Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

'Communication is difficult': Speech, language and communication needs of people with young onset or rarer forms of non-language led dementia.

BACKGROUND: People with behavioural variant frontotemporal dementia, Lewy body dementia, posterior cortical atrophy and young onset Alzheimer's disease may experience language and communication difficulties. However, the role of speech and language interventions for people with these non-language led dementias has received little attention. AIMS: This study aimed to explore the experiences and perspectives of people living with these conditions, and their families, regarding their language and communication difficulties and how speech and language therapy could address these needs. METHODS: This study employed a qualitative design to explore the experiences of people living with or caring for somebody with behavioural variant frontotemporal dementia, Lewy body dementia, posterior cortical atrophy or young onset Alzheimer's disease, and to understand their opinions about speech and language therapy. Participants were recruited from a support service connected to a dementia clinic to attend one of five focus group meetings. Videorecorded focus groups and interviews were transcribed, and reflexive thematic analysis was used to analyse data from people affected by each type of dementia. RESULTS: A total of 25 participants were recruited to the study, with representation across the different forms of non-language led dementias. The four main themes identified were: (1) communication difficulties as a key difficulty, (2) loss and loneliness, (3) speech and language therapy, and (4) the role of the caregiver. Sixteen subthemes were also identified which highlighted individual issues across disease types. DISCUSSION: Although all the forms of dementia studied here are not considered to be language-led, people with these conditions and/or their care partners identified speech, language and communication as common challenges. These communication difficulties were reported to have a negative impact on their social participation and mental health and participants felt speech and language interventions could help. There is a need for research exploring speech and language interventions developed for and with people with non-language led dementias and their care partners, to ensure they meet the needs of the people they are designed for. WHAT THIS PAPER ADDS: What is already known on the subject People with primary progressive aphasia present with speech, language and communication difficulties, and several speech and language interventions have been developed to meet the needs of this population. However, people with non-language led dementias may also experience speech, language and communication difficulties, and little is known about interventions that may address these difficulties. What this paper adds to existing knowledge People living with or caring for somebody with behavioural variant frontotemporal dementia, Lewy body dementia, posterior cortical atrophy and young onset Alzheimer's disease report experiencing speech, language and communication difficulties that impact on the person with dementia's social participation and mood. Participants in this study also shared their opinions about how speech and language interventions could help, from the earliest stages of the disease. What are the potential or actual clinical implications of this work? Speech and language therapists need to address the individual speech, language and communication needs of people with dementias, even those that are not thought to be language-led. Current speech and language therapy service provision does not meet the needs of people with non-language led dementias and further research is required to develop interventions and services to meet these needs.

"I Want to Do Something" - Exploring What Makes Activities Meaningful for Community-Dwelling People Living With Dementia: A Focused Ethnographic Study.

Supporting ageing in place, quality of life, and activity engagement are public health priorities for people with dementia. The importance of maintaining opportunities for meaningful activities has been widely acknowledged for those with dementia in long-term care, but little is known about what makes activities meaningful for, and how they are experienced by, people with different types of dementia in their own homes. This study used focussed ethnographic methods to explore the motivations and meanings of everyday activity engagement within the homes of 10 people with memory-led Alzheimer's disease and 10 people with posterior cortical atrophy. While participants' interactions with their everyday environments were challenged by their diagnoses, they were all finding ways to continue meaning-making via various activities. The main findings are encapsulated in three themes: (1) The fun and the function of activities; (2) Reciprocities of care, and (3) The constitution and continuity of (a changing) self. Ongoing engagement with both fun and functional activities offered participants living with different dementias opportunities to connect with others, to offer care and support (as well as receive it), and to maintain a sense of self and identity. Implications are discussed regarding the development and delivery of tailored interventions and support to enable continued engagement in meaningful activities for people with different types of dementia living in the community.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Altered visual and haptic verticality perception in posterior cortical atrophy and Alzheimer's disease.

