa-tion may be accounted for by the ability of the righthemisphere to attend to both sides of spacewhereasthe left hemisphere attends to the right side of spaceonly (i.e., there is some lateralization of function).The angular gyrus and parahippocampal gyrus maybe the critical neuroanatomical substrates under-pinning the development of visual neglect [18,19].In terms of clinical assessment, the Glasgow

Coma Scale (GCS) is the instrument most com-monly used for monitoring the level of conscious-ness [20]. Introduced originally to assess the sever-ity of traumatic head injuries, it has subsequentlybeen applied in other clinical situations (e.g., delir-ium, stroke), although its validity in some of thesecircumstances remains to be confirmed. In the indi-vidual patient, use of the individual componentsof the GCS (best eye, verbal, and motor responseor EVM) is more useful than the summed score(out of 15), although for the purposes of demo-graphic research use of the summed score is prefer-able. It should be noted that a GCS score of 15/15does not guarantee intact attention, as deficitsmay be subtle, and therefore it may be necessaryto undertake other tests of attentional functionbefore other neuropsychological instruments areadministered.Many tests of attention are available. Examples

included the Trail Making Test, the ContinuousPerformance Test, the Paced Auditory Serial Addi-tion Test (PASAT) and its visual equivalent (PVSAT),and the Symbol Digit Modalities Test. Simple bed-side tests that tap attentional mechanisms includeorientation in time and place, digit span forwardand/or backward (also WAIS-R Digit Span subtest),reciting the months of the year or the days of theweek backward, or counting back from 30 downto 1. Distractibility may be evident if the patientloses his or her way, or starts the more automaticforward recital. In the Mini-Mental State Examin-ation (MMSE), the most commonly administeredbedside or office test of cognitive function [21],subtracting 7 from 100 repeatedly (serial sevens:

4 1: Cognitive function

93,86,79,72,65, etc.) or spelling the word worldbackward are labeled as tests of attention or concen-tration, but it should be realized that failure in thesetests may be for reasons other than impaired atten-tion (e.g., poor mental arithmetic abilities in serialsevens).Neglect may be clinically obvious, for example if

a patient fails to dress one side of the body, but it issometimes more subtle, in which case its presencemay be sought using cancelation tests (e.g., starsin an unstructured array, or letters in a structuredarray), figure copying (e.g., the ReyOsterrieth com-plex figure), line bisection tasks, numbering a clockface, or drawing frommemory.

1.1.2 General intelligence (IQ)

Formal neuropsychological assessment ofteninvolves testing of general intelligence (IQ) beforeany specific assessment of the individual domainsof cognitive function. This is legitimate as a gen-eral intelligence factor g seems to account for asignificant proportion of the individual differencesamong test scores for groups of people [22]. Generalintellectual function is most often measured byadministration of one of the Wechsler IntelligenceScales, most often the Wechsler Adult IntelligenceScale-Revised (WAIS-R) [23] or the Wechsler AdultIntelligence Scale-III (WAIS-III) [24]. Updatingof these tests is required periodically because ofchanges in the abilities of the normative group fromwhich standardized scores are derived [22]. Studiesover time and from around the world suggest thatIQ is rising at the rate of three points every decade,the Flynn effect [25].Administration of these tests may take up to two

hours or more, sometimes necessitating more thanone testing session to avoid patient fatigue. Sub-tests in these batteries fall into two categories, ver-bal and performance, the former including testsof general knowledge, vocabulary, comprehension,and verbal abstract thinking (e.g., digit span, arith-metic, similarities), and the latter including testsof perceptual organization, complex visuospatial

function, and psychomotor speed (e.g., digit sym-bol, picture completion and arrangement, blockdesign, object assembly). These subtests yield anindex of verbal intelligence, verbal IQ (VIQ), andof performance intelligence, performance IQ (PIQ),as well as an overall full scale IQ (FSIQ). Based onextensive normative data from healthy North Amer-icans and Europeans, these measures have a meanscore of 100 with a standard deviation of 15 suchthat 95% of the population will fall within the range70130. Generally VIQ and PIQ are correlated, butoccasional discrepancies may be seen in normalindividuals. The belief that the VIQPIQ split canbe reliably used to infer the lateralization of brainpathology (VIQ more impaired in left-sided lesions,PIQ with right-sided lesions) should be viewed withsome caution [26].When assessing individuals complaining of cog-

nitive disorders, especially memory disorders, anIQ score per se may not be particularly helpful.However, change in IQ, possibly reflecting cognitivedecline, is more useful, but it is seldom the case thatan individual patient will have undergone previ-ous testing with which a comparison may be made.Previous educational and occupational history maygive clues to premorbid intelligence, as may per-formance on verbal subtests of the WAIS batteries.This difficulty may also be partially circumventedby administering a test specifically designed to esti-mate premorbid intellectual abilities, such as theNational Adult Reading Test (NART) [27], becausethe overlearned ability to read a series of words withirregular spelling-to-sound correspondences is rel-atively preserved in a number of neurodegenera-tive disorders (there are exceptions such as fronto-temporal lobar degenerations causing linguisticsyndromes; Sections 2.2.2 and 2.2.3). The NART IQmay then be compared with the Wechsler FSIQ togive some indication of whether general intellectualfunction is stable or has declined. A difference of20 points is probably significant, 40 points certainlyso.Nonverbal tests of general intelligence are

also available, such as the Progressive Matricesdescribed by Raven [28,29]. Other tests examining

1.1 Domains of cognitive function 5

general cognitive functioning by means of neuro-psychological batteries and assessment of premor-bid intelligence are available.

