Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy.

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer's disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer's disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer's disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer's disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer's disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer's disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer's disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer's disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer's disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer's disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.

Verbal adynamia in parkinsonian syndromes: behavioral correlates and neuroanatomical substrate.

Verbal adynamia (impaired language generation, as during conversation) has not been assessed systematically in parkinsonian disorders. We addressed this in patients with Parkinson's dementia, progressive supranuclear palsy and corticobasal degeneration. All disease groups showed impaired verbal fluency and sentence generation versus healthy age-matched controls, after adjusting for general linguistic and executive factors. Dopaminergic stimulation in the Parkinson's group selectively improved verbal generation versus other cognitive functions. Voxel-based morphometry identified left inferior frontal and posterior superior temporal cortical correlates of verbal generation performance. Verbal adynamia warrants further evaluation as an index of language network dysfunction and dopaminergic state in parkinsonian disorders.

Prominent effects and neural correlates of visual crowding in a neurodegenerative disease population.

Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n=26), typical Alzheimer's disease (n=17) and healthy control subjects (n=14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy provides a neurodegenerative disease model for exploring the basis of crowding. These data have significant implications for patients with, or who will go on to develop, dementia-related visual impairment, in whom acquired excessive crowding likely contributes to deficits in word, object, face and scene perception.

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

Visualizing the emergence of posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a neurodegenerative condition characterized by a progressive loss of visual processing skills and other posterior functions. Diagnosis is often delayed in PCA as symptoms can be difficult for the patient to articulate and for the clinician to detect. Diagnosis is particularly challenging in the earliest stages of the disease since visual symptoms are often mistaken as being related to ocular rather than cortical dysfunction. This report describes a 61-year-old man who volunteered as a healthy control participant in a longitudinal research study and was followed up for 5 years. During that time he showed a gradual decline in posterior cortical functions including visuoperceptual, visuospatial, and literacy impairments in the context of intact verbal episodic memory. Structural image analysis revealed atrophy which was initially most marked in inferior temporal and posterior parietal cortices before spreading to occipital cortices and subsequently to more anterior regions. Based on the clinical, neuropsychological and neuroimaging features, a diagnosis of PCA was made. The present case represents a unique opportunity to study and visualize the evolution of PCA from the very earliest symptomatic stages.

Basic visual function and cortical thickness patterns in posterior cortical atrophy.

Posterior cortical atrophy (PCA) is characterized by a progressive decline in higher-visual object and space processing, but the extent to which these deficits are underpinned by basic visual impairments is unknown. This study aimed to assess basic and higher-order visual deficits in 21 PCA patients. Basic visual skills including form detection and discrimination, color discrimination, motion coherence, and point localization were measured, and associations and dissociations between specific basic visual functions and measures of higher-order object and space perception were identified. All participants showed impairment in at least one aspect of basic visual processing. However, a number of dissociations between basic visual skills indicated a heterogeneous pattern of visual impairment among the PCA patients. Furthermore, basic visual impairments were associated with particular higher-order object and space perception deficits, but not with nonvisual parietal tasks, suggesting the specific involvement of visual networks in PCA. Cortical thickness analysis revealed trends toward lower cortical thickness in occipitotemporal (ventral) and occipitoparietal (dorsal) regions in patients with visuoperceptual and visuospatial deficits, respectively. However, there was also a lot of overlap in their patterns of cortical thinning. These findings suggest that different presentations of PCA represent points in a continuum of phenotypical variation.

Global gray matter changes in posterior cortical atrophy: a serial imaging study.

BACKGROUND: Posterior cortical atrophy (PCA) is a neurodegenerative condition predominantly associated with Alzheimer's disease (AD) pathology. Cross-sectional imaging studies have shown different atrophy patterns in PCA patients compared with typical amnestic Alzheimer's disease (tAD) patients, with greatest atrophy commonly found in posterior regions in the PCA group, whereas in the tAD group, atrophy is most prominent in medial temporal lobe regions. However, differential longitudinal atrophy patterns are not well understood. METHODS: This study assessed longitudinal changes in brain and gray matter volumes in 17 PCA patients, 16 tAD patients, and 18 healthy control subjects. Both patient groups had symptom durations of approximately 5 years. RESULTS: Progressive gray matter losses in both PCA and tAD patients were relatively widespread throughout the cortex, compared with control subjects, and were not confined to areas related to initial symptomatology. A multivariate classification analysis revealed a statistically significant group separation between PCA and tAD patients, with 72.7% accuracy (P < .01). CONCLUSION: Progression from an initially focal presentation to a more global pattern suggests that these different clinical presentations of AD might converge pathologically over time.

