Relationship of plasma biomarkers to digital cognitive tests in Alzheimer's disease.

INTRODUCTION: A major limitation in Alzheimer's disease (AD) research is the lack of the ability to measure cognitive performance at scale-robustly, remotely, and frequently. Currently, there are no established online digital platforms validated against plasma biomarkers of AD. METHODS: We used a novel web-based platform that assessed different cognitive functions in AD patients (N = 46) and elderly controls (N = 53) who were also evaluated for plasma biomarkers (amyloid beta 42/40 ratio, phosphorylated tau ([p-tau]181, glial fibrillary acidic protein, neurofilament light chain). Their cognitive performance was compared to a second, larger group of elderly controls (N = 352). RESULTS: Patients with AD were significantly impaired across all digital cognitive tests, with performance correlating with plasma biomarker levels, particularly p-tau181. The combination of p-tau181 and the single best-performing digital test achieved high accuracy in group classification. DISCUSSION: These findings show how online testing can now be deployed in patients with AD to measure cognitive function effectively and related to blood biomarkers of the disease. Highlights: This is the first study comparing online digital testing to plasma biomarkers.Alzheimer's disease patients and two independent cohorts of elderly controls were assessed.Cognitive performance correlated with plasma biomarkers, particularly phosphorylated tau (p-tau)181.Glial fibrillary acidic protein and neurofilament light chain, and less so the amyloid beta 42/40 ratio, were also associated with performance.The best cognitive metric performed at par to p-tau181 in group classification.

An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study.

BACKGROUND: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease. METHODS: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. DISCUSSION: This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer's disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03489044 . Registered on April 5, 2018.

Lateral parietal contributions to memory impairment in posterior cortical atrophy.

Objective: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive impairment in visuospatial and perceptual function. Recent findings show that memory functioning can also be compromised early in the course of disease. In this study, we investigated the neural basis of memory impairment in PCA, and hypothesised that correlations would be observed with parietal cortex rather than classic medial temporal memory structures. Methods: Eighteen PCA patients, 15 typical Alzheimer's disease (tAD) patients and 21 healthy controls underwent memory testing with the Rey Auditory Verbal Learning Test (RAVLT) word list and MRI. Voxel-based morphometry (VBM) was used to identify regions in the parietal and medial temporal lobes that correlated with memory performance. Results: Compared with controls, PCA patients were impaired at learning, immediate and delayed recall and recognition of the RAVLT. Learning rate and immediate recall was significantly better in PCA compared to tAD, whereas there was no difference in delayed recall. Recognition memory also was not statistically different between patient groups, but PCA patients made significantly more false positive errors than tAD patients. VBM analysis in the PCA patients revealed a significant correlation between total learning and grey matter density in the right supramarginal gyrus, right angular gyrus and left postcentral gyrus. The left post central gyrus also significantly correlated with immediate and delayed recall and with recognition memory. No correlations were detected in the medial temporal lobe. Conclusions: The findings provide novel evidence that early verbal memory impairment is frequently observed in PCA, and is associated with damage to lateral parietal structures. The results have implications for the diagnosis and management of PCA.

Association between precuneus volume and autobiographical memory impairment in posterior cortical atrophy: Beyond the visual syndrome.