1.1.3 Memory

Memory is a nonuniform, distributed cognitivefunction or subassembly [30]. In other words,subdivisions in memory function may be differ-entiated, which involve various neuroanatomicalsubstrates.Current taxonomies of memory propose a dis-

tinction between declarative (also known as explicitor conscious memory) and nondeclarative mem-ory (implicit, procedural, unconscious memory).Declarative or explicit memories are intentionalor conscious recollections of previous experience.Declarativememorymay be subdivided further intoepisodic memory and semantic memory. Episodicmemories are specific personal events, sometimesknown as autobiographical memories, which aretime and place (context) specific, whereas seman-tic memories are facts, a database of culturallyapproved knowledge independent of any specificcontext. A distinction may also be drawn betweenanterogradememory, the laying down of newmem-ories, and retrograde memory, the store of pre-viously encoded material. An autobiographicalsemantic dissociation of retrograde memory lossmay be noted. In contrast with explicit memory,implicit memories refer to a heterogeneous collec-tion of faculties, such as skill learning, priming, andconditioning, which are not available to consciousthought or report [3133].In clinical practice, lay observers and primary

care physicians frequently distinguish betweenproblems with short-term memory and long-term memory, most usually referring to materi-al learned recently or in the more distant past,respectively. Such a division persists in profes-sional terminology, although the meanings are dif-ferent. Professional short-term memory is analo-gous to working memory, best conceptualizedas an attentional function (Section 1.1.1). Patientshort-term memory is in fact one component of

professional long-term memory (which encom-passes all the subdivisions previously mentioned),specifically that for the learning of new information.Amnesia is the syndrome of impaired memory andnew learning, whichmay be variously characterizedas anterograde or retrograde and acute/transientor chronic/persistent. Anterograde amnesia may beclinically manifested as repeated questioning aboutday-to-day matters, inability to carry out simplechores, or repeating the same information. A betterdistinction may be between recent and remotememory.The neuroanatomical substrates of explicit mem-

ory are partially understood, based on studies ofexperimental animals and of patients developingmemory problems as a consequence of focal brainlesions that may be examined by means of neuro-psychological testing and, more recently, neuro-imaging. The literature makes reference tohippocampal, diencephalic, and frontal andbasal forebrain amnesia, largely based on lesionand neuropathological studies. Structures in themedial temporal lobe, centered on the hippocam-pus, and in the diencephalon surrounding thethird ventricle are thought to be crucial to episodicmemory. Lesions anywhere along the circuit origin-ally described by Papez (entorhinal area of theparahippocampal gyrus, perforant and alvearpathways, hippocampus, fimbria and fornix, mam-millary bodies, mammillothalamic tract, anteriorthalamic nuclei, internal capsule, cingulate gyrus,and cingulum) may lead to anterograde and ret-rograde amnesia. Furthermore, memory functionsare lateralized in a material-specific manner, withverbal memory functions being associated with thedominant (usually left-sided) structures, and visualmemory with the nondominant (usually right) side[34,35].The experience of the patient known as HM was

a key indicator of the importance of these struc-tures for memory function (Section 4.1). Becauseof his medically refractory epilepsy, HM underwentbilateral medial temporal lobectomy, encompass-ing the amygdala, entorhinal cortex, anterior den-tate gyrus, hippocampus, and subiculum. Surgery

6 1: Cognitive function

was followed by a dense anterograde amnesia, andretrograde amnesia covering about a decade priorto the surgery [36]. Similar outcomes have beenreported, following unilateral surgery, presumablybecause of subclinical contralateral pathology [37].Evocative terms used to describe the predicamentof HM and other similarly affected patients includemarooned in the moment, fossilized in the past,and living in a world of isolated impressions. HMwas followed up for many years with essentially noimprovement in his neuropsychological deficits. Hisimportance in the field of memory research contin-ues to be emphasized [38].There are many causes of memory disorder

[32,39,40]. Impairment of episodic memory is themost common presenting feature of Alzheimersdisease (AD; Section 2.1), sometimes occurring inisolation although other cognitive deficits may beapparent on clinical or neuropsychological assess-ment. For this reason, and because AD is the mostcommon cause of dementia, neuropsychologicaltest batteries, particularly bedside tests, are oftenweighted toward memory testing, to the relativeexclusion of other cognitive domains such as execu-tive function, which has consequences when usingsuch tests to try to identify other neurocognitive dis-orders inwhichmemory is not the principal domainaffected. Anterograde amnesia may also occur as aconsequence of open or closed head injury (post-traumatic amnesia), WernickeKorsakoff syndrome(Section 8.3.1.1), herpes simplex encephalitis (Sec-tion 9.1.1), limbic encephalitis of paraneoplasticor nonparaneoplastic origin (Sections 6.12.1 and6.12.2, respectively), strategic brain infarcts (Section3.2), and surgery to remove temporal lobe or thirdventricle lesions (Section 7.2.3). Transient amnesiasmay be of epileptic origin (transient epileptic amne-sia; Section 4.3.1) or, in transient global amnesia,of probable vascular etiology (Section 3.6.2). Psy-chogenic amnesia may also enter the differentialdiagnosis of transient amnesia (Section 12.5.1). Inaddition, a temporal gradient of retrograde amnesiamay be present in some of these conditions, but rarecases of focal retrograde amnesia with relative spar-ing of anterograde memory have been described,

sometimes following head injury or an encephaliticillness [41].Many tests are available to neuropsychologists to

probe the specific areas of episodic and semanticlong-term memory. The Wechsler Memory Scale,now in its third edition (WMS-III), is a battery test-ing auditory and visual declarative (and working)memory. Other specific tests of episodic memorysometimes deployed include the Buschke SelectiveReminding Test [42], the California Verbal LearningTest [43], the Hopkins Verbal Learning Test [44], theCamden Recognition Memory Test and the Topo-graphical Recognition Memory Test [45,46], and theRey Auditory Verbal Learning Test. Recall of the ReyOsterrieth Complex Figure may be used as a test ofvisual memory. Retrograde memory may be investi-gated using the AutobiographicalMemory Interview[47], which covers both personal semantic informa-tion and autobiographical incidents, although thismay underestimate the true extent of retrogradeamnesia, missing islands of memory loss uniqueto the individual. The Famous Faces Test may beused to study remote memory [48]. Integrity ofthe semantic network, including semantic memory,may be tested using category (or semantic) fluencytests (Section 1.1.7). Reading words with irregu-lar sound-to-spelling correspondence may producesurface dyslexia (regularization errors) in patientswith impaired access to or breakdown of semanticnetworks. Other tests accessing associative seman-tic networks include the Pyramids and Palm TreesTest [49].Of the frequently used bedside neuropsycho-