There is increasing theoretical and empirical support for the brain combining multisensory information to determine the direction of gravity and hence uprightness. A fundamental part of the process is the spatial transformation of sensory signals between reference frames: eye-centred, head-centred, body-centred, etc. The question 'Am I the right way up?' posed by a patient with posterior cortical atrophy (PCA) suggests disturbances in upright perception, subsequently investigated in PCA and typical Alzheimer's disease (tAD) based on what looks or feels upright. Participants repeatedly aligned to vertical a rod presented either visually (visual-vertical) or haptically (haptic-vertical). Visual-vertical involved orienting a projected rod presented without or with a visual orientation cue (circle, tilted square (±18°)). Haptic-vertical involved orientating a grasped rod with eyes closed using a combination of side (left, right) and hand (unimanual, bimanual) configurations. Intraindividual uncertainty and bias defined verticality perception. Uncertainty was consistently greater in both patient groups than in control groups, and greater in PCA than tAD. Bias in the frontal plane was strongly directionally affected by visual cue tilt (visual-vertical) and grip side (haptic-vertical). A model was developed that assumed verticality information from multiple sources is combined in a statistically optimal way to produce observed uncertainties and biases. Model results suggest the mechanism that spatially transforms graviceptive information between body parts is disturbed in both patient groups. Despite visual dysfunction being typically considered the primary feature of PCA, disturbances were greater in PCA than tAD particularly for haptic-vertical, and are considered in light of posterior parietal vulnerability. KEY POINTS: The perception of upright requires accurate and precise estimates of orientation based on multiple noisy sensory signals. The question 'Am I the right way up?' posed by a patient with posterior cortical atrophy (PCA; purported 'visual variant Alzheimer's') suggests disturbances in the perception of upright. What looks or feels upright in PCA and typical Alzheimer's disease (tAD) was investigated by asking participants to repeatedly align to vertical a rod presented visually (visual-vertical) or haptically (haptic-vertical). PCA and tAD groups exhibited not only greater perceptual uncertainty than controls, but also exaggerated bias induced by tilted visual orientation cues (visual-vertical) and grip side (haptic-vertical). When modelled, these abnormalities, which were particularly evident in PCA haptic-vertical performance, were compatible with disruption of a mechanism that spatially transforms verticality information between body parts. The findings suggest an important role of posterior parietal cortex in verticality perception, and have implications for understanding spatial disorientation in dementia.

A cross-sectional study of memory and executive functions in patients with sporadic inclusion body myositis.

INTRODUCTION/AIMS: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterized by muscle deposition of various proteins typically associated with Alzheimer disease and other neurodegenerative diseases. Although cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. In this study we investigated whether cognitive performance of patients with IBM differs from population norms, focusing on cognitive domains affected in early Alzheimer disease (memory, executive function), and to test whether disease duration and the level of disability of IBM are associated with cognitive function. METHODS: Twenty-four patients with IBM (mean [standard deviation]: age, 62.0 [7.2] years; disease duration, 9.6 [4.8] years) were assessed cross-sectionally on neuropsychological tests covering multiple cognitive domains, including the Preclinical Alzheimer Cognitive Composite (PACC). Performance was compared with published normative data adjusted for age, sex, and education (National Alzheimer's Coordinating Center; N = 3268). Associations were examined between PACC score, disease duration, and level of disability (assessed using the IBM Functional Rating Scale [IBMFRS]). RESULTS: Across all cognitive tests, group performance was within ±1 standard deviation of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, P = .87) or IBMFRS total score (ρ = 0.14, P = .52). DISCUSSION: Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients and will be of value for clinicians and patients alike.

Impairments of auditory scene analysis in posterior cortical atrophy.

Although posterior cortical atrophy is often regarded as the canonical 'visual dementia', auditory symptoms may also be salient in this disorder. Patients often report particular difficulty hearing in busy environments; however, the core cognitive process-parsing of the auditory environment ('auditory scene analysis')-has been poorly characterized. In this cross-sectional study, we used customized perceptual tasks to assess two generic cognitive operations underpinning auditory scene analysis-sound source segregation and sound event grouping-in a cohort of 21 patients with posterior cortical atrophy, referenced to 15 healthy age-matched individuals and 21 patients with typical Alzheimer's disease. After adjusting for peripheral hearing function and performance on control tasks assessing perceptual and executive response demands, patients with posterior cortical atrophy performed significantly worse on both auditory scene analysis tasks relative to healthy controls and patients with typical Alzheimer's disease (all P < 0.05). Our findings provide further evidence of central auditory dysfunction in posterior cortical atrophy, with implications for our pathophysiological understanding of Alzheimer syndromes as well as clinical diagnosis and management.

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.

Sequences of cognitive decline in typical Alzheimer's disease and posterior cortical atrophy estimated using a novel event-based model of disease progression.