Posterior cortical atrophy is a neurodegenerative syndrome characterised by progressive disruption of visual and perceptual processing, associated with atrophy in the parieto-occipital cortex. Current diagnostic criteria describe relative sparing of episodic memory function, but recent findings suggest that anterograde memory is often impaired. Whether these deficits extend to remote memory has not been addressed. A large body of evidence suggests that the recollection of an autobiographical event from the remote past coincides with the successful retrieval of visual images. We hypothesised that the profound visual processing deficits in posterior cortical atrophy would result in impaired autobiographical memory retrieval. Fourteen posterior cortical atrophy patients, eighteen typical Alzheimer's disease patients and twenty-eight healthy controls completed the Autobiographical Interview. Autobiographical memory in posterior cortical atrophy was characterised by a striking loss of internal, episodic detail relative to controls and to same extent as typical Alzheimer's disease patients, in conjunction with an increase in external details tangential to the memory described. The memory narratives of posterior cortical atrophy patients showed a specific reduction in spatiotemporal and perceptual detail. Voxel-based morphometry analysis revealed atrophy of the parieto-occipital cortices in posterior cortical atrophy but relatively spared hippocampi bilaterally, compared with characteristic atrophy of the medial temporal lobes in typical Alzheimer's disease. Analysis of brain regions showing posterior cortical atrophy-specific atrophy revealed a correlation between perceptual details in autobiographical memory and grey matter density in the right precuneus. This study demonstrates remote memory impairment in posterior cortical atrophy despite relatively preserved medial temporal lobe structures. The results demonstrate, for the first time, profound autobiographical memory impairment in PCA and suggest that this is driven by the well-recognised deficits in higher-order visual processing. The findings are discussed in the context of posterior parietal contributions to imagery and memory, and the clinical implications of autobiographical memory impairment for diagnostic and management protocols in posterior cortical atrophy.

Utility of testing for apraxia and associated features in dementia.

INTRODUCTION: Existing literature suggests that the presence or absence of apraxia and associated parietal deficits may be clinically relevant in differential diagnosis of dementia syndromes. AIM: This study investigated the profile of these features in Alzheimer's disease (AD) and frontotemporal dementia (FTD) spectrum disorders, at first presentation. METHODS: Retrospective case note analysis was undertaken in 111 patients who presented to the Oxford Cognitive Disorders Clinic, Oxford, UK, including 29 amnestic AD, 12 posterior cortical atrophy (PCA), 12 logopenic primary progressive aphasia (lvPPA), 20 behavioural variant FTD (bvFTD), 7 non-fluent variant PPA (nfvPPA), 6 semantic variant PPA (svPPA) and 25 patients with subjective cognitive impairment (SCI). The clinical features of interest were: limb apraxia, apraxia of speech (AOS), and left parietal symptoms of dyslexia, dysgraphia, and dyscalculia. RESULTS: The prevalence of limb apraxia was highest in PCA, amnestic AD, lvPPA and nfvPPA. AOS was only observed in nfvPPA. Associated parietal features were more prevalent in AD spectrum than FTD spectrum disorders. Group comparisons between key differential diagnostic challenges showed that lvPPA and nfvPPA could be significantly differentiated on the presence of left parietal features and AOS, and amnestic AD could be differentiated from bvFTD, svPPA and SCI by limb apraxia. Regression analysis showed that limb apraxia could successfully differentiate between AD and FTLD spectrum disorders with 83% accuracy. DISCUSSION: Disease-specific profiles of limb apraxia and associated deficits can be observed. FTD and AD spectrum disorders can be difficult to differentiate due to overlapping cognitive symptoms, and measures of apraxia, in particular, appear to be a promising discriminator.

Memory Impairment at Initial Clinical Presentation in Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is characterized by core visuospatial and visuoperceptual deficits, and predominant atrophy in the parieto-occipital cortex. The most common underlying pathology is Alzheimer's disease (AD). Existing diagnostic criteria suggest that episodic memory is relatively preserved. The aim of this study was to examine memory performance at initial clinical presentation in PCA, compared to early-onset AD patients (EOAD). 15 PCA patients and 32 EOAD patients, and 34 healthy controls were entered into the study. Patients were tested on the Addenbrooke's Cognitive Examination (ACE-R), consisting of subscales in memory and visuospatial skills. PCA and EOAD patients were significantly impaired compared to controls on the ACE total score (p < 0.001), visuospatial skills (p < 0.001), and memory (p < 0.001). Consistent with the salient diagnostic deficits, PCA patients were significantly more impaired on visuospatial skills compared to EOAD patients (p < 0.001). However, there was no significant difference between patient groups in memory. Further analysis of learning, recall, and recognition components of the memory subscale showed that EOAD and PCA patients were significantly impaired compared to controls on all three components (p < 0.001), however, there was no significant difference between EOAD and PCA patients. The results of this study show that memory is impaired in the majority of PCA patients at clinical presentation. The findings suggest that memory impairment must be considered in assessment and management of PCA. Further study into memory in PCA is warranted, since the ACE-R is a brief screening tool and is likely to underestimate the presence of memory impairment.

