REVIEW

Cognition in Corticobasal Syndrome and Progressive Supranuclear Palsy: A Review James R. Burrell, BA, BSc(Med), MBBS(Hons), PhD, FRACP,1,2 John R. Hodges, MBBS, MD, FRCP,1,2 and James B. Rowe, BA, BM, BCh, PhD, FRCP3,4,5 1

Neuroscience Research Australia, Sydney, Australia 2 University of New South Wales, Sydney, Australia 3 Department of Clinical Neurosciences, Cambridge University, Cambridge, United Kingdom 4 Behavioral and Clinical Neuroscience Institute, Cambridge, United Kingdom 5 Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, United Kingdom

ABSTRACT:

Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped together as “Parkinson’s-Plus” syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson’s disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS; the relevance of spe-

Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical

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*Correspondence to: Prof. John R. Hodges, Neuroscience Research Australia and University of New South Wales, Barker Street, Randwick, Sydney, NSW 2031, Australia; [email protected]

Funding agencies: J.B.R. is supported by the Wellcome Trust (088324), and his work on PSP is supported by the PSP Association, the Medical Research Council, and the James F. MacDonnell Foundation. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 15 January 2014; Revised: 18 February 2014; Accepted: 27 February 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25872

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cific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments.

K e y W o r d s : corticobasal syndrome; progressive supranuclear palsy; cognition

scientists alike. It is appropriate that they are considered together, because there is considerable overlap in terms of underlying pathology and clinical phenotypes, which not infrequently overlap during the course of the disorders. They are often termed “Parkinson’sPlus” syndromes, but this term, we feel, is inappropriate, because they are clinically and pathologically distinct from Parkinson’s disease (PD). The term Parkinson’s-Plus may have come to dominate the teaching and diagnosis because of the historical bias toward diagnosis and management by movement disorder specialists. It is, however, now clear that the clinical course is typically dominated by behavioral and cognitive changes that may affect quality of life and carer burden considerably, perhaps as much as the accompanying movement disorder itself.

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FIG. 1. MRIs of CBS. Coronal T1-weighted MRI demonstrates atrophy of the dorsolateral frontal cortex (A), peri-insular region (A and B), and parietal lobes (C and D). In this example, the right hemisphere is more affected than the left, reflected in a larger right lateral ventricle. Marked variability in patterns of atrophy is observed in CBS.

In this review, we consider the two disorders separately, for clarity, but we recognize a significant degree of clinical and neuropathological overlap. Although the main focus is on the cognitive features, these must be placed in a broader clinical setting.

CBS Evolution of Concept Unlike most other neurodegenerative diseases, CBS was described relatively recently, with the report of three cases by Rebeiz et al. in 1967.1 From the outset, a wide range of motor deficits were recognized, including limb apraxia, alien limb phenomenon (ALP), tremor, impaired gait, abnormalities of eye movements, dystonia, hyperreflexia, and rigidity, which can occur in any combination. Cognitive deficits were reported, but initially considered a late-stage phenomenon. It is now clear that most, if not all, patients with CBS have cognitive and/or behavioral features from early in the course of their illness. Indeed, the presence of such deficits has been incorporated into some diagnostic criteria.2

Pathology and Imaging Substrates of Cognitive Change Originally described in association with a distinct pathological entity, corticobasal degeneration, several different pathologies have been associated with CBS, including PSP,3-6 frontotemporal lobar degeneration

with transactivation response (TAR) DNA binding protein 43 kDa (TDP-43) inclusions,7 and Alzheimer’s disease (AD).7-9 Conversely, otherwise typical pathological changes of corticobasal degeneration have been associated with non-CBS clinical presentations. This heterogeneity is almost certainly relevant to variability reported in studies of cognition and makes it important to identify biomarkers of underlying pathology in CBS. Quantitative MRI methods have consistently demonstrated atrophy of the primary motor cortex,9-12 with variable involvement of inferior parietal,13-15 left supplementary motor area,13 and basal ganglia (Fig. 1 AD).9,12 CBS cases resulting from underlying taupositive corticobasal degeneration may have atrophy that is relatively localized to the frontal cortex,10 and a similar pattern of atrophy, albeit less severe, may be observed in (pathological) PSP.11 More widespread atrophy extending to involve the posterior temporal and parietal lobes may indicate underlying Alzheimer’s pathology.7,9-11 CBS cases resulting from underlying TDP-43 pathology may have more frontal involvement.7,11 Furthermore, abnormalities of white matter tracts connecting the frontal and parietal lobes has been documented using diffusor tensor imaging13,16 and may be helpful in the distinction of CBS from PSP.16 Widespread hypometabolism on fluorodeoxyglucose PET (FDG-PET) of the frontal, temporal, and parietal lobes, as well as the basal ganglia, have been described in CBS, particularly contralateral to the most affected side (Fig. 2).17-21

