Behavioural and neural characteristics of navigation impairments in preclinical Alzheimer’s disease

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk preclinical individuals. This thesis focuses on spatial navigation deficits, which are increasingly shown to be present in atrisk individuals, because the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Experimental chapters 2 and 3, show that a novel test battery captures navigation deficits that precede the onset of verbal and non-verbal episodic memory deficits in preclinical disease and that resting-state functional connectivity between the EC and the PCC underpins such deficits. Evidence for moderate test re-test reliability in the same non-clinical sample is presented in chapter 4. Moving beyond detection of preclinical disease, and towards prevention, in chapter 5 we examined whether marine fish oils help preserve the volume of AD vulnerable brain regions and found that low circulating DHA blood concentration predicts preservation of hippocampal and entorhinal volume in preclinical AD. This is potentially due to increased DHA uptake from the blood to the brain due to preclinical disease. Taken together, the research advances our conceptual understanding of the pathological and compensatory changes that characterise preclinical AD and offers important information toward generating more accurate risk profiles for AD vulnerable adults

Path Integration Changes as a Cognitive Marker for Vascular Cognitive Impairment?—A Pilot Study

Path integration spatial navigation processes are emerging as promising cognitive markers for prodromal and clinical Alzheimer’s disease (AD). However, such path integration changes have been less explored in Vascular Cognitive Impairment (VCI), despite neurovascular change being a major contributing factor to dementia and potentially AD. In particular, the sensitivity and specificity of path integration impairments in VCI compared to AD is unclear. In the current pilot study, we explore path integration performance in early-stage AD and VCI patient groups and hypothesize that: (i) medial parietal mediated egocentric processes will be more affected in VCI; and (ii) medial temporal mediated allocentric processes will be more affected in AD. This cross-sectional study included early-stage VCI patients (n = 9), AD patients (n = 10) and healthy age-matched controls (n = 20). All participants underwent extensive neuropsychological testing, as well as spatial navigation testing. The spatial navigation tests included the virtual reality “Supermarket” task assessing egocentric (body-based) and allocentric (map-based) navigation as well as the “Clock Orientation” test assessing egocentric and path integration processes. Results showed that egocentric integration processes are only impaired in VCI, potentially distinguishing it from AD. However, in contrast to our prediction, allocentric integration was not more impaired in AD compared to VCI. These preliminary findings suggest limited specificity of allocentric integration deficits between VCI and AD. By contrast, egocentric path integration deficits emerge as more specific to VCI, potentially allowing for more specific diagnostic and treatment outcome measures for vascular impairment in dementia

Geospatial Analysis of Environmental Risk Factors for Missing Dementia Patients

BACKGROUND: Dementia-related missing incidents are highly prevalent but still poorly understood. This is particularly true for environmental/geospatial risk factors, which might contribute to these missing incidents. OBJECTIVE: The study aimed to conduct a retrospective, observational analysis on a large sample of missing dementia patient case records provided by the police (n = 210), covering dates from January 2014 to December 2017. In particular, we wanted to explore 1) whether there were any hotspot regions of missing incidents and 2) the relationship between outdoor landmark density and missing incidents. METHODS: Global spatial autocorrelation (Moran's I) was used to identify the potential hotspot regions for missing incidents. Meanwhile, spatial buffer and regression modelling were used to determine the relationship between outdoor landmark density and missing incidents. RESULTS: Our demographics measures replicated and extended previous studies of dementia-related missing incidents. Meanwhile, no hotspot regions for missing incidents were identified, while higher outdoor landmark density led to increased missing incidents. CONCLUSION: Our results highlight that missing incidents do not occur in isolated hotspots of regions but instead are endemic in patients regardless of location. Higher outdoor landmark density emerges as a significant geospatial factor for missing incidents in dementia, which crucially informs future safeguarding/intervention studies

Memory precision of object-location binding is unimpaired in <i>APOE</i> ε4-carriers with spatial navigation deficits.

Funder: Wellcome TrustResearch suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer's disease. In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for Alzheimer's dementia. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n = 26 ε3ε3, n = 20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localization errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object's position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, Bayesian analyses found good evidence that ε3ε4 carriers did not remember fewer object locations [F(1, 42) = 0.450, P = 0.506, BF01 = 3.02], nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers [F(1, 42) = 0.12, P = 0.726, BF01 = 3.19]. Because the participants in the sample presented here were a subset of a study on apolipoprotein ε4-carrier status and spatial navigation in the Sea Hero Quest game [Coughlan et al., 2019. PNAS, 116(9)], we obtained these data to contrast genetic effects on the two tasks within the same sample (n = 33). Despite the smaller sample size, wayfinding deficits among ε3ε4 carriers could be replicated [F(1, 33) = 5.60, P = 0.024, BF10 = 3.44]. Object-location memory metrics and spatial navigation scores were not correlated (all r P > 0.1, 0 10 < 3). These findings show spared object-location binding in the presence of a detrimental apolipoprotein ε4 effect on spatial navigation. This suggests that the sensitivity of memory fidelity and binding tasks may not extend to individuals with one ε4-allele in their early to mid-60s. The results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest cognitive changes in Alzheimer's disease, even before episodic memory

Test-retest reliability of spatial navigation in adults at-risk of Alzheimer’s disease

The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer‘s disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test–retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable test-retest reliability. Further research in larger sample sizes is desirable

Functional connectivity between the entorhinal and posterior cingulate cortices underpins navigation discrepancies in at-risk Alzheimer’s disease