Different patterns of spoken and written word comprehension deficit in aphasic stroke patients.

This study presents neuropsychological evidence for differences in the semantic representations underpinning spoken and written word comprehension. Potential modality-based discrepancies in the semantic system were examined by testing whether spoken word (auditory-verbal input) and written word (visual-verbal input) comprehension exhibited the same effect profile on variables typically used to distinguish so-called access and storage disorders (e.g., response consistency, sensitivity to item frequency). The study was based on the premise that damage to a common set of semantic representations should have an equivalent impact upon comprehension performance irrespective of input modality, whereas damage to partially dissociable semantic representations may give rise to different qualities of deficit (access/storage) in the comprehension of stimuli presented in different input modalities (spoken/written). The study involved two patients with global aphasia following left middle cerebral artery stroke (F.B.I. and H.O.P.). The two patients showed matched performance on conventional tests of single word comprehension with clear evidence of semantic impairment for stimuli presented in both the spoken and written input modalities. However, in H.O.P., spoken and written word comprehension was affected in the same way by variations in stimulus category, frequency, and multiple stimulus presentations, whilst in F.B.I., there were clear differences between input modalities with all three variables. More specifically, F.B.I.'s written word comprehension was significantly affected by category (living > nonliving) and frequency (high > low) but not multiple presentations (single = multiple), more consistent with degradation of stored representations (storage deficit). By contrast, his spoken word comprehension was unaffected by category (living = nonliving) and frequency (high = low) but was affected by multiple presentations (single > multiple; serial position effects), more consistent with impaired access to stored representations (access deficit). These spoken/written input modality differences were observed on tasks matched closely for output modality, stimulus identity, and executive control requirements. It is argued that subtle differences in comprehension performance for stimuli presented in different input modalities may reflect damage to multimodal representations, which are intermediate between unimodal and amodal representations on a continuum of convergence within the semantic system. These ideas are discussed in the context of existing "distributed-only", "distributed-plus-convergence", or "distributed-plus-hub" models of conceptual knowledge.

Abnormal visual phenomena in posterior cortical atrophy.

Individuals with posterior cortical atrophy (PCA) report a host of unusual and poorly explained visual disturbances. This preliminary report describes a single patient (CRO), and documents and investigates abnormally prolonged colour afterimages (concurrent and prolonged perception of colours complimentary to the colour of an observed stimulus), perceived motion of static stimuli, and better reading of small than large letters. We also evaluate CRO's visual and vestibular functions in an effort to understand the origin of her experience of room tilt illusion, a disturbing phenomenon not previously observed in individuals with cortical degenerative disease. These visual symptoms are set in the context of a 4-year longitudinal neuropsychological and neuroimaging investigation of CRO's visual and other cognitive skills. We hypothesise that prolonged colour after-images are attributable to relative sparing of V1 inhibitory interneurons; perceived motion of static stimuli reflects weak magnocellular function; better reading of small than large letters indicates a reduced effective field of vision; and room tilt illusion effects are caused by disordered integration of visual and vestibular information. This study contributes to the growing characterisation of PCA whose atypical early visual symptoms are often heterogeneous and frequently under-recognised.

Progressive logopenic/phonological aphasia: erosion of the language network.

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. Five of nine patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.

The differential dependence of abstract and concrete words upon associative and similarity-based information: Complementary semantic interference and facilitation effects.

