Search

ObjectiveTo investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study.MethodsCognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant’s perspective on SCD was evaluated in relation to MyCog score.ResultsAnxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) −0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant’s perception of SCD was generally in accordance with that of the participant.ConclusionsThis cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer’s disease pathology and SCD.

In the first multicentre, international longitudinal investigation of disease progression in posterior cortical atrophy, Firth et al. reveal distinct trajectories of cognitive decline and patterns of tissue loss compared to typical Alzheimer’s disease. Mapping this heterogeneity provides a basis for understanding the factors underlying variability in neurodegenerative disease expression., 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.

Posterior cortical atrophy (PCA) is a degenerative condition characterized by a progressive deterioration of visual processing. Dyslexia constitutes an early and frequent visual symptom of the disease and previous comprehensive investigations in series of individuals have extensively documented a characteristic abundance of visual errors as the most prevalent error category in this population. Here we describe the profile of a patient with PCA, C.P., who presents an unusual prevalence of phonological, instead of purely visual, errors in his reading, in the context of an otherwise classic PCA phenotype. In keeping with the well-known PCA profile, C.P. exhibited deficits at the pre-lexical level with elements of crowding and defective early visual processing impairments but additionally showed an unusually prominent disruption of phonological processing. We also argue that our patient may have a refractory access type deficit in reading given that accuracy doubled with the introduction of a five-second response-stimulus interval. To our knowledge, no previous case of a refractory deficit affecting word reading has been reported in PCA. Our examination builds on previous knowledge about reading behaviour in PCA and describes a singular example of the rich phenotypic heterogeneity within the syndrome.

Background Understanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer’s disease (FAD) cohort to characterise preclinical cognitive change. Methods Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline. Results Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum. Conclusions Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer’s disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.

Aim To measure changes in visuo-perceptual processing in patients with Parkinson9s disease without dementia. Methods Images of cats and dogs that had been skewed by varying amounts were shown to patients with idiopathic Parkinson9s disease (defined by QSBB criteria) (n=16) and healthy controls (n=11). Mean disease duration was 4 years (Standard deviation 3 years). Average L-DOPA equivalent dose was 554 mg (SD 487 mg). On each trial, participants were asked to identify the presented animal to generate psychophysical curves of skew against correctness and determine the threshold for identifying the correct animal. Visual acuity, UPDRS-scores and neuropsychology performance was measured for each participant. Results Patients with Parkinson9s disease, but without dementia, showed impaired ability to identify images that had been skewed, compared with healthy controls. The threshold for detection in patients was 61.2 degrees (SD 7.1 degrees), compared with 67.9 degrees (SD 2.1 degrees) in healthy participants, W=143, p=0.0056. The groups did not differ in visual acuity or neuropsychological performance. Conclusions We show subtle but definite impairment of complex visual processing in the initial phases of Parkinson9s disease in patients without overt cognitive impairment. This work has important implications for understanding the diagnosis, biology and progression of Parkinson9s disease.