logical test instruments, some are specific cogni-tive tests for memory, such as the Memory Impair-ment Screen (MIS) [50] and the Free andCued Selec-tive Reminding (or Five Words) Test [51]. General,multidomain, cognitive screening instruments (e.g.,MMSE [21], Addenbrookes Cognitive Examination[52,53], and Montreal Cognitive Assessment [54])test memory to a greater or lesser extent; for exam-ple, the MMSE has only perfunctory examination ofmemory function (registration of the names of threeobjects, e.g., ball, flag, tree, and recall after distractoritems). Longer (supraspan) word lists are used in the

1.1 Domains of cognitive function 7

DemTect [55] and the Hopkins Verbal Learning Test[44], and the latter includes both recall and recog-nition paradigms to try to ascertain whether fail-ures result from encoding or retrieval defects. Gen-erally, examination of implicit memory functions isnot undertaken in clinical practice.Rather less has been written about forgetting, as

opposed to remembering, but this is presumablyalso a physiological memory function [56]. It wasNietzsches belief that For healthy and effectiveaction, it is as important to forget as to remem-ber, and forgetting, even more than memory, mustbe an effect of time rather than will (On theUses and Disadvantages of History for Life). Thephenomenon of accelerated long-term forgettinghas attracted increasing attention in recent times,wherebymemory tests applied at extended intervals(usually greater than 24 hours) may disclose antero-grade memory impairments not seen in standardtest paradigms. This may be of particular relevanceto some of thememory disorders seen in the contextof epilepsy (Chapter 4).

1.1.4 Language

Language, the wind-swift motion of the brain(Sophocles Antigone, line 355), historically pro-vided the first unequivocal evidence that loss of ahigher brain function could be ascribed to dam-age to a specific brain region, based on the workof Paul Broca and, possibly, Marc Dax in the mid-nineteenth century [57]. The work of Carl Wernickewas also seminal in establishing the neural sub-strates of language function, indicating that lan-guage is a localized function. Every medical studentnow knows that most individuals, whether left- orright handed, have language in the dominant hemi-sphere, although around 30% of left handers andless than 1% of right handers have language in thenondominant hemisphere.Aphasia, a primary disorder of language, is often

mirrored by similar defects in reading (alexia) andwriting (agraphia), all of which are amenable toclinical localization, within certain limitations [58],often on the basis of simple bedside examination.

In addition to the Broca (nonfluent, anterior, motor,expressive) and Wernicke (fluent, posterior, sen-sory, receptive) types of aphasia, clinical distinc-tions may be drawn between conduction apha-sia (impaired repetition) and transcortical aphasias(preserved repetition). A classification of aphasiasas perisylvian (Broca, Wernicke, conduction), andextrasylvian has also been proposed [59].It may be necessary to test auditory comprehen-

sion before undertaking any other neuropsychologi-cal testing of language; for example, using the TokenTest [60] in which commands of increasing lengthand complexity are given for manipulating a deckof colored tokens of differing size and shape (somehave objected to theword token, preferring item[61]). Sentence comprehension skills may be ascer-tained by performance of the Test for the Recep-tion of Grammar [62]. Wernicke-type aphasia typi-cally hasmarked comprehension impairments, withfluent speech output but often with poverty of con-tent, sometimes reduced to ameaningless jumble ofwords (jargon aphasia). Although Broca-type apha-sia is often characterized as having preserved com-prehension, this in fact may be impaired for morecomplex syntax.There are many tests of language available to

neuropsychologists. Comprehensive batteriesinclude the Boston Diagnostic Aphasia Exami-nation (BDAE) [63], the Western Aphasia Battery(WAB) [64], the Psycholinguistic Assessment of Lan-guage Processing in Aphasia (PALPA) [65], and theComprehensive Aphasia Test [66]. Specific tests ofnaming often deployed include the Graded NamingTest [67] and the Boston Naming Test [68].At the bedside, listening to speech output will

generally permit a simple classification of apha-sia as fluent or nonfluent, and also detect para-phasias (phonemic or semantic) and neologisms.From questioning or instructing the patient duringhistory taking and clinical examination, compre-hension difficulties may be evident. Testing of rep-etitionmay differentiate aphasias in which this abil-ity is relatively preserved (transcortical aphasias)or impaired (conduction aphasia). Naming skillshave less localizing value, although marked anomia

8 1: Cognitive function

should raise the suspicion of semantic problems,either degradation of or access to semantic stores.Reading and writing function should also be exam-ined, even if spoken language function seems intact,as various syndromes of alexia and agraphia aredescribed. Idea density in written material reflectslanguage processing ability.Of the frequently used bedside neuropsycho-

logical test instruments, most are heavily weightedfor language function, such that patients with pri-marily linguistic disorders (e.g., semantic dementia,aphasic presentations of AD) may find it difficult orimpossible to complete them.

1.1.5 Perception

That perceptions are not a faithful brain response toexternal stimuli but are to some extent constructedby the brain, based on the expectations of timeand culture, has been known by philosophers sinceKant, and perception as illusion has been impli-citly understood by artists such as Magritte (thetreachery of images) andmanifested by artists suchas Escher in certain of his graphical works (e.g.,Ascending and Descending, Belvedere).Higher-order deficits of sensory processing, not

explicable in terms of failure of primary sensoryfunction, or a disorder of attention, intellectualdecline, or a failure to name the stimulus (anomia),are known as agnosias, a term coined by SigmundFreud in 1891 and literally meaning not know-ing or without knowledge [69]. Before this, Lis-sauer in 1890 [70] (abridged translation by Shal-lice and Jackson [71]), speaking of Seelenblind-heit, literally soul-blindness or technically psy-chic blindness, drew a distinction between apper-ceptive deficits and associative deficits. In the for-mer, a defect of higher-order complex perceptualprocessing was deemed to be present, whereas inthe latter, perception was held to be intact but adefect in givingmeaning to the percept was present.The debate continues as to whether all agnosias,although clinically distinguishable as apperceptiveor associative, are in fact attributable to faultyperception [72].

