Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Lobar Microbleeds in the Posterior Cortical Atrophy Syndrome: A Comparison to Typical Alzheimer's Disease.

PURPOSE OF THE STUDY: Posterior cortical atrophy is a clinico-radiographical syndrome that presents with higher-order visual dysfunction and is most commonly due to Alzheimer's disease. Understanding factors associated with atypical presentations of Alzheimer's disease, such as posterior cortical atrophy (PCA), holds promise to shape our understanding of AD pathophysiology. Thus, we aimed to compare MRI evidence of lobar microbleeds (LMBs) in posterior cortical atrophy (PCA) syndrome to typical AD (tAD) and to assess and compare MRI evidence of cerebral amyloid angiopathy (CAA) in each group. FINDINGS: We retrospectively collected clinical and MRI data from participants with PCA (n = 26), identified from an institutional PCA registry, and participants with tAD (n = 46) identified from electronic health records from a single institution. LMBs were identified on susceptibility-weighted imaging (SWI); the Fazekas grade of white matter disease was assessed using FLAIR images, and Boston criteria version 2.0 for cerebral amyloid angiopathy were applied to all data. The proportion of participants with PCA and LMB (7.7%) was lower than for tAD (47.8%) (p = 0.005). The frequency of "probable" CAA was similar in both groups, while "possible" CAA was more frequent in tAD (30.4%) than PCA (0%) (p = 0.001). The Fazekas grades were not different between groups. Lobar microbleeds on SWI were not more common in PCA than in typical AD. Clinicopathological investigations are necessary to confirm these findings. The factors that contribute to the posterior cortical atrophy phenotype are unknown.

Case report: pre-symptomatic clinical and metabolic profile in posterior cortical atrophy and dementia with Lewy bodies.

A research participant was monitored over nearly two decades at Mayo Clinic, undergoing annual neurologic assessments, neuropsychological tests, and multimodal imaging. Initially, he was cognitively normal but developed symptoms consistent with Posterior Cortical Atrophy (PCA) during the study. Early tests indicated mild, yet normal-range declines in language and visuospatial skills. FDG-PET scans revealed increased metabolism in posterior brain regions long before symptoms appeared. Advanced analysis using a novel in-house machine-learning tool predicted concurrent Alzheimer's disease and dementia with Lewy bodies. Autopsy confirmed a mixed neurodegenerative condition with significant Alzheimer's pathology and dense neocortical Lewy bodies. This case underscores the value of longitudinal imaging in predicting complex neurodegenerative diseases, offering vital insights into the early neurocognitive changes associated with PCA and dementia with Lewy bodies.

The Graded Incomplete Letters Test (GILT): a rapid test to detect cortical visual loss, with UK Biobank implementation.

Impairments of object recognition are core features of neurodegenerative syndromes, in particular posterior cortical atrophy (PCA; the 'visual-variant Alzheimer's disease'). These impairments arise from damage to higher-level cortical visual regions and are often missed or misattributed to common ophthalmological conditions. Consequently, diagnosis can be delayed for years with considerable implications for patients. We report a new test for the rapid measurement of cortical visual loss - the Graded Incomplete Letters Test (GILT). The GILT is an optimised psychophysical variation of a test used to diagnose cortical visual impairment, which measures thresholds for recognising letters under levels of increasing visual degradation (decreasing "completeness") in a similar fashion to ophthalmic tests. The GILT was administered to UK Biobank participants (total n=2,359) and participants with neurodegenerative conditions characterised by initial cortical visual (PCA, n=18) or memory loss (typical Alzheimer's disease, n=9). UK Biobank participants, including both typical adults and those with ophthalmological conditions, were able to recognise letters under low levels of completeness. In contrast, participants with PCA consistently made errors with only modest decreases in completeness. GILT sensitivity to PCA was 83.3% for participants reaching the 80% accuracy cut-off, increasing to 88.9% using alternative cut-offs (60% or 100% accuracy). Specificity values were consistently over 94% when compared to UK Biobank participants without or with documented visual conditions, regardless of accuracy cut-off. These first-release UK Biobank and clinical verification data suggest the GILT has utility in both rapidly detecting visual perceptual losses following posterior cortical damage and differentiating perceptual losses from common eye-related conditions.

