Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.

Abnormalities in cellular metabolism are seen early in Alzheimer's disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients' astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

Highly Superior Autobiographical Memory (HSAM): A Systematic Review.

Individuals possessing a Highly Superior Autobiographical Memory (HSAM) demonstrate an exceptional ability to recall their own past, excelling most when dates from their lifetime are used as retrieval cues. Fully understanding how neurocognitive mechanisms support exceptional memory could lead to benefits in areas of healthcare in which memory plays a central role and in legal fields reliant on witnesses' memories. Predominantly due to the rareness of the phenomenon, existing HSAM literature is highly heterogenous in its methodologies used. Therefore, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed the first systematic review on this topic, to collate the existing behavioural, neuroanatomical, and functional HSAM data. Results from the 20 experimental selected studies revealed that HSAM is categorised by rapidly retrieved, detailed and accurate autobiographical memories, and appears to avoid the normal aging process. Functional neuroimaging studies showed HSAM retrieval seems characterised by an intense overactivation of the usual autobiographical memory network, including posterior visual areas (e.g., the precuneus). Structural neuroanatomical differences do not appear to characterise HSAM, but altered hippocampal resting-state connectivity was commonly observed. We discuss theories of HSAM in relation to autobiographical encoding, consolidation, and retrieval, and suggest future directions for this research.

Accelerated atrophy in dopaminergic targets and medial temporo-parietal regions precedes the onset of delusions in patients with Alzheimer's disease.

People with Alzheimer's disease (AD) and delusions have worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study investigated whether there are any detectable differences in grey matter (GM) volume and cognitive changes in the year before symptom onset between patients with AD who did and did not develop delusions. Two matched samples of AD patients, 63 who did (PT-D) and 63 who did not develop delusions (PT-ND) over 1 year, were identified from the Alzheimer's Disease Neuroimaging Initiative database. The Neuropsychiatric Inventory (NPI) was used to assess the presence of delusions. Sixty-three additional matched healthy controls (HC) were selected. Repeated-measures ANCOVA models were used to investigate group-by-time effects on the volume of selected GM regions of interest and on cognitive performance. No neurocognitive differences were observed between patient groups prior to symptom onset. Greater episodic memory decline and GM loss in bilateral caudate nuclei, medio-temporal and midline cingulo-parietal regions were found in the PT-D compared with the PT-ND group. A pattern of faster GM loss in brain areas typically affected by AD and in cortical and subcortical targets of dopaminergic pathways, paralleled by worsening of episodic memory and behavioural symptoms, may explain the emergence of delusions in patients with AD.

The neural signatures of psychoses in Alzheimer's disease: a neuroimaging genetics approach.

Psychoses in Alzheimer's disease (AD) are associated with worse prognosis. Genetic vulnerability for schizophrenia (SCZ) may drive AD-related psychoses, yet its impact on brain constituents is still unknown. This study aimed to investigate the association between polygenic risk scores (PRSs) for SCZ and psychotic experiences (PE) and grey matter (GM) volume in patients with AD with (AD-PS) and without (AD-NP) psychosis. Clinical, genetic and T1-weighted MRI data for 800 participants were extracted from the ADNI database: 203 healthy controls, 121 AD-PS and 476 AD-NP. PRSs were calculated using a Bayesian approach and analysed at ten p-value thresholds. Standard voxel-based morphometry was used to process MRI data. Logistic regression models including both PRSs for SCZ and PE, and an AD-PRS were used to predict psychosis in AD. Associations between PRSs and GM volume were investigated in the whole sample and the three groups independently. Only the AD-PRS predicted psychosis in AD. Inconsistent associations between the SCZ-PRS and PE-PRS and GM volumes were found across groups. The SCZ-PRS was negatively associated with medio-temporal/subcortical volumes and positively with medial/orbitofrontal volumes in the AD-PS group. Only medio-temporal areas were more atrophic in the AD-PS group, while there was no significant correlation between psychosis severity and GM volume. Although not associated with psychoses, the SCZ-PRS was correlated with smaller medio-temporal and larger orbitofrontal volumes in AD-PS. Similar alterations have also been observed in SCZ patients. This finding suggest a possible disconnection between these regions associated with psychoses in more advanced AD.

Self-reported hearing difficulties are associated with loneliness, depression and cognitive dysfunction during the COVID-19 pandemic.

OBJECTIVE: To investigate whether hearing difficulties exacerbate the damaging effects of enforced social distancing due to the COVID-19 pandemic on isolation and loneliness, and lead to accelerated mental health issues and cognitive dysfunction. DESIGN: Rapid online survey. Participants completed a series of online questionnaires regarding hearing ability, socialisation (pre- and during-pandemic), loneliness, anxiety, depression and cognitive function. STUDY SAMPLE: A total of 80 participants over the age of 70 with access to the internet. RESULTS: There was a significant reduction in socialisation levels from pre-pandemic in this population. Hearing difficulties were significantly associated with greater levels of loneliness, depression and self-perceived cognitive dysfunction after controlling for age, gender, and level of education. Additionally, compared to pre-pandemic, people with hearing difficulties had increased odds of reporting worsened anxiety, depression, and memory during the COVID-19 pandemic, although only the effect of hearing difficulties on the change in memory reached statistical significance after controlling for age, gender, and level of education. CONCLUSIONS: The worse the self-reported hearing abilities are, the greater the negative impact of enforced social distancing on depression, loneliness and cognitive function.