Although auditory and tactile agnosias aredescribed, they seem to be relatively rare in com-parison with visual agnosia, which has certainlybeen more extensively studied. The visual agnosiasmay be relatively selective; for example, an inabilityto recognize previously known human faces orequivalent stimuli, known as prosopagnosia. Thismay be developmental or acquired in origin, thelatter usually a consequence of cerebrovasculardisease causing bilateral occipitotemporal lesions,but occasionally it occurs as a feature of neuro-degenerative disease, sometimes in relative isola-tion, associated with focal right temporal lobe atro-phy (progressive prosopagnosia [73]). Pure alexiaor pure word blindness is an agnosia for wordsthat results in a laborious letter-by-letter readingstrategy to arrive at a words identity. Pure alexiamay be conceptualized as a consequence of damageto a brain region mediating whole word recognitionthat may be located in the medial left occipital lobeand posterior fusiform gyrus [74]. The rare syn-drome of pure word deafness (Section 1.3.4) maybe a form of auditory agnosia. Finger agnosia, theinability to identify which finger has been toucheddespite knowing that a finger has been touched,is a form of tactile agnosia, which may be seenas one feature of Gerstmann syndrome althoughit may occur in isolation [75]. Likewise, Braillealexia may, in some instances, be a form of tactileagnosia [76].The existence of two visual processing path-

ways within the brain was first proposed by Unger-lieder and Mishkin [77]: an occipitoparietal dorso-lateral (where) visual processing stream and anoccipitotemporal ventromedial (what) stream. Inrare cases, these pathways may be affected selec-tively; for instance, the ventral stream, specificallythe lateral occipital area, in a famous patient withvisual-form agnosia following carbon monoxidepoisoning. Her perceptual identification of shapeand form was lost, although she could still perceivecolor and the fine detail of surfaces (visual texture),and her visuomotor (vision for action) skills werestrikingly preserved [78]. Optic ataxia, impaired vol-untary reaching for a visually presented target with

1.1 Domains of cognitive function 9

misdirection and dysmetria, is the sign typically evi-dent in dorsal stream lesions. The workings of thevisuomotor control system are not available to con-sciousness (unconscious vision), unlike the visualidentification of objects.A specific inability to see objects in motion, akin-

etopsia or cerebral visual motion blindness, despitepreserved perception of other visual attributes suchas color, form, and depth, has been described inassociation with selective lesions to area V5 ofthe visual cortex [79]. Although exceptionally rare,such cases suggest a distinct neuroanatomical sub-strate for movement vision, as do cases in whichmotion vision is selectively spared in a scotomatousarea (Riddochs syndrome [80]). Perception withina blind visual field without conscious awarenesshas been termed blindsight [81].Cases of isolated progressive visual agnosia were

presented by De Renzi [82], and Benson et al. [83]drew attention to a disorder comprising alexia,agraphia, visual agnosia, with or without compo-nents of Balint and Gerstmann syndromes, andtranscortical sensory aphasia, but with relativepreservation of memory until late in the course,a disorder they named posterior cortical atrophy(PCA) in the absence of neuropathological data.It is now believed that most PCA cases have ADpathology, although other pathologies have beendescribed including dementia with Lewy bodies(DLB), corticobasal degeneration (CBD), and priondisease [84].Various means may be used by neuropsycholo-

gists specifically to test visual perceptual and visuo-constructive functions. These may be individualtests such as Judgment of Line Orientation (thoughtto tap right occipital lobe function); copy of theReyOsterrieth Complex Figure ([85,86]; translationby Corwin and Bylsma [87]) or the Taylor Fig-ure [88]; decoding embedded (Poppelreuter) figures[89]; or parts of test batteries, such as the WAIS-RBlock Design (visuospatial construction); or dedi-cated batteries such as the Visual Object and SpacePerception Battery (VOSP) [90].Of the frequently used bedside neuro-

psychological test instruments, the MMSE has only

perfunctory examination of visuospatial func-tion, requiring copying a drawing of intersectingpentagons [21]. Clock Drawing is, at least in part,a visuospatial test, but requires other skills. TheAddenbrookes Cognitive Examination (ACE) addscopying a wire (Necker) cube and clock drawing[52], and ACE-R adds counting dots and identifyingfragmented letters [53].

1.1.6 Praxis

The term apraxia was coined by Steinthal in 1871but the phenomena of higher-level motor controldisorders were first systematically studied by Liep-mann [91], who defined apraxia as an inability toperform purposeful skilled movements as a resultof neurological dysfunction, usually associated withleft-sided lesions. Part of the definition of apraxiais one of exclusion, as the observed motor difficul-ties should not be caused by sensory loss, weak-ness, tremors, dystonia, optic ataxia, chorea, bal-lismus, athetosis, myoclonus, ataxia, or epilepticseizures. For example, deficits previously labeledas constructional apraxia or dressing apraxiaare better explained as visuoperceptual and/orvisuospatial deficits, as is the misdirected reach-ing for visual targets typical of optic ataxia. Trad-itionally, a distinction has been drawn betweenideational and ideomotor apraxias, although bothare often present in left hemisphere damage [9295]. Ideomotor apraxia in Brocas aphasia maybe conceptualized as a disconnection syndrome(Section 1.3.4).Cases of isolated progressive apraxia were pre-

sented by De Renzi [82]. Apraxia may be a featureof neurodegenerative disease, classically CBD (Sec-tion 2.4.4), although AD can present with a similarphenotype (biparietal atrophy; Section 2.1), evenwith alien limb behavior.Praxic difficulties may be tested for in vari-

ous ways, including gesture naming, decision andrecognition; gesture to verbal command, to visual ortactile tools; imitation of real or nonsense gestures;and tool selection. There are also test batteries forapraxia assessment [95].