INTRODUCTION: This work aims to characterize the sequence in which cognitive deficits appear in two dementia syndromes. METHODS: Event-based modeling estimated fine-grained sequences of cognitive decline in clinically-diagnosed posterior cortical atrophy (PCA) ( n=94 ) and typical Alzheimer's disease (tAD) ( n=61 ) at the UCL Dementia Research Centre. Our neuropsychological battery assessed memory, vision, arithmetic, and general cognition. We adapted the event-based model to handle highly non-Gaussian data such as cognitive test scores where ceiling/floor effects are common. RESULTS: Experiments revealed differences and similarities in the fine-grained ordering of cognitive decline in PCA (vision first) and tAD (memory first). Simulation experiments reveal that our new model equals or exceeds performance of the classic event-based model, especially for highly non-Gaussian data. DISCUSSION: Our model recovered realistic, phenotypical progression signatures that may be applied in dementia clinical trials for enrichment, and as a data-driven composite cognitive end-point.

Consensus classification of posterior cortical atrophy.

INTRODUCTION: A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. METHODS: Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. RESULTS: A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome-level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. DISCUSSION: There was strong agreement regarding the definition of the core clinico-radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single-center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

Auditory spatial processing in Alzheimer's disease.

The location and motion of sounds in space are important cues for encoding the auditory world. Spatial processing is a core component of auditory scene analysis, a cognitively demanding function that is vulnerable in Alzheimer's disease. Here we designed a novel neuropsychological battery based on a virtual space paradigm to assess auditory spatial processing in patient cohorts with clinically typical Alzheimer's disease (n = 20) and its major variant syndrome, posterior cortical atrophy (n = 12) in relation to healthy older controls (n = 26). We assessed three dimensions of auditory spatial function: externalized versus non-externalized sound discrimination, moving versus stationary sound discrimination and stationary auditory spatial position discrimination, together with non-spatial auditory and visual spatial control tasks. Neuroanatomical correlates of auditory spatial processing were assessed using voxel-based morphometry. Relative to healthy older controls, both patient groups exhibited impairments in detection of auditory motion, and stationary sound position discrimination. The posterior cortical atrophy group showed greater impairment for auditory motion processing and the processing of a non-spatial control complex auditory property (timbre) than the typical Alzheimer's disease group. Voxel-based morphometry in the patient cohort revealed grey matter correlates of auditory motion detection and spatial position discrimination in right inferior parietal cortex and precuneus, respectively. These findings delineate auditory spatial processing deficits in typical and posterior Alzheimer's disease phenotypes that are related to posterior cortical regions involved in both syndromic variants and modulated by the syndromic profile of brain degeneration. Auditory spatial deficits contribute to impaired spatial awareness in Alzheimer's disease and may constitute a novel perceptual model for probing brain network disintegration across the Alzheimer's disease syndromic spectrum.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer's disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer's disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment.

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

INTRODUCTION: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. METHODS: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. RESULTS: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). DISCUSSION: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

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.

Exploring experiential differences in everyday activities - A focused ethnographic study in the homes of people living with memory-led Alzheimer's disease and posterior cortical atrophy.

BACKGROUND: Supporting ageing in place, quality of life and activity engagement are public health priorities for people living with dementia, but little is known about the needs and experiences of community-dwelling people with rarer forms of dementia with lesser known symptoms. Posterior cortical atrophy (PCA) is a rare form of dementia usually caused by Alzheimer's disease but which is characterised by diminished visual processing (rather than a dominant memory problem), which poses challenges for maintaining independence and accessing appropriate support. METHODS: This study used a comparative qualitative design and focussed ethnographic methods to explore experiential differences in activity engagement for 10 people with the most common, memory-led presentation of Alzheimer's disease and 10 people with posterior cortical atrophy within their everyday home environments. RESULTS: While the data collection revealed much rich variation in individual and contextual factors, some tentative high-level differences in the experiences of everyday activities could be drawn out, seemingly attributable to the different diagnoses' differing dominant symptoms. These included people with posterior cortical atrophy being less likely to use environmental cues to initiate activities, and more likely to withhold from asking for support because of preserved insight into the impact of this on carers. This lack of initiation of activities could be misinterpreted as apathy. People with posterior cortical atrophy also were discouraged from engaging in activities by disorientation within the home, and difficulties localising, identifying and manipulating objects. People with the more common, memory-led presentation of Alzheimer's disease exhibited more memory-based difficulties with engaging with activities such as forgetting planned activities, where to locate the items required for an activity and the steps involved. Despite these distinct symptom-led challenges, all participants and their family members demonstrated resourcefulness and resilience in making creative adaptations to support continued engagement in everyday activities, supporting the widely reported management strategies of people with dementia of the Alzheimer's type more generally. CONCLUSIONS: These findings offer helpful insights into some the differing impacts dementia related visual and memory impairments can have on everyday activity engagement, which will be helpful for others navigating these challenges and the health and social care practitioners working with people affected by these conditions. The findings also highlight the vast individual variation in the multitude of individual and contextual factors involved in everyday activity engagement, and suggest important areas for future work utilising methods which are similarly high in ecological validity and accessibility as the home-based focussed ethnographic methods utilised here.

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis.

BACKGROUND: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort. METHODS: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2. FINDINGS: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I2=77%), 60% (56-64; I2=35%) were women, and 80% (72-89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid ß in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I2=89%), Lewy body disease (44%, 25-62; I2=77%), and cerebrovascular injury (42%, 24-60; I2=88%). INTERPRETATION: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity. FUNDING: None.

Revealing Individual Neuroanatomical Heterogeneity in Alzheimer Disease Using Neuroanatomical Normative Modeling.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology. To explore this, we used neuroanatomical normative modeling to index regional patterns of variability in cortical thickness. We aimed to characterize individual differences and outliers in cortical thickness in patients with AD, people with mild cognitive impairment (MCI), and controls. Furthermore, we assessed the relationships between cortical thickness heterogeneity and cognitive function, ß-amyloid, phosphorylated-tau, and ApoE genotype. Finally, we examined whether cortical thickness heterogeneity was predictive of conversion from MCI to AD. METHODS: Cortical thickness measurements across 148 brain regions were obtained from T1-weighted MRI scans from 62 sites of the Alzheimer's Disease Neuroimaging Initiative. AD was determined by clinical and neuropsychological examination with no comorbidities present. Participants with MCI had reported memory complaints, and controls were cognitively normal. A neuroanatomical normative model indexed cortical thickness distributions using a separate healthy reference data set (n = 33,072), which used hierarchical Bayesian regression to predict cortical thickness per region using age and sex, while adjusting for site noise. Z-scores per region were calculated, resulting in a Z-score brain map per participant. Regions with Z-scores <-1.96 were classified as outliers. RESULTS: Patients with AD (n = 206) had a median of 12 outlier regions (out of a possible 148), with the highest proportion of outliers (47%) in the parahippocampal gyrus. For 62 regions, over 90% of these patients had cortical thicknesses within the normal range. Patients with AD had more outlier regions than people with MCI (n = 662) or controls (n = 159) (F(2, 1,022) = 95.39, p = 2.0 × 10-16). They were also more dissimilar to each other than people with MCI or controls (F(2, 1,024) = 209.42, p = 2.2 × 10-16). A greater number of outlier regions were associated with worse cognitive function, CSF protein concentrations, and an increased risk of converting from MCI to AD within 3 years (hazard ratio 1.028, 95% CI 1.016-1.039, p = 1.8 × 10-16). DISCUSSION: Individualized normative maps of cortical thickness highlight the heterogeneous effect of AD on the brain. Regional outlier estimates have the potential to be a marker of disease and could be used to track an individual's disease progression or treatment response in clinical trials.

Effects of the visual environment on object localization in posterior cortical atrophy and typical Alzheimer's disease.

Introduction: Visual processing deficits in Alzheimer's disease are associated with diminished functional independence. While environmental adaptations have been proposed to promote independence, recent guidance gives limited consideration to such deficits and offers conflicting recommendations for people with dementia. We evaluated the effects of clutter and color contrasts on performances of everyday actions in posterior cortical atrophy and memory-led typical Alzheimer's disease. Methods: 15 patients with posterior cortical atrophy, 11 with typical Alzheimer's disease and 16 healthy controls were asked to pick up a visible target object as part of two pilot repeated-measures investigations from a standing or seated position. Participants picked up the target within a controlled real-world setting under varying environmental conditions: with/without clutter, with/without color contrast cue and far/near target position. Task completion time was recorded using a target-mounted inertial measurement unit. Results: Across both experiments, difficulties locating a target object were apparent through patient groups taking an estimated 50-90% longer to pick up targets relative to controls. There was no evidence of effects of color contrast when locating objects from standing/seated positions and of any other environmental conditions from a standing position on completion time in any participant group. Locating objects, surrounded by five distractors rather than none, from a seated position was associated with a disproportionately greater effect on completion times in the posterior cortical atrophy group relative to the control or typical Alzheimer's disease groups. Smaller, not statistically significant but directionally consistent, ratios of relative effects were seen for two distractors compared with none. Discussion: Findings are consistent with inefficient object localization in posterior cortical atrophy relative to typical Alzheimer's disease and control groups, particularly with targets presented within reaching distance among visual clutter. Findings may carry implications for considering the adverse effects of visual clutter in developing and implementing environmental modifications to promote functional independence in Alzheimer's disease.