Visual Agnosia Mimicking Memory Impairment: A Case Report of Posterior Cortical Atrophy.

Vision specialists will benefit from increased awareness of posterior cortical atrophy (PCA) syndrome. Failure to adequately identify the chief complaint as a visual symptom may lead to incorrect diagnosis or diagnostic delay. A previously healthy, 59-year-old woman presented with a 5-year history of 'losing her stuff'. Upon psychiatric and neuro-ophthalmological evaluation, this symptom was better recognised as a feature of visual agnosia and simultanagnosia. She also presented with multiple previously unrecognised symptoms indicative of higher visual processing dysfunction, such as alexia without agraphia, ocular motor apraxia, optic ataxia, prosopagnosia, akinetopsia and topographagnosia, so further assessment to investigate for PCA was carried out. After a work-up including cognitive assessment, brain structural/functional imaging, and laboratory tests she was diagnosed with visual-variant Alzheimer's disease. Patients with PCA merit a detailed review of their symptoms, as well as the use of office tests such as cognitive evaluation tools, different types of perimetry, colour vision tests, and non-delayed psychiatric consultation for correct management and assessment. This report will emphasise five key aspects to be considered when evaluating patients with PCA.

Visual imagery deficits in posterior cortical atrophy.

Visual imagery has a close overlapping relationship with visual perception. Posterior cortical atrophy (PCA) is a neurodegenerative syndrome marked by early impairments in visuospatial processing and visual object recognition. We asked whether PCA would therefore also be marked by deficits in visual imagery, tested using objective forced-choice questionnaires, and whether imagery deficits would be selective for certain properties. We recruited four patients with PCA and a patient with integrative visual agnosia due to bilateral occipitotemporal strokes for comparison. We administered a test battery probing imagery for object shape, size, colour lightness, hue, upper-case letters, lower-case letters, word shape, letter construction, and faces. All subjects showed significant impairments in visual imagery, with imagery for lower-case letters most likely to be spared. We conclude that PCA subjects can show severe deficits in visual imagery. Further work is needed to establish how frequently this occurs and how early it can be found.

"I felt like I had been put on the shelf and forgotten about" - lasting lessons about the impact of COVID-19 on people affected by rarer dementias.

BACKGROUND: The public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer's disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping. METHODS: This was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes. RESULTS: 184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement. CONCLUSIONS: This study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of - and may inform the development of - tailored support for these underrepresented groups more generally.

Longitudinal rates of atrophy and tau accumulation differ between the visual and language variants of atypical Alzheimer's disease.

INTRODUCTION: Atypical variants of Alzheimer's disease (AD) include the visual variant, known as posterior cortical atrophy (PCA), and the language variant, known as logopenic progressive aphasia (LPA). Clinically, rates of disease progression differ between them. METHODS: We evaluated 34 PCA and 29 LPA participants. Structural magnetic resonance imaging and 18 F-flortaucipir positron emission tomography were performed at baseline and at 1-year follow-up. Rates of change in tau uptake and grey matter volumes were compared between PCA and LPA with linear mixed-effects models and voxel-based analyses. RESULTS: PCA had faster rates of occipital atrophy. LPA had faster rates of left temporal atrophy and faster rates of tau accumulation in the parietal, right temporal, and occipital lobes. Age was negatively associated with rates of atrophy and tau accumulation. DISCUSSION: Longitudinal patterns of neuroimaging abnormalities differed between PCA and LPA, although with divergent results for tau accumulation and atrophy. HIGHLIGHTS: The language variant of Alzheimer's disease accumulates tau faster than the visual variant. Each variant shows faster rates of atrophy than the other in its signature regions. Age negatively influences rates of atrophy and tau accumulation in both variants.

APOE ε4 influences within and between network functional connectivity in posterior cortical atrophy and logopenic progressive aphasia.