FIG. 2. FDG-PET changes in CBS. FDG-PET images from a CBS patient demonstrate frontoparietal hypometabolism. The degree of hypometabolism in CBS is often asymmetrical and worse contralateral to the clinically most affected side.

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Diagnostic Criteria Numerous diagnostic criteria for CBS have been proposed,2,22-26 but the absence of a pathological gold standard, and the variable clinical features, has hampered universal acceptance of any one set of criteria. Nonetheless, the proposed criteria share several important constructs and emphasize the distinctive features of the syndrome. For example, most criteria require the presence of an asymmetric, progressive, motor syndrome characterized by limb apraxia, parkinsonism, dystonia, myoclonus, and ALP.24,26 Some criteria list sustained response to levodopa (e.g., for greater than 1 year) as an exclusion criterion.2,23,24 From a cognitive perspective, parietal lobe dysfunction, characterized by sensory or visual neglect26 and visuospatial dysfunction on neuropsychological testing, has been emphasised. In addition, the presence of progressive nonfluent aphasic syndrome is recognized as an important feature of the syndrome.2,24-26 Unfortunately, even the new consensus clinical diagnostic criteria for CBS and corticobasal degeneration25 do not reduce the high rates of misdiagnosis,27 and new biomarkers of corticobasal degeneration pathology are required.

Cognition in CBS One of the challenges in reviewing the literature is the potential for bias in the reported frequency of cognitive dysfunction in CBS.28 For instance, movement disorder neurologists may not immediately appreciate the degree of cognitive impairment that could accompany prominent motor dysfunction. Similarly, in patients presenting with progressive aphasia, subtler motor dysfunction is easily overlooked. Even given these biases, multidomain cognitive impairment is reported in a significant proportion of CBS patients and can be documented using cognitive screening tools such as the Addenbrooke’s Cognitive Examination Revised (ACE-R).21,28-31 Patients with CBS may demonstrate impairments in executive function21,28-30,32 and memory,21,28,30,32 but these deficits are nonspecific and do not distinguish CBS from other neurodegenerative diseases, such as frontotemporal dementia, PSP, or AD. By contrast, CBS is characterized by more distinguishing deficits in language,28,32 visuospatial dysfunction, and social cognition.

Language Language dysfunction is common in CBS patients, often as the presenting symptom,9,33 and typically overlaps with that observed in the progressive nonfluent aphasic phenotype of frontotemporal dementia.2,31 More specifically, patients present with agraphia,1,22,34 which has both central and peripheral components, often in association with word-finding difficulty in

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spontaneous speech, and impaired single-word and sentence repetition.9 Although estimates vary significantly, approximately one third of CBS patients have obvious speech and language disturbance.15,35-40 In addition, the incidence of language dysfunction may increase as the syndrome progresses.28 For example, one early study reported speech disturbance in 11% of cases at diagnosis, increasing to 70% at the last follow-up assessment.15 Importantly, subtler language dysfunction may be detected in a significant proportion of patients, even in the absence of clinically apparent aphasia,30,35,39 when detailed testing is performed. Apraxia of speech may be a marker of underlying tau pathology,41 whereas disproportionately impaired sentence repetition, of the type observed in logopenic progressive aphasia,42 has been shown to be more common in CBS with underlying amyloid pathology, as detected by Pittsburgh compound B (PiB)-PET imaging.9 Future studies should, we suggest, examine these associations using more sophisticated language tasks developed for use in primary progressive aphasia.