10 1: Cognitive function

1.1.7 Executive function

The term executive function is used to encompassvarious cognitive abilities, including the formula-tion of goals; organization, planning, execution,and monitoring of a sequence of actions; problemsolving; and abstract thinking. It also overlapswith sustained attention. The term dysexecutivesyndrome may be used to describe dysfunction inany or all of these areas, which is most often asso-ciated with pathological processes in the frontallobes [96,97]. Because of the heterogeneity of thesefunctions, some authors dislike the umbrella termof executive function, and prefer to describe thespecific function impaired. Moreover, frontal lobedamage may result in various clinical phenotypes,in which behavioral change is often the mostsalient feature. Orbitofrontal injury may result indisinhibition, as described in Phineas Gage, oneof the most famous patients in the annals of clin-ical neuropsychology, who sustained markedbehavioral change following traumatic frontal lobeinjury [98], although other patterns of clinical andcognitive change may be observed with frontallobe injury; for example, apathetic (frontal con-vexity) and akinetic (medial frontal) syndromesare also described. Because most tests of executivefunction probe planning and strategy, mediatedby dorsolateral prefrontal cortex, some patientswith exclusive orbitofrontal damage, for examplewith behavioral (frontal) variant frontotemporaldementia (Section 2.2.1), may complete these testswithout conspicuous errors.Because of the overarching nature of the con-

struct of executive function, no single test is ade-quate to assess its integrity [99]. Many tests knownto be sensitive to aspects of executive dysfunctionare available. Perhaps the most frequently used arethe Stroop Test and the Modified Wisconsin CardSorting Test (MWCST). In the Stroop Test, patientsare required to read a list of color names, printedin colors that differ from the name, followed byreading the colors in which each name is printed,thus having to inhibit the reading of each colorname (i.e., inhibition of inappropriate responses)

[100]. MWCST uses a set of cards marked with sym-bols of different shape, color, and number, whichmay be sorted in various ways. Sorting rules arechanged by the examiner without informing thesubject, requiring problem solving skills. Difficultyswitching category is typical of frontal lobe damage,leading to perseveration with previous categories[101]. Clearly MWCST, unlike the Stroop Test, callsfor novel responses. MWCST may not be specificto frontal lobe dysfunction, as patients with hip-pocampal lesions may commit perseverative errors[102].Oral tests of verbal fluency, or controlled oral

word association tests (COWAT), may be dividedinto those testing phonological, letter, or lexical flu-ency (naming to letter), such as the FAS test (nameas many words beginning with the letters F, A, orS as possible in one minute each), and those test-ing semantic or category fluency (naming to set;in one minute name as many animals, fruits, ormusical instruments as possible). Letter fluency hasbeen characterized as a test of mental flexibility(as well as of expressive language) probing execu-tive function, which is particularly impaired (defec-tive exemplification [103]) with left frontal lesions(without aphasia), whereas category fluency exam-ines the integrity of the semantic network. Designfluency, a visual analog of verbal fluency, may bemore impaired with right frontal lesions [104]. Ver-bal fluency tasks are attractive because they are brief(one minute each) and require no special equip-ment, but account may need to be taken of patientage and education when considering test norms[105].There are many other tests available to neur-

opsychologists to probe executive functions, some-times along with other domains. These includeRavens Progressive Matrices, the Porteus Mazes,Tower tests (London, Hanoi), Trail-Making Test(especially Part B), the HalsteadReitan Cate-gory Test, the Weigl Color Form Sorting Test[106], the Cognitive Estimates Test [107], andthe Verbal Switching Test [108]. The Hayling andBrixton Tests for sentence completion and spa-tial anticipation are tests of rule following and

1.2 Neuropsychological assessment 11

verbal suppression of a familiar response [109].Certain WAIS-R subtests are sensitive to aspectsof executive/frontal lobe function, such as theSimilarities test of verbal abstraction and the DigitSymbol test of psychomotor speed. Tests of decisionmaking and risk taking, faculties which may alsobe encompassed under the rubric of executivefunction [110] and mediated by prefrontal cortexand the amygdala, include the Iowa Gambling Test[111] and the Cambridge Gamble Task [112].There are also batteries of tests such as the Behav-

ioral Assessment of the Dysexecutive Syndrome(BADS) [113] and the DelisKaplan Executive Func-tion System (D-KEFS) [114], but because these takesome time to administer, they are best reservedfor specific investigation of known frontal prob-lems. The Frontal Lobe Personality Change Ques-tionnaire (FLOPS) may be used to assess behavioralchange and includes a carer version, useful for gain-ing collateral information; likewise the Iowa Rat-ing Scale of Personality Change [115]. Verbal flu-ency tests are incorporated into test batteries suchas the Dementia Rating Scale [116] and the CERADBattery [117].At the bedside or in the clinic, GoNo Go

tests may be applied to assess failure of inhibitoryresponses, or stimulusboundedness; for example,asking the patient to tap twice in response to a sin-gle tap given by the examiner, and once in responseto two taps. Repeating alternating sequences, forexample of hand gestures (fistpalm) or of writing(m n m n m n) may be used to similar purpose.The Trails A and B Test also requires a sequenceof letters or numbers to be followed (one of theseis incorporated in the Montreal Cognitive Assess-ment [54]). Interpretation of proverbs is a popul-ar bedside test, concrete interpretation sug-gesting frontal lobe problems. Of the bedsideneuropsychlogical test instruments, the MMSE hasbeen criticized for its lack of assessment of executivefunction [21], one shortcoming which the Adden-brookes Cognitive Examination seeks to addressby using letter and category verbal fluency tests[52,53]. Other batteries that tap executive functioninclude the Frontal Assessment Battery [118], the

Frontal Behavioral Inventory [119], and the Middel-heim Frontality Score [120].

1.2 Neuropsychological assessment

1.2.1 Formal neuropsychological assessment

There are many tests available to the neuro-psychologist for the evaluation of cognitive func-tion, either global function or individual domains[121123]. Of course, it must be remembered thatany neuropsychological test may havemultiple sen-sory, motor, perceptual and cognitive demands, andhence pure tests of any single cognitive domainare the exception rather than the rule. The varietyof tests available may bewilder the nonspecialist.Moreover, the choice of different test instrumentsin different studies may make direct comparisonsdifficult: variable test sensitivity to a particular cog-nitive domain may explain discrepancies betweenstudies.Neuropsychologists insist, rightly, that special-

ist training is required for the correct administra-tion and interpretation of neuropsychological tests.Clinical neurologists, therefore, will rely on theirneuropsychologist colleagues for the performanceand interpretation of these formal tests, as theyfall outside neurologists expertise and may takesubstantial time to administer, being incompatiblewith clinical schedules. Nonetheless, some form ofneuropsychological testing, often labeled as bed-side to distinguish it from formal testing, is withinthe scope of neurologists and may be of diagnosticuse.

1.2.2 Bedside neuropsychologicalassessment

Numerous tests and test batteries that may beapplied within one to 30 minutes are available,encompassing not only cognitive function butalso functional, behavioral, and global assessment[21,5255,124126]. Because of the brevity thatmakes them clinically applicable, these instruments

12 1: Cognitive function

often have certain shortcomings, which neurolo-gists need to bear in mind: a raw score derivedfrom a series of tests is not necessarily diagnos-tic, although itmay increase the likelihood of a par-ticular diagnosis. The potential for incongruous oranomalous performance of tests in a medicolegalsetting has been noted [127]. Many other situationalinfluences may also impact on testing of cognitiveskills, such as fatigue, emotional status, medicationuse, pain, and stress [128]. These also need to betaken into account when considering the results ofcognitive testing, as do factors such as educationaland background experience. Many norms are alsoculturally weighted.It is outside the scope of this volume to discuss

frequently used bedside or office cognitive screen-ing instruments, for which information the reader isreferred elsewhere [124126]. When evaluating pos-sible cognitive disorders, particularly those involv-ing memory impairment, in addition to history tak-ing and examination, it is also important to obtainsome collateral history from a relative, friend, orcarer familiar with the subject as part of the evalu-ation [129,130]. Simple clinical observations mayalso assist with diagnosis. A patient who attends theclinic alone despite having been instructed to bringa relative or friend is very unlikely to have a cognitivedisorder [131]. Looking to a relative, friend, or carerfor assistance when asked to volunteer informa-tion or answer questions, the head-turning sign,is suggestive of the presence of a cognitive disorder[132,133].

1.3 Syndromes of cognitive impairment

1.3.1 Normal aging

Various motor, sensory, and cognitive changes inneurological function occur with increasing age[134]. To what extent these changes reflect nor-mal aging, however that may be defined, or towhat extent they reflect an increasing burden of age-related neurological disease, remains uncertain. Inconsequence, the inevitable physiological changes

that occur in cognition with increasing age maybe difficult to distinguish from the earliest stagesof pathological brain disorders causing cognitiveimpairments.A distinction may be drawn between crystallized

intelligence, characterized by practical problemsolving skills, knowledge gained from experience,and vocabulary, and fluid intelligence, character-ized by the ability to acquire and use new infor-mation, as measured by the solution of abstractproblems and speeded performance [135]. Crys-tallized intelligence is assumed to be cumulative;longitudinal studies of vocabulary, for example,show no decline through old age. By contrast, fluidintelligence does change with age; performanceon tests such as Ravens Progressive Matrices andDigit Symbol Substitution decline marginally upto the age of 40 years and then more rapidly.Such physiological cognitive decline may be evi-dent in early middle age (4549 years) [136]. Thereis general consensus that typical cognitive aginginvolves losses in processing speed, cognitive flex-ibility, and the efficiency of working memory (sus-tained attention). In other words, it may take moretime and/or more trials to learn new informa-tion. Cognitive domains such as access to remotelylearned information, including semantic networks,and retention of well-encoded new information arespared with typical aging; this may permit testingof these domains to be used as sensitive indica-tors of disease processes. It may be that memorydecline in healthy aging is secondary to declinein processing speed and efficiency, as control-ling for processing speed may attenuate or elim-inate age-related differences in memory perform-ance, unlike the situation withmemory impairmentin dementia.Longitudinal studies of neuropsychological func-

tion indicate that there is considerable variabilityin normal older adults across different skills, andconsistency across different domains may not nec-essarily be observed. Clearly this needs to be takeninto account when assessing whether perceivedcognitive decline is pathological or normal, thatis in defining neuropsychological norms for aging.

1.3 Syndromes of cognitive impairment 13

Furthermore, norms for IQ are increasing overtime [22,25]. Likewise, norms may need to be age-weighted rather than age-corrected to detect cog-nitive impairment related to AD, the prevalence ofwhich increases exponentially with increasing age.Notwithstanding these difficulties, the defini-

tion of a syndrome (or syndromes) of cognitiveimpairment greater than expected for age, oftentermed mild cognitive impairment, which is (are)the harbinger of progressive cognitive decline, theprodromal phases of neurodegenerative disordermay now be identifiable, with consequent implica-tions for potential therapeutic intervention.