Is knowledge of famous people compromised in mild cognitive impairment?

OBJECTIVE: : This study addressed the issue of whether person naming deficits in mild cognitive impairment (MCI) occurred with deficits in person semantic knowledge and whether person knowledge was more impaired than general semantics. BACKGROUND: : Recent definitions of MCI are beginning to encompass cognitive impairments outside the domain of episodic memory. Increasing evidence suggests that semantic memory may also be compromised in this patient group, including tasks of person naming and identification. METHODS: : Thirteen MCI patients and 14 control subjects matched for age and education performed parallel semantic batteries designed to probe person and general semantic knowledge. RESULTS: : On the person battery, the MCI patients demonstrated impairment relative to controls, on tasks of category fluency, naming, identification, verbal and nonverbal associative and sorting tasks, as well as matching names to faces. By contrast, on the general semantic battery impairments, they were impaired only on category fluency and the nonverbal sorting and associative tasks. A composite measure of person knowledge tasks was also sensitive to disease severity as measured by Mini-Mental State Examination. CONCLUSIONS: : These results support the existence of deficits in MCI across various domains of person knowledge, and the suggestion that deterioration of unique semantic exemplars may be sensitive to incipient Alzheimer disease.

Relapsing encephalopathy in a patient with α-methylacyl-CoA racemase deficiency.

α-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies.

Naming of objects, faces and buildings in mild cognitive impairment.

Accruing evidence suggests that the cognitive deficits in very early Alzheimer's Disease (AD) are not confined to episodic memory, with a number of studies documenting semantic memory deficits, especially for knowledge of people. To investigate whether this difficulty in naming famous people extends to other proper names based information, three naming tasks - the Graded Naming Test (GNT), which uses objects and animals, the Graded Faces Test (GFT) and the newly designed Graded Buildings Test (GBT) - were administered to 69 participants (32 patients in the early prodromal stage of AD, so-called Mild Cognitive Impairment (MCI), and 37 normal control participants). Patients were found to be impaired on all three tests compared to controls, although naming of objects was significantly better than naming of faces and buildings. Discriminant analysis successfully predicted group membership for 100% controls and 78.1% of patients. The results suggest that even in cases that do not yet fulfil criteria for AD naming of famous people and buildings is impaired, and that both these semantic domains show greater vulnerability than general semantic knowledge. A semantic deficit together with the hallmark episodic deficit may be common in MCI, and that the use of graded tasks tapping semantic memory may be useful for the early identification of patients with MCI.

The hippocampal region is involved in successful recognition of both remote and recent famous faces.

There is currently a debate regarding the precise role of medial temporal regions in memory, in particular regarding the time scale of their involvement in conscious recollection of information stored in long-term memory. Using event-related fMRI, we have attempted to contribute to this debate by identifying brain regions associated with the successful recognition of famous faces from two different periods: "Old" faces of people who became famous in the 1960s-1970s and "Recent" faces of people who became famous in the 1990s. We demonstrate that the hippocampus is involved in the successful recognition of famous faces from both periods and does not appear to distinguish between these two periods. We also highlight a network of brain regions, including the left prefrontal cortex, the retrosplenial cortex, the temporo-parietal junction, the caudate and the right cerebellum, which is activated in association with successful recognition of famous faces. Finally, an analysis of the results obtained during a post hoc episodic recognition task shows the specific involvement of anterior hippocampus in the successful encoding of the unfamiliar faces, which were presented during the fame decision task, suggesting a functional distinction between anterior and posterior parts of the hippocampus, the former being specifically involved in successful episodic encoding and the latter being associated with successful retrieval of semantic information.