INTRODUCTION: Presence of apolipoprotein E (APOE) ε4 has shown greater predisposition to medial temporal involvement in posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA). Little is known about its influence on memory network connectivity, a network comprised of medial temporal structures. METHODS: Fifty-eight PCA and 82 LPA patients underwent structural and resting state functional magnetic resonance imaging (MRI). Bayesian hierarchical linear models assessed the influence of APOE ε4 on within and between-network connectivity for five networks. RESULTS: APOE ε4 carriers showed reduced memory and language within-network connectivity in LPA and increased salience within-network connectivity in PCA compared to non-carriers. Between-network analysis showed evidence of reduced DMN connectivity in APOE ε4 carriers, with reduced DMN-to-salience and DMN-to-language network connectivity in PCA, and reduced DMN-to-visual network connectivity in LPA. DISCUSSION: The APOE genotype influences brain connectivity, both within and between-networks, in atypical Alzheimer's disease. However, there was evidence that the modulatory effects of APOE differ across phenotype. HIGHLIGHTS: APOE genotype is associated with reductions in within-network connectivity for the memory and language networks in LPA APOE genotype is associated with reductions in language-to-visual connectivity in LPA and PCA APOE genotype has no effect on the memory network in PCA.

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.

Posterior cortical atrophy: Primary occipital variant.

BACKGROUND: Posterior cortical atrophy (PCA) is one of the atypical Alzheimer's disease variants, characterized by predominant visuospatial and visuoperceptual deficits, with established dorsal and ventral subtypes. A third primary occipital (caudal) variant has been suggested. We aimed to determine its demographics, clinical manifestations, and biomarker findings. METHODS: Fifty-two PCA patients were investigated. Patients underwent neuropsychological assessment, magnetic resonance imaging, and fluorodeoxyglucose (FDG)-, amyloid-, and tau-positron emission tomography (tau-PET) scans. Normalized regional FDG-PET values were represented as z-scores relative to a control population. Patients were divided into "primary occipital" and "other PCA" subgroups according to FDG-PET-defined criteria, with primary occipital defined as patients in which the z-scores for occipital subregions were at least one standard deviation lower (SD) (i.e., more abnormal) than the z-scores in all other brain regions. Global amyloid-PET, temporo-parietal FDG-PET, and temporal tau-PET regions-of-interest (ROIs) were calculated. RESULTS: Nine patients were classified as primary occipital; they were older (p = 0.034) and had more years of education (p = 0.007) than other PCA patients. The primary occipital group performed worse on the Ishihara test for color perception (p < 0.001), while other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p = 0.005). Overall neuropsychiatric symptom burden was lower in the primary occipital group (p < 0.001). The FDG-PET meta-ROI was higher in the primary occipital subtype (p = 0.006), but no differences were observed in amyloid- and tau-PET. CONCLUSIONS: Our findings suggest that primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia, and less hypometabolism in temporo-parietal meta-ROI compared to established phenotypes.

Clinical and metabolic imaging features of late-onset and early-onset posterior cortical atrophy.

BACKGROUND AND PURPOSE: Late-onset (LO) and early-onset (EO) dementia show neurobiological and clinical differences. Clinical and 18 fluoro-deoxy-glucose positron emission tomography (FDG-PET) features of LO and EO posterior cortical atrophy (LO_PCA, EO_PCA), the visual variant of Alzheimer's disease (AD), were compared. LO_PCA patients were also compared with a group of patients with LO typical AD (tAD). METHODS: Thirty-seven LO_PCA patients (onset age ≥ 65 years), 29 EO_PCA patients and 40 tAD patients who all underwent a standard neuropsychological battery were recruited; PCA patients were also assessed for the presence of posterior signs and symptoms. Brain FDG-PET was available in 32 LO_PCA cases, 23 EO_PCA cases and all tAD cases, and their scans were compared with scans from 30 healthy elderly controls. Within the entire PCA sample FDG uptake was also correlated with age at onset as a continuous variable. RESULTS: The main difference between the two PCA groups was a higher prevalence of Bálint-Holmes symptoms in EO cases, which was associated with the presence of severe bilateral occipito-temporo-parietal hypometabolism, whilst LO_PCA patients showed reduction of FDG uptake mainly in the right posterior regions. The latter group also showed mesial temporal hypometabolism, similarly to the tAD group, although with a right rather than left lateralization. Correlation analysis confirmed the association between older age and decreased limbic metabolism and between younger age and decreased left parietal metabolism. CONCLUSIONS: The major involvement of the temporal cortex in LO cases and of the parietal cortex in EO cases reported previously within the AD spectrum holds true also for the visual variant of AD.