We report mirror-image effects of interference and facilitation in the semantic processing of identical sets of abstract and concrete words in a patient F.B.I. with global aphasia following a large left middle cerebral artery stroke. Interference was elicited when the tasks involved comprehending the spoken form of each word, but facilitation was found when the patient read aloud the written forms of the same words. More importantly, irrespective of whether the dynamic effect was one of facilitation or interference, effects of semantic association were observed for abstract words, whilst effects primarily of semantic similarity were observed for concrete words. These results offer further neuropsychological evidence that the more abstract a word, the greater its dependence upon associative information and the smaller its dependence upon similarity-based information. The investigations also contribute to a converging body of evidence that suggests that this theory generalizes across different experimental paradigms, stimuli, and participants and also across different cognitive processes within individual patients. The data support a graded rather than binary or ungraded model of the relationships between concreteness, association, and similarity, and the basis for concrete words' greater dependence upon similarity-based information is discussed in terms of the development of taxonomic structures and categorical thought in young children.

The relationship between visual crowding and letter confusability: towards an understanding of dyslexia in posterior cortical atrophy.

Visual crowding is a form of masking in which target identification is hindered by excessive feature integration from other stimuli in the vicinity. It has previously been suggested that excessive visual crowding constitutes one specific form of early-visual-processing deficit, which may be observed in individuals with posterior cortical atrophy (PCA). This study investigated whether excessive visual crowding plays a significant role in the acquired dyslexia of two PCA patients, whose reading was characterized by visual paralexias. The patients were administered a series of letter, flanked letter, and word recognition tasks, and the effects of letter spacing and letter confusability upon response accuracy and latency were measured. In both patients, the results showed (a) evidence of excessive visual crowding, (b) a significant interaction between letter spacing and confusability on flanked letter identification tasks, and (c) effects of letter confusability affecting flanked but not unflanked letter identification. However, only mild improvements in reading accuracy were achieved in the experimental manipulations of interletter spacing within words because these manipulations had a dual effect: Increasing spacing improved individual letter identification but damaged whole-word form and/or parallel letter processing. We consider the implications of these results for the characterization of dyslexia in PCA, the design of reading rehabilitation strategies, and the relationship between visual crowding and letter confusability. In particular, we argue that the reading deficits observed in our patients cannot be accounted for solely in terms of a very low signal-to-noise ratio for letter identification, and that an additional crowding deficit is implicated in which excessive integration of fundamental letter features leads to the formation of incorrect letter percepts.

Pure progressive amnesia and the APPV717G mutation.

We report an isolated, slowly progressive, pure amnestic phenotype in a 59-year-old member of a family affected by autosomal dominant familial Alzheimer disease. Early-onset Alzheimer disease in this family was associated with a V717G mutation in the amyloid precursor protein gene (APP). Subjective impairment of episodic memory began in our subject at the age of 44 years and subsequent, longitudinal neuropsychologic assessment confirmed progressive, severe, global impairment of memory functions over a period of 14 years with preservation of other cognitive domains. The mean annual hippocampal atrophy rate, determined by volumetric magnetic resonance imaging was intermediate between values previously associated with cognitively normal individuals and those with sporadic Alzheimer disease.

A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.

The Influence of refractoriness upon comprehension of non-verbal auditory stimuli.

An investigation of non-verbal auditory comprehension in two patients with global aphasia following stroke is reported. The primary aim of the investigation was to establish whether refractory access disorders can affect non-verbal input modalities. All previous reports of refractoriness, a cognitive syndrome characterized by response inconsistency, sensitivity to temporal factors and insensitivity to item frequency, have involved comprehension tasks which have a verbal component. Two main experiments are described. The first consists of a novel sound-to-picture and sound-to-word matching task in which comprehension of environmental sounds is probed under conditions of semantic relatedness and semantic unrelatedness. In addition to the two stroke patients, the performance of a group of 10 control patients with non-vascular pathology is reported, along with evidence of semantic relatedness effects in sound comprehension. The second experiment examines environmental sound comprehension within a repetitive probing paradigm which affords assessment of the effects of semantic relatedness, response consistency and presentation rate. It is demonstrated that the two stroke patients show a significant increase in error rate across multiple probes of the same set of sound stimuli, indicating the presence of refractoriness within this non-verbal domain. The implications of the results are discussed with reference to our current understanding of the mechanisms of refractoriness.

Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

BACKGROUND: A 55-year-old woman was followed over a 13-year period as part of a longitudinal study of people at risk for familial dementia. She was a member of a family with an autosomal dominant familial dementia that fulfilled consensus criteria for frontotemporal lobar degeneration. The patient was initially asymptomatic but developed progressive behavioral and cognitive decline characterized by apathy, impaired emotion recognition, mixed aphasia and parietal lobe dysfunction. INVESTIGATIONS: Clinical assessments, neuropsychometry, volumetric brain MRI, and genetic mutation screening. DIAGNOSIS: Progranulin-associated frontotemporal lobar degeneration. MANAGEMENT: Explanation of the patient's condition and genetic counseling for her family.

Agnosia for bird calls.

The cognitive organisation of nonverbal auditory knowledge remains poorly defined. Deficits of environmental sound as well as word and visual object knowledge are well-recognised in semantic dementia. However, it is unclear how auditory cognition breaks down in this disorder and how this relates to deficits in other knowledge modalities. We had the opportunity to study a patient with a typical syndrome of semantic dementia who had extensive premorbid knowledge of birds, allowing us to assess the impact of the disease on the processing of auditory in relation to visual and verbal attributes of this specific knowledge category. We designed a novel neuropsychological test to probe knowledge of particular avian characteristics (size, behaviour [migratory or nonmigratory], habitat [whether or not primarily water-dwelling]) in the nonverbal auditory, visual and verbal modalities, based on a uniform two-alternative-forced-choice procedure. The patient's performance was compared to healthy older individuals of similar birding experience. We further compared his performance on this test of bird knowledge with his knowledge of familiar human voices and faces. Relative to healthy birder controls, the patient showed marked deficits of bird call and bird name knowledge but relatively preserved knowledge of avian visual attributes and retained knowledge of human voices and faces. In both the auditory and visual modalities, his knowledge of the avian characteristics of size and behaviour was intact whereas his knowledge of the associated characteristic of habitat was deficient. This case provides further evidence that nonverbal auditory knowledge has a fractionated organisation that can be differentially targeted in semantic dementia.

A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study.

BACKGROUND: The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. METHODS: A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used. RESULTS: Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p < 0.05) evidence of a carry-over effect on MMSE. Therefore, the analysis of treatment effect on MMSE was restricted to the first 12-week period. Treatment effect at 6 weeks was statistically significant (difference = 2.5 in favour of donepezil, 95% CI 0.1 to 5.0, p < 0.05). Treatment effect at 12 weeks was close, but not statistically significant (difference = 2.0 in favour of donepezil, 95% CI -0.1 to 4.5, p > 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil. CONCLUSIONS: In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated. TRIAL REGISTRATION: Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010.

Extensive and temporally ungraded retrograde amnesia in encephalitis associated with antibodies to voltage-gated potassium channels.

BACKGROUND: Encephalitis associated with antibodies to voltage-gated potassium channels (VGKC-Ab) is characterized by epilepsy, behavioral changes, and anterograde memory impairment. Magnetic resonance imaging reveals abnormal signal predominantly restricted to the mediotemporal lobes. OBJECTIVE: To determine the temporal extent and potential reversibility of retrograde amnesia in 3 patients with VGKC-Ab-associated encephalitis. DESIGN: Case report. SETTING: Clinical. Patients Three patients diagnosed as having VGKC-Ab-associated encephalitis underwent cognitive testing before and after immunotherapy. MAIN OUTCOME MEASURES: In addition to standard neuropsychological tests, retrograde memory was assessed using 2 novel tests. Memory for past newsworthy events was assessed using a public events test; test material was divided into epochs of 5 years and spanned approximately 25 years. This was complemented by a famous faces test in which patients were required to identify individuals from the recent and remote past. RESULTS: All 3 patients were found to have temporally ungraded retrograde amnesia dating back more than 20 years. Magnetic resonance imaging in all patients revealed high-signal abnormalities predominantly affecting the hippocampi. Subsequent testing performed after immunotherapy revealed subjective improvement but no evidence of a temporal gradient in the recovery of past memories. CONCLUSIONS: Encephalitis associated with VGKC-Ab results in extensive and temporally ungraded retrograde amnesia that is partially reversible with immunotherapy. Magnetic resonance imaging high-signal abnormalities were primarily restricted to the hippocampi. These data are supportive of theories postulating a role for the hippocampus in the storage and retrieval of all past memories, irrespective of age, rather than theories of memory consolidation that propose an involvement of the hippocampus only in the temporary storage of memories.