Visuospatial Function One of the most distinctive cognitive deficits encountered in CBS is marked visuospatial dysfunction,2,8,9,30,35,38,43 which is included in most diagnostic criteria for CBS.2,26,44 Few studies have specifically examined the frequency of visuospatial dysfunction in CBS, although most patients do demonstrate impairment on formal testing.30,33,35,38 Visuospatial deficits in CBS can be quite striking, and patients may even develop Balint’s syndrome (simultanagnosia, oculomotor apraxia, and optic ataxia).45 One difficulty in the assessment of visuospatial function is that many tasks may be confounded by the other deficits encountered in CBS. For example, many tasks require the manipulation of a pencil to copy or produce a complex figure; such tasks may be confounded by significant limb apraxia, not to mention other motor deficits. In addition, an individual subject’s approach to drawing or copying a complex figure (e.g., interlocking pentagons or clockface) is heavily dependent on executive function, which may be impaired, resulting in poor performance regardless of visuospatial ability. Very few studies have examined visuospatial dysfunction in CBS using tasks, such as the visual object and space perception battery (VOSP),46 that only require perception of visual information (e.g. “dot” counting or “incomplete letter” perception). Using this task, one study found that 28% to 52% of CBS patients were impaired, depending on which component of the test was analyzed. Interestingly, the burden of amyloid pathology, as indicated by the intensity of PiB binding, has been shown to inversely correlate very tightly with

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performance on the VOSP in CBS,9 suggesting that visuospatial dysfunction should be investigated in future studies as a potential marker of underlying Alzheimer’s pathology.

Social Cognition Changes in behavior and personality, similar to those observed in frontotemporal dementia, are common in CBS.9,23,28,32,47 Surprisingly, however, very few studies have examined social cognition systematically. Case studies have reported on facial apraxia resulting in the inability to express facial emotional expressions48 and flat aprosodic speech in some patients,32,49,50 suggesting that the ability to express emotions is compromised. This may also extend to the ability to recognize emotional facial expressions.48 Indeed, one study has demonstrated impaired facial emotion recognition ability in CBS, which was positively correlated with reduced levels of insight.51 Whether these deficits extend to more ecologically valid measures of emotional functioning remains unclear, as do the neural correlates underling these apparent deficits. Other aspects of social cognition have also been relatively unexplored. Empathy has been examined using caregiver reports, with patients demonstrating similar levels of empathy as controls,52 although performance at the individual level was highly variable. As such, disturbances in socioemotional cognition may contribute to the high levels of psychiatric and behavioral symptoms in these patients and clearly warrant further investigation.

Challenges and Future Directions The greatest challenge in the study of CBS is the clinical, radiological, neuropsychological, and pathological heterogeneity of the syndrome. To complicate matters, in any individual patient, the clinical features may evolve over time. The nomenclature that has emerged to describe CBS is confusing for most neurologists, let alone other doctors, patients, and their families. A clear distinction must be made between CBS— a variable, but recognizable, clinical syndrome—and the pathological entity corticobasal degeneration, which may present as one of several different, but overlapping, clinical syndromes. Cognitive dysfunction is undoubtedly common in CBS, but the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. The development of novel targeted therapies for underlying tauopathy, for example, emphasizes the importance of establishing an accurate, and early, molecular diagnosis in CBS. Could more detailed clinical phenotyping be helpful in determining the underlying pathology? For example,

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recent subclassification of nonfluent aphasia syndromes has been used to detect the logopenic progressive aphasia phenotype of AD42,53,54; could a similar dissection of language deficits in CBS yield reliable clues to underlying Alzheimer’s pathology, in the way that apraxia of speech appears to predict underlying tau pathology? Finally, better in vivo biomarkers, in addition to PiB-PET, are desperately needed to help refine clinicopathological correlation. In particular, new PET ligands to detect underlying pathologies (e.g., tau or TDP-43) would be ideal to explore clinical or prognostic differences between causative pathologies as well as improve selection of patients for drug trials. Group-wise differences, determined in studies using sophisticated imaging studies, need to be translated for use in individual patients to establish an early, accurate molecular diagnosis in CBS; such attempts are already underway in frontotemporal dementia and other neurodegenerative diseases.55,56

PSP Evolution of Concept It is 50 years since Steele et al. reported on nine cases of patients “who displayed an unusual progressive neurological disorder with ocular, motor and mental features.”57 This became known as Steele-RichardsonOzlewski syndrome, and later as PSP. Patients typically present with backward falls, akinesia and rigidity (often axial), and a characteristic slowing and restriction of vertical eye movements. Cognitive and behavioral changes are very common in PSP and contribute to the impaired quality of life58 and carer burden. The consensus clinical research diagnostic criteria for many years have been Litvan et al.59: over 40 years of age; progression; falls within a year of onset; and vertical supranuclear gaze palsy or slowing of vertical saccades. PSP pathology is confirmed in approximately 95% of cases,59,60 and the clinical diagnosis, is supported by early onset of cognitive impairment. In the last decade, a new distinction has been drawn between (1) patients with neuropathological PSP who manifest the distinctive clinical syndrome described by Steele at al. and captured by long-standing clinical diagnostic criteria; these are now increasingly referred to as PSP-Richardson syndrome or PSP-RS61; and (2) patients with neuropathological PSP whose syndrome resembles PD ante mortem, who are increasingly referred to as PSP-Parkinsonism or PSP-P.61,62 The boundary between CBS and PSP is also sometimes unclear,5,63 and the presence of vertical gaze palsy in otherwise typical CBS presentations is recognized in the new diagnostic criteria for CBS,25 which include “CBS-PSP.” Other clinical presentations are associated with PSP pathology, including pure akinesia and gait

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FIG. 3. MRI changes in PSP. On a mid-line sagittal section, (A, detail in B) the upper brainstem atrophy is severe and gives rise to the appearance of a hummingbird (C), from which the “hummingbird sign” derives its name. In (D), the mid-line of a patient with CBS, of similar global functional impairment and MMSE, shows no such atrophy in this region. The changes associated with PSP are dynamic, as shown by the sequence (E–G) from a single patient. At presentation age 65 years (E), there was mild nondisabling forgetfulness only and normal appearances on MRI. Two years later (F), he had slowing of vertical saccades, reduced verbal fluency, and poor postural reflexes. By year 4 (G), he was unable to walk independently and had severe vertical gaze paresis, dysarthophonia, nonfluency, severe akinesia, and apathy. The hummingbird sign was evident at 4 years, shown in (G). The changes at 2 years in (F) are subtle, but represent too rapid a change from baseline to be considered normal. In (H), the axial slice also shows marked atrophy and the appearance of “Mickey mouse” (white box).

freezing64,65 and primary cognitive change (sometimes closely resembling the behavioral variant of frontotemporal dementia). The nosology of these “atypical PSP” cases is still in development and reflects partly the paucity of pathologically validated biomarkers.

Pathology and Imaging Substrates of Cognitive Change The neuropathology of PSP is distinctive, with hyperphosphorylation and aggregation of the microtubule-associated protein tau in the pallidum, subthalamic nucleus, red nucleus, substantia nigra, pontine tegmentum, striatum, oculomotor nucleus, medulla, and dentate nucleus.66 Cortical pathology is widespread, including neuronal loss and tau deposition in the superior frontal gyrus, the supramarginal gyrus extending along the superior temporal lobe.67 One of the consequences of PSP that may affect cognition is the change in critical neurotransmitters with PET and autoradiographic evidence for reductions of cortical gamma-aminobutyric acid A receptors, acetylcholine, and monoamine vesicular transporters in the striatum and frontal cortex.68-70 PET will also be vital for biomarker development. For example, 18-F-80771 and PB372 bind to aggregated tau species, including the four-repeat tau of PSP. At the time of writing, preliminary studies have been presented, but this is likely