The impact of social isolation due to the COVID-19 pandemic on patients with dementia and caregivers.

OBJECTIVE: Social distancing to limit COVID-19 transmission has led to extensive lifestyle changes, including for people with dementia (PWD). The aim of this study, therefore, was to assess the impact of lockdown on the mental health of PWD and their carers. METHODS: Forty-five carers of PWD completed a telephone interview during the baseline assessment of the SOLITUDE study to gather information on life conditions and changes in symptoms of PWD during lockdown. Associations between changes in symptoms of PWD and carers' concerns and mental health were investigated. RESULTS: About 44% of carers experienced anxiety and irritability and reported changes in behavioural and cognitive symptoms in PWD. These changes were associated with worse carers' mental health and concerns about faster disease progression (χ2 = 13.542, p < 0.001). CONCLUSION: COVID-19-related social isolation has had a negative impact on patients' and carers' mental health. Potential long-term neurocognitive consequences require further investigation.

Functional cognitive disorder: dementia's blind spot.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.

Fully automated cognitive screening tool based on assessment of speech and language.

INTRODUCTION: Recent years have seen an almost sevenfold rise in referrals to specialist memory clinics. This has been associated with an increased proportion of patients referred with functional cognitive disorder (FCD), that is, non-progressive cognitive complaints. These patients are likely to benefit from a range of interventions (eg, psychotherapy) distinct from the requirements of patients with neurodegenerative cognitive disorders. We have developed a fully automated system, 'CognoSpeak', which enables risk stratification at the primary-secondary care interface and ongoing monitoring of patients with memory concerns. METHODS: We recruited 15 participants to each of four groups: Alzheimer's disease (AD), mild cognitive impairment (MCI), FCD and healthy controls. Participants responded to 12 questions posed by a computer-presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification. RESULTS: CognoSpeak could distinguish between participants in the AD or MCI groups and those in the FCD or healthy control groups with a sensitivity of 86.7%. Patients with MCI were identified with a sensitivity of 80%. DISCUSSION: Our fully automated system achieved levels of accuracy comparable to currently available, manually administered assessments. Greater accuracy should be achievable through further system training with a greater number of users, the inclusion of verbal fluency tasks and repeat assessments. The current data supports CognoSpeak's promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.

Dementia Research Fit for the Planet: Reflections on Population Studies of Dementia for Researchers and Policy Makers Alike.

In recent years, a rapidly increasing collection of investigative methods in addition to changes in diagnostic criteria for dementia have followed "high-tech" trends in medicine, with the aim to better define the dementia syndrome and its biological substrates, mainly in order to predict risk prior to clinical expression. These approaches are not without challenge. A set of guidelines have been developed by a group of European experts in population-based cohort research through a series of workshops, funded by the Joint Program for Neurodegenerative Disorders (JPND). The aims of the guidelines are to assist policy makers and researchers to understand (1) What population studies for ageing populations should encompass and (2) How to interpret the findings from population studies. Such studies are essential to provide evidence relevant to the understanding of healthy and frail brain ageing, including the dementia syndrome for contemporary and future societies by drawing on the past.

Association Between Gait, Cognition, and Gray Matter Volumes in Mild Cognitive Impairment and Healthy Controls.

AIMS: To assess the correlation between cognitive functioning and 3 gait parameters (gait speed, cadence, and stride length) in persons with mild cognitive impairment (MCI) and cognitively healthy controls and investigate linear correlations between gait and gray matter volumes. MATERIALS AND METHODS: Participants were recruited at IRCCS San Camillo Hospital, Venice, Italy (MCI=43; age-matched controls=43). Participants underwent comprehensive neuropsychological assessment. Gait speed, cadence, and stride length, were assessed with the BTS FREEMG 300 device. Three-dimensional (3D) T1-weighted MR images were acquired using a 1.5 T Philips Achieva MRI system with a Turbo Field Echo sequence. RESULTS: In MCI there was a positive correlation between gait speed and memory tests (P<0.05). In controls all 3 gait parameters correlated with executive functioning (P<0.01). Temporal and limbic areas (ie, superior temporal gyrus, thalamus and parahippocampal gyrus) were associated with gait parameters in MCI whereas in controls the associations were with frontal areas (ie, middle, inferior, and superior frontal gyrus) and in the cerebellum (anterior and posterior lobe). CONCLUSIONS: Our results highlight a distinct pattern of association between gray matter volume and gait parameters in MCI patients and controls (temporal areas in MCI and frontal areas in healthy elderly), suggesting a relationship between dementia-related pathology and gait dysfunction.