Dissociating person-specific from general semantic knowledge: roles of the left and right temporal lobes.

The cognitive architecture and neural underpinnings of different semantic domains remains highly controversial. We report two patients with focal temporal lobe atrophy who presented with contrasting and theoretically informative dissociations of person-specific versus general semantic knowledge. Subject J.P. showed severely impaired person-specific semantics, with relative preservation of knowledge about objects and animals, while subject M.A. exhibited the opposite pattern of performance (good knowledge of people in the context of impoverished general semantics). Voxel-based morphometric analysis of MR images in the two cases established predominantly right temporal atrophy associated with J.P.'s deficit for person knowledge and predominantly left temporal atrophy in M.A. who was impaired in general conceptual knowledge.

Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive implications.

OBJECTIVE: To characterize presenting symptomatology in patients with semantic dementia (SD) and to investigate whether left and right temporal variants of the disease have distinct behavioral and cognitive profiles. METHODS: Retrospective examination of case notes was performed in 47 consecutive referrals of patients with a clinical diagnosis of SD. Patients (and informants) were interviewed and underwent neuropsychological testing within 6 months of assessment. Patients were designated as having predominantly left (L > R; n = 36) or right (R > L; n = 11) temporal lobe atrophy based on MRI or CT of the brain. RESULTS: R > L and L > R SD groups did not differ in terms of presenting age (mean 63.4 +/- 7.4 years), symptom duration (3.6 +/- 2.3 years), or Mini-Mental State Examination scores (22.1 +/- 6.7). The most frequently reported behavioral symptoms were food fads, irritability, depression, and preoccupation with puzzles; cognitive deficits included word-finding difficulties, reduced comprehension, difficulty with person identification, and reduced conversation. The frequency of several symptoms differed significantly between groups. The following aspects were more likely to be associated with major right temporal atrophy: social awkwardness, job loss, loss of insight, and difficulty with person identification. Word-finding difficulties and reduced comprehension were more salient features of L > R patients. Both groups showed deficits on semantic memory tests, as expected for this syndrome, but several items yielded greater impairment for L > R than R > L. CONCLUSIONS: Patients with left and right predominant SD present with distinct behavioral-cognitive profiles. Characterization of these features may assist in the early and accurate diagnosis of SD.

Is knowledge of famous people disproportionately impaired in patients with early and questionable Alzheimer's disease?

Twenty-two patients with early dementia of Alzheimer's type (DAT) and 31 controls were administered tests of person-specific semantics (Experiment 1). DAT patients were impaired on all test components. In Experiment 2, 31 DAT patients, 28 questionable DAT (QDAT) patients, and 42 controls were administered the Graded Naming Test (GNT) and the newly designed Graded Faces Test (GFT), matched for difficulty with the GNT. DAT patients were impaired throughout but showed an advantage for naming objects over faces. The QDAT patients were impaired on the GFT only. Of the 7 QDAT patients who evolved to DAT within 1-2 years, 6 showed initial impairment on the GFT, whereas 17 of the nonconverters scored normally on the GFT. Results suggest greater and earlier vulnerability of person knowledge than general semantic knowledge in DAT.

Mild cognitive impairment: a clinically useful but currently ill-defined concept?

The term mild cognitive impairment (MCI) has gained wide currency among clinicians, and particularly dementia researchers, to denote patients with memory deficits who do not yet fulfil the criteria for dementia, but are at high risk of conversion. MCI is therefore regarded as the prodromic or pre-dementia stage of Alzheimer's disease. The accurate categorization of these subjects has far-reaching implications, both for research in this field and for those individuals who fall within this diagnostic group. Despite a wealth of studies examining the neuropsychological, neuroimaging and biological profiles of this population, the characterization of MCI remains controversial. This brief overview discusses a number of the issues related to this topic and questions the currently accepted criteria.