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to be a fast-moving field in the next few years, with radical implications for diagnosis, stratification, and endpoints for clinical trials. Structural and functional brain imaging have revealed a distinctive pattern of change during the progression of PSP. Neuroradiological hallmarks emphasize signs that reflect severe mid-brain atrophy, such as the “hummingbird sign,” “mickey mouse sign,” or “morning glory sign” (Fig. 3A-C). The changes in brain structure are dynamic (Fig. 3E,F), with rates of midbrain loss estimated at approximately 3% per annum, compared to less than 0.5% in age-matched controls.73,74 The distribution of atrophy from voxel-based morphometry75-80 is less widespread than expected from the distribution of high pathological burden.67 The difference may reflect delays between participation in imaging studies and postmortem examination. It may also indicate that neuropathological features, such as tau inclusions, are only weakly correlated with the extensive cell loss that underpins the atrophy detected by MRI. Caudate atrophy has been evident in some MRI reports,81,82 together with severe hypometabolism from FDG-PET,83 as well as abnormal striatofrontal connections,84 suggesting that even if atrophy is not observed, caudate dysfunction may play a part in the cognitive phenotype described. An exciting area of recent work has been the impact of PSP on distributed neurocognitive networks, which can be identified even “at rest.” The spatial distribution

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FIG. 4. Verbal fluency is very sensitive to the presence of PSP. Here, receiver operator characteristic curves demonstrate how well simple letter fluency alone can distinguish PSP from PD and CBS.90 The black line indicates the trade-off between sensitivity and specificity when distinguishing patients between two diagnostic possibilities (the blue areas represent bootstrap 95% confidence intervals). It can be observed in the left panel that there is a value of fluency that is highly sensitive and specific for PSP (vs. PD). The rule of thumb from this figure is that seven P-words or less in 1 minute suggests PSP, more than seven PD, with over 90% accuracy even before other features of the disease are considered. CBS is less well distinguished from PD (middle panel) or PSP (right panel) by verbal fluency alone. AUC, area under the curve, with the observed value and confidence intervals in brackets.

of these functional networks mirrors anatomical connectivity and may serve to promote the progression of disease85,86; PSP markedly changes the distribution and dynamics of these resting-state networks, as measured by functional MRI84 and magnetoencephalography.87

Cognition Cognitive changes were described in the first cases of PSP to be reported on and remain almost universal. Approximately 10% present with cognitive symptoms,73 and approximately 70% will have a form of dementia during the course of the illness.88,89 In PSPRS, two thirds fall below the normal range of the ACE-R at presentation, but with little change over the next 12 to 18 months.90,91 The Mini–State Mental Examination (MMSE), by contrast, is relatively insensitive to the domains of cognition most affected by PSP.73,90,92 Several studies have identified correlations between global cognitive performance and cortical hypometabolism in vivo and with cortical pathology postmortem.77,78,81,93-96 Rather than such summary cognitive measures, it is useful to consider the specific cognitive domains affected by PSP. These include behavioral change (apathy, irritability, childishness, and impulsivity), executive dysfunction, memory, visuospatial, and language and social cognitive deficits. Profound apathy of PSP is common and a supportive feature in diagnostic criteria. The neuropsychology, pharmacology, and functional anatomy of apathy in PSP is not well understood, but it affects over 80% of patients, as indicated by carer ratings of motivation97 and clinical ratings of initiation.98 It is often one of the earliest features, even if not recognized as such before diagnosis. Apathy may be misdiagnosed as depression, but affective symptoms are not necessarily linked to apathy. Akinesia may also be misinterpreted as apathy, especially by those less familiar with the disorder. PSP-RS impairs executive functions that are associated (but not synonymous) with frontal lobe function.