Perspectives and a Systematic Scoping Review on Longitudinal Profiles of Posterior Cortical Atrophy Syndrome.

PURPOSE OF REVIEW: To provide perspectives on the importance of understanding longitudinal profiles of posterior cortical atrophy (PCA) and report results of a scoping review to identify data and knowledge gaps related to PCA survival and longitudinal clinical and biomarker outcomes. RECENT FINDINGS: Thirteen longitudinal studies were identified; all but two had fewer than 30 participants with PCA. Relatively few longitudinal data exist, particularly for survival. In PCA, posterior cortical dysfunction and atrophy progress at faster rates compared to non-posterior regions, potentially up to a decade after symptom onset. Unlike typical AD, PCA phenotype-defined cognitive dysfunction and atrophy remain relatively more severe compared to other regions throughout the PCA course. Select cognitive tests hold promise as PCA outcome measures and for staging. Further longitudinal investigations are critically needed to enable PCA inclusion in treatment trials and to provide appropriate care to patients and enhance our understanding of the pathophysiology of dementing diseases.

The clinical approach to the identification of higher-order visual dysfunction in neurodegenerative disease.

PURPOSE OF REVIEW: This review is intended to assist the reader in gaining the knowledge and skills necessary for the recognition and assessment of higher-order visual dysfunction due to neurodegenerative diseases including Alzheimer's disease, dementia with Lewy bodies, Parkinson's dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, and the posterior cortical atrophy syndrome. Clinical problem-solving and pattern recognition must be developed and practiced to accurately diagnosis disturbances of higher-order visual function, and knowledge of higher-order visual brain regions and their visual syndromes forms the foundation for deciphering symptoms presented by patients and/or their care partners. Tests of higher-order visual dysfunction must be assembled by the clinician and assessment can take time and effort. The use of screening tests, follow-up visits, and formal neuropsychological referrals are critical components for accurate diagnosis and these principles are reviewed here. RECENT FINDINGS: A recent survey of neuro-ophthalmologists revealed that over half of the respondents report that 5-10% of their new patient referrals carry a diagnosis of neurodegenerative disease and many patients were referred for visual symptoms of unknown cause. Despite over a century of discovery related to higher-order visual functions of the human brain, translation of discovery to the clinical assessment of patients has been slow or absent. As with the approach to translational medicine in general, to see meaningful progress, an interdisciplinary approach is indispensable. The first step involves the application of discoveries from the field visual neuroscience by clinicians from the fields of ophthalmology, neurology, and neuropsychology, and from the disciplines of neuro-ophthalmology and behavioral neurology. The unmet need for recognition, assessment, and management of higher-order visual dysfunction in neurodegeneration is evident and clinicians can contribute to closing the gap by using the approach and the tools outlined in the review.

Better conversations: a language and communication intervention for aphasia in posterior cortical atrophy.

Posterior cortical atrophy (PCA) describes a neurodegenerative syndrome characterized by progressive difficulties in cortical visual and other posterior cortical functions consistent with parieto-occipital and occipito-temporal involvement. It is increasingly recognized that many patients develop difficulties with other aspects of daily living, in particular, with language and communication. We present a case emphasizing how language difficulties may emerge in PCA. Difficulties are interpreted as arising from interacting effects of linguistic deficits and impaired detection of nonverbal (particularly, visual) turns that normally facilitate, schedule, and disambiguate the exchange of verbal messages between speakers. We propose that relatively simple speech and language therapy interventions may hold promise in addressing language and communication difficulties as secondary features of PCA by targeting the behaviors of both the person with PCA and their communication partners.