1.3.2 Mild cognitive impairment (MCI)

Age-related cognitive decline insufficient to ful-fil validated criteria for the diagnosis of ADhas attracted a variety of labels over the past50 years, including benign senescent forgetful-ness, age-associated memory impairment (AAMI),age-associated cognitive decline (AACD), cogni-tive decline no dementia (CIND), and mild cogni-tive impairment (MCI). A degree of consensus hasdeveloped around the concept of MCI [137141],although there is not unanimity [142,143]. MCI maybe defined by the presence of a subjective mem-ory complaint, preferably corroborated by an infor-mant; evidence of objective memory impairmentfor age and level of education; largely normal gen-eral cognitive function; essentially intact activitiesof daily living (ADL); and failure to fulfil criteria fordementia [137]. Global rating scales have been usedto define MCI, such as a Clinical Dementia Rating(CDR) [144] score of 0.5 or a Global DeteriorationScale (GDS) [145] score of 3, butMCI remains a clin-ical diagnosis. Complex ADL may be impaired inMCI [146].MCI may be clinically and etiologically heteroge-

neous. At presentation, memory complaint is themost common feature, so-called amnestic MCI.Other variants have been described, specifically sin-gle nonmemory domain MCI and multiple domainMCI. Multiple domain MCI might reflect singleor multiple etiologies [138]. The possibility that

MCI may reflect conditions such as dysphoria,vascular disease, and miscellaneous disorders thatmay cause cognitive impairment such as obstruc-tive sleep apnea, alcohol misuse, head injury, andmetabolic or nutritional deficiencies, some of themtreatable, has been emphasized by several authors[143]. A category of MCI in Parkinsons disease, PD-MCI, has been described [147], and vascular cogni-tive impairment (VCI) may be differentiated fromvascular dementia (Section 3.1). The neuropsycho-logical profile of AD-relatedMCI is discussed in Sec-tion 2.1.2.

1.3.3 Dementia

The diagnosis of dementia is currently based onfulfilment of clinical diagnostic criteria, for exam-ple those in the generic DSM, the ICD, or the ded-icated criteria for specific dementia subtypes. DSM-IV-TR [148], for example, requires for a dementiadiagnosis the development of multiple cognitivedeficits that include memory impairment, of grad-ual onset and progressive course, sufficiently severeto cause impairment in occupational or social func-tioning, not better accounted for by another diagno-sis. Application of such diagnostic criteria to largecohorts of patients may classify different numbersof patients as having dementia, with differences upto a factor of 10 found in one study [149]. One rea-son for this variability is that many diagnostic cri-teria are heavily weighted toward memory impair-ment. Because memory impairment is the mostsalient feature in AD, the most common causeof dementia, many diagnostic criteria, for exam-ple those for vascular dementia, have been inad-vertently Alzheimerized, with undue emphasisplaced on memory loss at the expense of other cog-nitive features [150]. A type 2 dementia which,unlike type 1 dementia, is lacking cortical featuressuch as amnesia, has been proposed, and in whichdemonstrable executive control function impair-ments are sufficient to cause disability [151].Another potentially confusing outcome of the

emphasis of diagnostic criteria onmemory is tautol-ogy: syndromes with a diagnostic label of dementia,

14 1: Cognitive function

such as frontotemporal dementia and DLB, whichmay not necessarily fulfil diagnostic criteria fordementia in their early stages, for example in thecase of frontotemporal dementia, because the ini-tial features are executive (frontal) dysfunction andnoncognitive behavioral change [152]. Unequivocalcognitive deficits may not be sufficient to meet cri-teria for dementia, requiring a lexicon of other terms[153].Other diagnoses entering the differential diagno-

sis of dementia include delirium (Section 12.1) anddepression (Section 12.3.1).

1.3.3.1 Cortical versus subcortical dementia

Albert et al. [154] first used the term subcorti-cal dementia to describe the cognitive impair-ments seen in progressive supranuclear palsy (PSP;Section 2.4.3): forgetfulness, slowness of thoughtprocesses (bradyphrenia), alteration of personal-ity with marked apathy and depression, and animpaired ability to manipulate acquired knowledge.These deficits were felt to be qualitatively distinctfrom those seen in cortical dementias, typically AD,which included impairments in memory (amne-sia), language (aphasia), perception (agnosia), andskilled learnedmovements (apraxia). The term lim-bic dementia has sometimes been used for syn-dromes with marked amnesia and evidence for lim-bic system pathology such as AD. Whereas in sub-cortical dementias cueing or recognition paradigmsmay improve performance in delayed recall mem-ory tests, suggesting ineffective retrieval but withrelatively preserved encoding of material, in corti-cal dementias such strategies may be ineffective,suggesting impaired encoding as well as retrieval.The term subcortical was selected because ofthe resemblance of the deficits to those seen withbifrontal lobe disease, also reflected in the concur-rent emotional and movement deficits in the twotypes: subcortical dementias tended to be associ-ated with apathy and depression and prominentdisorders of muscle tone, posture, and gait, whereascortical dementias were attended with cognitive

anosognosia and disinhibition and an absence ofmovement disorder [155].Objections to the concept of subcortical demen-

tia have been raised [156]. Cortical and subcorticalareas are not functionally independent, but over-lapping. Because white matter has an essentiallyintegrative function, reciprocally linking corticaland subcortical structures, white matter pathologymight be expected to result in functional disconnec-tion of brain areas, and disordered brain function ata site distant from a lesion (diaschisis) is a well rec-ognized phenomenon (Section 1.3.4). This may beseen, for example, with frontal lobe dysfunction inmultiple sclerosis (MS) (Section 6.1) [157], and hasalso been suggested in X-linked adrenoleukodys-trophy (Section 5.5.2.2) [158]. Identical or simi-lar clinical phenotypes may result from patholo-gies affecting either gray matter or subjacent whitematter (e.g., subcortical aphasias [59]). Against thisargument, however, false localization of neurologi-cal signs usually deemed indicative of higher, cor-tical cognitive function (e.g., agnosia, neglect) israrely reported [159].Cognitive impairment and/or dementia in a vari-

ety of disorders has been labeled as subcortical,including Huntingtons disease (HD; Section 5.1.1)[160], Parkinsons disease (PD; Section 2.4.1) [161],multiple sclerosis (Section 6.1) and other whitemat-ter disorders [162,163], and certain forms of vascularcognitive impairment (subcortical ischemic vascu-lar dementia; Section 3.1.2) [164]. In the case of themovement disorders PSP, HD, and PD, it has beenhypothesized that the basal ganglia, in addition totheir role in control of movement, support a basicattentional mechanism, facilitating the synchro-nization of cortical activity underlying the selec-tion and promulgation of an appropriate sequenceof thoughts; this focused attention differs fromarousal, vigilance, or alertness. Basal ganglia dam-age thus results in a failure of synchronization,man-ifested as abulia and bradyphrenia [165].Whatever the precise physiological relationship of

cortex and subcortex in supporting cognitive func-tion, the cortical/subcortical terminology may still

1.3 Syndromes of cognitive impairment 15

have some clinical utility in the differential diagno-sis of dementia syndromes [166,167].