Diagnosis and Management of Posterior Cortical Atrophy.

Purpose of review: The study aims to provide a summary of recent developments for diagnosing and managing posterior cortical atrophy (PCA). We present current efforts to improve PCA characterisation and recommendations regarding use of clinical, neuropsychological and biomarker methods in PCA diagnosis and management and highlight current knowledge gaps. Recent findings: Recent multi-centre consensus recommendations provide PCA criteria with implications for different management strategies (e.g. targeting clinical features and/or disease). Studies emphasise the preponderance of primary or co-existing Alzheimer's disease (AD) pathology underpinning PCA. Evidence of approaches to manage PCA symptoms is largely derived from small studies. Summary: PCA diagnosis is frequently delayed, and people are likely to receive misdiagnoses of ocular or psychological conditions. Current treatment of PCA is symptomatic - pharmacological and non-pharmacological - and the use of most treatment options is based on small studies or expert opinion. Recommendations for non-pharmacological approaches include interdisciplinary management tailored to the PCA clinical profile - visual-spatial - rather than memory-led, predominantly young onset - and psychosocial implications. Whilst emerging disease-modifying treatments have not been tested in PCA, an accurate and timely diagnosis of PCA and determining underlying pathology is of increasing importance in the advent of disease-modifying therapies for AD and other albeit rare causes of PCA.

Symptom-led staging for primary progressive aphasia.

The primary progressive aphasias (PPA) present complex and diverse challenges of diagnosis, management and prognosis. A clinically-informed, syndromic staging system for PPA would take a substantial step toward meeting these challenges. This study addressed this need using detailed, multi-domain mixed-methods symptom surveys of people with lived experience in a large international PPA cohort. We administered structured online surveys to caregivers of patients with a canonical PPA syndromic variant (nonfluent/agrammatic (nvPPA), semantic (svPPA) or logopenic (lvPPA)). In an 'exploratory' survey, a putative list and ordering of verbal communication and nonverbal functioning (nonverbal thinking, conduct and wellbeing, physical) symptoms was administered to 118 caregiver members of the UK national PPA Support Group. Based on feedback, we expanded the symptom list and created six provisional clinical stages for each PPA subtype. In a 'consolidation' survey, these stages were presented to 110 caregiver members of UK and Australian PPA Support Groups, and refined based on quantitative and qualitative feedback. Symptoms were retained if rated as 'present' by a majority (at least 50%) of respondents representing that PPA syndrome, and assigned to a consolidated stage based on majority consensus; the confidence of assignment was estimated for each symptom as the proportion of respondents in agreement with the final staging for that symptom. Qualitative responses were analysed using framework analysis. For each PPA syndrome, six stages ranging from 1 ('Very mild') to 6 ('Profound') were identified; earliest stages were distinguished by syndromic hallmark symptoms of communication dysfunction, with increasing trans-syndromic convergence and dependency for basic activities of daily living at later stages. Spelling errors, hearing changes and nonverbal behavioural features were reported at early stages in all syndromes. As the illness evolved, swallowing and mobility problems were reported earlier in nfvPPA than other syndromes, while difficulty recognising familiar people and household items characterised svPPA and visuospatial symptoms were more prominent in lvPPA. Overall confidence of symptom staging was higher for svPPA than other syndromes. Across syndromes, functional milestones were identified as key deficits that predict the sequence of major daily life impacts and associated management needs. Qualitatively, we identified five major themes encompassing 15 subthemes capturing respondents' experiences of PPA and suggestions for staging implementation. This work introduces a prototypical, symptom-led staging scheme for canonical PPA syndromes: the PPA Progression Planning Aid (PPA 2 ). Our findings have implications for diagnostic and care pathway guidelines, trial design and personalised prognosis and treatment for people living with these diseases.