Differential effects from cognitive rehabilitation and high-definition tDCS in posterior cortical atrophy: A single-case experimental design.

Posterior cortical atrophy (PCA) is a progressive neurodegenerative syndrome characterized by visual-perceptual deficits, which impact daily life. Recent research has focused on non-pharmacological techniques to ameliorate these deficits, with the most common being cognitive rehabilitation. The present study investigates the differential effects of high definition-transcranial direct current stimulation (HD-tDCS) and cognitive rehabilitation in a single-case experimental design with two separate experimental phases in a patient with PCA. Experimental Phase 1 consisted of 10 sessions of HD-tDCS targeting the pre-SMA/dACC and Phase 2 consisted of 10 sessions of cognitive rehabilitation. Normed and standardized scores from figure copy and recall tests served as the primary outcome measures for visuospatial processing. The participant showed no immediate or long-term changes in visuospatial measures following HD-tDCS intervention. However, cognitive rehabilitation showed immediate improvement in visuospatial memory (figure recall) and clinically significant improvement in visuospatial construction (figure copy). Visuospatial construction gains remained in the low average range in the 10-week follow-up while visuospatial memory returned to baseline. Results indicated differential effects between HD-tDCS and cognitive rehabilitation with cognitive rehabilitation showing clinically significant improvement in primary outcome measures with sustained improvement in the long-term follow-up measure. Additional research is warranted to confirm these effects.

APOE ε4 influences medial temporal atrophy and tau deposition in atypical Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD. METHODS: An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE Îµ4 on cross-sectional and longitudinal regional metrics. RESULTS: At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus. DISCUSSION: APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.

Rates of longitudinal change in 18 F-flortaucipir PET vary by brain region, cognitive impairment, and age in atypical Alzheimer's disease.

INTRODUCTION: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. METHODS: We assessed regional and interindividual variation in longitudinal change on 18 F-flortaucipir PET imaging in 24 amyloid beta (Aß)+ patients with atypical, early-onset amnestic or non-amnestic AD plus 62 Aß- and 132 Aß+ Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. RESULTS: In atypical AD, 18 F-flortaucipir uptake slowed or declined over time in areas with high baseline signal and older, more impaired individuals. ADNI participants had reduced longitudinal change in early Braak stage regions relative to late-stage areas. DISCUSSION: Results suggested radioligand uptake plateaus or declines in advanced neurodegeneration. Further research should investigate whether results generalize to other radioligands and whether they relate to changes of the radioligand binding site structure or accessibility.

Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.

Tau and Aß assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the ß-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

Clinical and radiological features of posterior cortical atrophy (PCA) in a GRN mutation carrier: a case report.

BACKGROUND AND PURPOSE: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome, defined by a distinctive clinical-radiological profile, with Alzheimer's disease (AD) pathology accounting for the majority of cases. The aim of this report was to present the case of a patient with impairment of visual and constructional abilities as initial manifestations. METHOD: The patient underwent a multidimensional assessment, including neuropsychological evaluation, structural and functional imaging and genetic screening. RESULTS: Neurological and neuropsychological assessment showed an impairment of constructive and visuo-spatial skills, associated with dyscalculia, simultanagnosia, optic ataxia and oculomotor apraxia. In accordance with the latest consensus criteria, a diagnosis of PCA was made. Consistent with the clinical findings, structural and functional imaging showed a peculiar pattern of atrophy with primary involvement of right parieto-occipital cortices, whereas cerebrospinal fluid biochemical analysis did not reveal a profile compatible with AD pathology. Genetic screening identified a known pathogenic GRN mutation. CONCLUSION: We present a case of PCA in a GRN mutation carrier in whom a concomitant AD pathological process was excluded. Consequently, although lacking histological data, our case suggests GRN-related pathology causative of PCA. Through this report we provide further evidence for a new neurodegenerative pathway leading to PCA, extending the clinical spectrum of GRN-associated phenotypes.