1.3.3.2 Thalamic dementia; brainstem andcerebellar cognitive impairment

An entity called thalamic dementia is also men-tioned in the literature, which refers to cognitiveimpairments in conditions with relatively selectivethalamic damage [168]. Most commonly this is aresult of vascular lesions, focal infarction (Section3.2.3), hypoperfusion related to a dural arterio-venous fistula (Section 3.4.2) [169], or neoplasia.In addition, relatively selective degeneration of thethalamus may occur. This may be due to a priondisease (Section 2.5) [170] such as fatal familialinsomnia (Section 2.5.3) [171], although cases ofselective thalamic degeneration with the pathologyof multiple system atrophy [170] or motor neurondisease [172], or without evidence of prion disease[173], have been reported. The neuropsychologicalfeatures may include forgetfulness, apathy, andhypersomnia.Cognitive impairment may also occur in patients

with isolated brainstem lesions of vascular, inflam-matory, neoplastic, infective, or metabolic origin(for examples: Sections 3.2.8, 8.2.3.2, and 9.4.3)[174178].Although traditionally viewed as a component of

the motor system, a cognitive role for the cerebel-lum has been recognized increasingly, with a spe-cific cerebellar cognitive affective syndrome beingdelineated by some authors [179], and characterizedby executive dysfunction (in set-shifting, planning,verbal fluency, abstract reasoning, working mem-ory) and difficulties with spatial cognition, mem-ory, and language, as well as personality change,associated with posterior lobe and vermis lesions.Cognitive impairment may occur in patients withisolated cerebellar lesions of vascular or neurode-generative origin (Sections 3.2.8, 3.3.3, and 5.2).Studies of relative pure cerebellar degenerationssuch as spinocerebellar ataxia (SCA) type 6 (Section5.2.1.4) have allowed the delineation of cerebellar

subregions that may play a role in verbal workingmemory [180].

1.3.4 Disconnection syndromes; callosaldementia

Disconnection syndromes may be defined asconditions in which there is an interruption ofinter- and/or intrahemispheral fiber tracts. Theconcept was originally advanced in the 1890s, buthas subsequently been revived and developed,perhaps most notably by Norman Geschwind in the1960s [181183].Disconnection syndromes result essentially

either from interruption of fibers within the cor-pus callosum or commissures (interhemisphericdisconnection syndromes), or of fibers within ahemisphere (intrahemispheric disconnection syn-dromes). Interhemispheric disconnection is mostgraphically seen in patients who have undergonesurgical commissurotomy for intractable seizuredisorders, so-called split-brain patients [184,185].Intrahemispheric disconnection syndromes arebest described in the domain of language. Althoughmass lesions and iatrogenesis (surgery) are obviouscauses of disconnection, functional disconnectionmay also result from inflammatory disorders ofwhite matter. A callosal dementia has been pos-tulated, characterized by callosal disconnection,Balints syndrome, gaze apraxia, and neurobe-havioral features such as alternating apathy andagitation [186].With complete interhemispheric disconnection,

for example with a tumor or following surgical sec-tion of the corpus callosum, a blindfolded patientcan correctly name objects placed in the right hand,but not those in the left, and objects in the left visualhemifield cannot be named or matched to a simi-lar object in the right hemifield. With posterior cal-losal section at the splenium, a partial interhemi-spheric disconnection, for example following leftposterior cerebral artery occlusion, patients cannotread or name colors, as information cannot passto the left hemispheric language areas. Copying of

16 1: Cognitive function

words and writing, both spontaneously and to dic-tation, is intact as information may pass to the lefthemisphere anterior to the site of damage: the syn-drome of aphasia without agraphia first describedby Dejerine in 1892.Various intrahemispheric disconnection syn-

dromes have been described. In conductionaphasia, patients have fluent but paraphasic speechand writing, with greatly impaired repetitiondespite relatively normal comprehension of thespoken and written word. This has been explainedtraditionally as being due to a lesion in the arcuatefasciculus/supramarginal gyrus disconnecting thesensory (Wernicke) and motor (Broca) languageareas. Ideomotor apraxia in Brocas aphasia, anapraxia of left hand movements to command,is ascribed to lesions disconnecting the corticalmotor areas anterior to the primary motor cortex.In pure word deafness, a form of auditory agnosia(Section 1.1.5), patients are able to hear and identifynonverbal sounds but unable to understand spokenlanguage, due to lesions in the white matter of theleft temporal lobe that isolate Wernickes area fromthe auditory cortex.AD has sometimes been conceptualized as a

disconnection syndrome [187,188]. AD pathol-ogy effectively isolates the hippocampus fromassociation cortices, basal forebrain, thalamus,and hypothalamus [189]. A multiple disconnectionmodel is currently favored to explain the cogni-tive dysfunction seen in MS, in which lesions ofsubcortical periventricular white matter fiber path-ways effectively disconnect cortical and subcorti-cal regions (Section 6.1) [190]. Cognitive impair-ment associated with carotid artery occlusive dis-ease (Section 3.1.1.1) may be a consequence of dis-connection of cortical regions caused by white mat-ter lesions and cerebral atrophy [191].

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