Robbins et al.99 identified deficits in short-term memory and spatial working memory with poor memory strategies. On the Tower of London planning task, PSP-RS increased initial thinking times (suggestive of bradyphrenia) and ability to solve the problem at the first attempt. Patients also perform poorly on attentional set shifting and the simpler Trail Making B task99-101 as well as a range of other executive88,102 and nonverbal reasoning tasks.29,92,99,103 Simple rule acquisition remains relatively intact.91,99 A useful bedside test of executive function is the Frontal Assessment Battery (FAB),104 incorporating abstract conceptualisation (cf. the Dementia Rating Scale), fluency90, sequencing (cf. the Luria three-step sequence), inhibition, and interference of motor commands. Executive function deficits are the most common cognitive impairment found in PSP,51,105 affecting three quarters of patients. Despite deficits in three quarters of patients at baseline, Ghosh et al.91 found little deterioration over 1 year, suggesting again that cognitive changes are an early feature of PSP. Verbal fluency, for both phonological and semantic categories, provides a rapid, easily administered test that approximated other, more complex executive tasks. Fluency is incorporated in the FAB and ACE and is severely impaired by PSP-RS.51,73,88,90,98,106 Indeed, at approximately 3 years from symptoms onset, letter fluency alone can discriminate between PSP-RS and idiopathic PD with 85% specificity and sensitivity.90 As a rule of thumb, seven or fewer Pwords per minute suggests PSP, whereas more than seven suggests another diagnosis (Fig. 4). Semantic fluency is less impaired than letter fluency,29,107,108 in contrast to Alzheimer’s dementia. PSP is often accompanied by impulsivity, despite paradoxically the presence of apathy. Impulsivity may be observed in terms of delay intolerance (e.g., getting up to walk, and falling down, when an assistant is but a few seconds away) or compulsive and impulsive eating. Pathological gambling and other impulse control

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disorders have been reported,109 but their expression may be masked by immobility and/or communication difficulty. The Neuropsychiatric Inventory disinhibition scale is elevated in PSP,66,110,111 and disinhibition, with inappropriate sexual behavior, aggression, or rage, may occur in 33% of those with PSP.105,112 Up to half of patients with PSP may show at least one antisocial behavior,69 including physical assault (30%), hypersexuality (30%), neglect of the traffic rules (30%), or public urination (10%). Impulsivity and inhibition deficits are also revealed by formal tests. For example, the inhibition subscales and grasp reflex of FAB, as well as the Hayling test of sentence completion, are impaired by PSP-RS at diagnosis.91 PSP also impairs antisaccades that depend on inhibition of the prepotent prosaccade113,114 and Stroop test performance.115 In addition to these behavioral deficits, PSP-RS also impairs patients’ awareness of their own errors,51 and the loss of such metacognition for poor performance correlates with impairments in emotion and social cognition. Loss of empathy and impaired social cognition is a core feature of behavioral variant frontotemporal dementia, but is also now recognized to be part of the cognitive syndrome of PSP.51,91,116 Half of patients report that social impairments are a negative influence on their quality of life,58 although it is not clear whether these self-perceived social impairments are the result of the loss of emotion knowledge or breakdown of higher-order social inferences, known as “theory of mind,” as observed in frontotemporal dementia.117 The social cognitive deficits in PSP-RS are supramodal, spanning visual and auditory domains, and are associated with atrophy in the network of frontal regions associated with integration of socially relevant information and interpretation of social meaning.77 Although we have emphasized executive and inhibitory deficits in PSP, approximately one third patients also manifest impairments of memory, including episodic memory30,98,118 and poor visuospatial functions. This is evident on objective tests such as the ACE-R or clinical dementia rating scales, although the subsequent rate of decline after diagnosis (during 18 months) is minimal. The severity of memory and visuospatial impairment relates partially to the stage of disease, rather than duration.98 Autobiographical memory is also subtly impaired,119 albeit without a temporal gradient. This may be, in part, related to executive impairments, affecting the retrieval of autobiographical memory.

ease, many studies have found that the cognitive impairments of PSP-RS are present by the time of diagnosis and change little over the next 12 to 18 months. This suggests that the window of opportunity to prevent cognitive impairment is much earlier than is possible while referral and accurate diagnosis are so delayed and, perhaps, while the diagnosis is so dependent on motor and oculomotor features of the disease. New markers of cognitive change are required to reliably detect relevant cognitive domains in the clinical setting, but also to support clinical trials to restore cognition in PSP. Such cognitive tools would need to minimize fatigue (short tests) and have high reproducibility but low practice effects. These cognitive biomarkers will be a valuable addition to other biomarkers, such as PET imaging of tau pathology. As the phenotype of PSP extends, and interacts with corticobasal degeneration, frontotemporal dementia, PD, aphasia, and pure akinesia, it will be essential to develop clearly operationalized, internally consistent diagnostic criteria. We suggest that cognition can play an important part in improved criteria, but it will require better operationalization of important facets such as apathy.

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