Navigation processes that are selectively mediated by functional activity in the entorhinal cortex may be a marker of preclinical Alzheimer's disease (AD). Here, we tested if a short path integration paradigm can detect the strongest genetic-risk phenotype of AD in large sample of apolipoprotein E (APOE)-genotyped individuals. We also examined the associations between APOE-mediated navigation process, subjective cognitive decline, and rest-stating network connectivity. Navigation discrepancies classified 77% the APOE-genotyped cohort into their respective low-risk ε3ε3 and high-risk ε3ε4 categories. When connectivity strength between entorhinal and the posterior cingulate cortices (also a functional correlate of strongest APOE-dependant behavioral characteristics) was considered, this classification accuracy increased to 85%. Our findings present a whole picture of at-genetic-risk AD, including select impairment in path integration, self-report cognitive decline, and altered network activity that is reminiscent of the pathological spread of preclinical AD disease. These findings may have important implications for the early detection of AD

APOE ε4 alters docosahexaenoic acid associations with preclinical markers of Alzheimer disease

Docosahexaenoic acid (DHA) is the main long chain omega-3 polyunsaturated fatty acids in the brain and accounts for 30% to 40% of fatty acids in the grey matter of the human cortex. Although the influence of DHA on memory function is widely researched, its association with brain volumes is under investigated and its association with spatial navigation is virtually unknown. This is despite the fact that spatial navigation deficits are a new cognitive fingerprint for symptomatic and asymptomatic Alzheimer’s disease (AD). We investigated the relationship between DHA levels and the major structural and cognitive markers of preclinical AD, namely hippocampal volume, entorhinal volume, and spatial navigation ability. Fifty-three cognitively normal adults underwent volumetric magnetic resonance imaging, measurements of serum DHA (including serum lysophosphatidylcholine DHA (LPC DHA)) and APOE ε4 genotyping. Relative regional brain volumes were calculated and linear regression models were fitted to examine DHA associations with brain volume. APOE genotype modulated serum DHA associations with entorhinal cortex volume and hippocampal volume. Linear models showed that greater serum DHA was associated with increased entorhinal cortex volume, but not hippocampal volume, in APOΕ ε4 non-carriers. APOE also interacted with serum LPC DHA to predict hippocampal volume. After testing interactions between DHA and APOE ε4 on brain volume, we investigated whether DHA and APOE interact to predict spatial navigation performance on a novel virtual reality diagnostic test for AD in an independent population of APOE genotyped adults (n = 46). Crucially, the APOE genotype modulated DHA associations with spatial navigation performance, showing that DHA was inversely associated with path integration in APOE ε4 carriers only. Interventions aiming to increase DHA status to protect against cognitive decline must consider APOE ε4 carrier status, and focus on higher doses of supplementary DHA to ensure adequate brain delivery

The Nottingham Fatigue After Stroke (NotFAST) study: factors associated with severity of fatigue in stroke patients without depression

Objective: To identify factors associated with post-stroke fatigue in a sample of stroke survivors without depression. Design: Cross-sectional cohort study. Setting: Recruitment was from four stroke units in the UK. Subjects: Participants were assessed within four weeks of first stroke; those with high levels of depressive symptoms (score ≥7 Brief Assessment Schedule Depression Cards) were excluded. Main measures: Participants were assessed four to six weeks after stroke on the Fatigue Severity Subscale of the Fatigue Assessment Inventory, the Rivermead Mobility Index, Nottingham Extended Activities of Daily Living scale, Beck Anxiety Index, Sleep Hygiene Index, 6m walk test, and measures of cognitive ability. Results: Of the 371 participants recruited, 103 were excluded and 268 were assessed. Of the latter, the mean age was 67.7 years (SD 13.5) and 168 (63%) were men. The National Institutes of Health Stroke Scale mean score was 4.96 (SD 4.12). Post-stroke fatigue was reported by 115 (43%) of participants, with 71 (62%) reporting this to be a new symptom since their stroke. Multivariate analysis using the Fatigue Severity Scale as the outcome variable found pre-stroke fatigue, having a spouse/partner, lower Rivermead Mobility Index score, and higher scores on both the Brief Assessment Schedule Depression Cards and Beck Anxiety Index were independently associated with post-stroke fatigue, accounting for approximately 47% of the variance in Fatigue Severity Scale scores. Conclusions: Pre-stroke fatigue, lower mood, and poorer mobility were associated with post-stroke fatigue

Dementia diagnosis in seven languages: the Addenbrooke’s Cognitive Examination-III in India

OBJECTIVE: With the rising burden of dementia globally, there is a need to harmonize dementia research across diverse populations. The Addenbrooke's Cognitive Examination-III (ACE-III) is a well-established cognitive screening tool to diagnose dementia. But there have been few efforts to standardize the use of ACE-III across cohorts speaking different languages. The present study aimed to standardize and validate ACE-III across seven Indian languages and to assess the diagnostic accuracy of the test to detect dementia and mild cognitive impairment (MCI) in the context of language heterogeneity.  METHODS: The original ACE-III was adapted to Indian languages: Hindi, Telugu, Kannada, Malayalam, Urdu, Tamil, and Indian English by a multidisciplinary expert group. The ACE-III was standardized for use across all seven languages. In total, 757 controls, 242 dementia, and 204 MCI patients were recruited across five cities in India for the validation study. Psychometric properties of adapted versions were examined and their sensitivity and specificity were established.  RESULTS: The sensitivity and specificity of ACE-III in identifying dementia ranged from 0.90 to 1, sensitivity for MCI ranged from 0.86 to 1, and specificity from 0.83 to 0.93. Education but not language was found to have an independent effect on ACE-III scores. Optimum cut-off scores were established separately for low education (≤10 years of education) and high education (>10 years of education) groups.  CONCLUSIONS: The adapted versions of ACE-III have been standardized and validated for use across seven Indian languages, with high diagnostic accuracy in identifying dementia and MCI in a linguistically diverse context

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities