Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer\u27s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Challenges in Dementia Studies

Alzheimer’s and other neurodegenerative diseases are generally incurable and often difficult to diagnose accurately. Yet early and accurate diagnosis of a neurodegenerative disease can potentially contribute to more effective treatment. Hence research efforts are moving towards early identification of high risk subjects and prevention of disease progression with biomarkers. Unfortunately dementia and biomarker studies are hampered by variables such as drop outs, challenges in comparing data sets, discordant biomarker sets, availability of histopathological confirmation at death, validity of cognitive testing, and nonlinear fluctuations in cognitive domains as disease progresses in vivo in subjects. This chapter is an assessment of the challenges in the early diagnosis of dementia, as well as a presentation of the issues faced in conducting dementia and biomarker studies

White Matter Inflammation And Executive Dysfunction: Implications For Alzheimer Disease And Vascular Cognitive Impairment

White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by which vascular injury exacerbates the cognitive impact of comorbid AD pathology and cerebrovascular pathology. To study the relationship between age, pathogenic amyloid precursor protein (APP), white matter inflammation, cerebrovascular disease, and executive dysfunction, the transgenic rat model of AD (TgAPP21) was evaluated for astrocytosis, microgliosis and cognitive impairment. The TgAPP21 rat was found to demonstrate spontaneously increased white matter microglia activation, impaired reversal learning, and a regressive impairment of behavioural flexibility, a key subdomain of executive function. The TgAPP21 rat also developed a precocious increase in white matter microglia activation. However, this was not matched by a continued increase in behavioural inflexibility, suggesting a dynamic and age-dependent relationship between white matter inflammation and behavioural flexibility. Hypertension induced by chronic angiotensin-II infusion impaired both wildtype (Wt) and TgAPP21 rats’ working memory and behavioural flexibility. However, while Wt rats demonstrated a linear increase in white matter astrocytosis in response to blood pressure elevation, normotensive TgAPP21 rats already had an increased baseline level of white matter astrocytosis and further increase in response to hypertension was not observed. TgAPP21 rats also demonstrated a greater vulnerability to cerebrovascular disease, as focal striatal ischemic injury resulted in reduced set shifting efficiency. Thus, the TgAPP21 rat is an important model for studying the complex relationship between age, pathogenic APP, and cerebrovascular disease and their impact on executive dysfunction. These findings support the emerging significance of white matter inflammation and executive dysfunction in the pathophysiology of ageing, AD, and VCI

Knockdown of heterochromatin protein 1 binding protein 3 recapitulates phenotypic, cellular, and molecular features of aging.

Identifying genetic factors that modify an individual\u27s susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a number of age-related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here, we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50%-75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimer\u27s disease brains. Specifically, neuroinflammatory-related pathways become activated following Hp1bp3 knockdown in combination with a robust decrease in genes involved in synaptic activity and neuronal function. To test the hypothesis that Hp1bp3 mediates susceptibility to cognitive deficits via a role in neuronal excitability, we performed slice electrophysiology demonstrate transcriptional changes after Hp1bp3 knockdown manifest functionally as a reduction in hippocampal neuronal intrinsic excitability and synaptic plasticity. In addition, as Hp1bp3 is a known mediator of miRNA biogenesis, here we profile the miRNA transcriptome and identify mir-223 as a putative regulator of a portion of observed mRNA changes, particularly those that are inflammatory-related. In summary, work here identifies Hp1bp3 as a critical mediator of aging-related changes at the phenotypic, cellular, and molecular level and will help inform the development of therapeutics designed to target either Hp1bp3 or its downstream effectors in order to promote cognitive longevity

Neuropsychological deficits in Posterior Cortical Atrophy and typical Alzheimer's disease:A meta-analytic review

Aims: To identify cognitive tests that best differentiate between Posterior Cortical Atrophy (PCA) and typical Alzheimer's Disease (tAD), as well as PCA and healthy control (HC) participants. Method: Medline, PsycInfo and Web of Science were systematically searched using terms related to PCA, tAD, and cognitive testing. Seventeen studies were identified, including 441 PCA, 391 tAD, and 284 HC participants. Standardised effect sizes of mean scores were calculated to measure performance differences on cognitive tests for PCA versus tAD and PCA versus HC groups. Meta-analyses used a random effects model. Results: The most discriminating cognitive tests for PCA and tAD presentations were measures of visuospatial function and verbal memory. Large, significant effect sizes were produced for all measures of visuospatial function, most notably for Rey-Osterrieth Copy (Hedges' g =-2.79), VOSP Fragmented letters (Hedges' g =-1.73), VOSP Dot Counting (Hedges' g =-1.74), and VOSP Cube Analysis (Hedges' g =-1.98). For measures of verbal memory, the RAVLT delay and Digit Span Backwards produced significant medium effects (Hedges' g = .62 and-.56, respectively). Conclusion: Establishing a common framework for testing individuals with PCA has important implications for diagnosis and treatment, and forms a practical objective for future research. Findings from this meta-analysis suggest that measures of visuospatial function and verbal memory would form an important part of this framework. Crown Copyright (c) 2021 Published by Elsevier Ltd. All rights reserved

Effects of probiotics supplementation on dementia and cognitive impairment: A systematic review and meta-analysis of preclinical and clinical studies

Background Dementia is a chronic syndrome characterized by cognitive and behavioral symptoms, which may include short-term memory impairment and problems related to orientation, language, attention and perception. Although cognitive impairment (CI) is increasingly considered the main geriatric condition predisposing to dementia, its early management could still promote symptomatic relief and delay disease progression. Recently, probiotics treatment has been studied as a potential new therapeutic approach to attenuate dementia-related decline and mild cognitive impairment (MCI). Therefore, we conducted a systematic review and meta-analysis to review and analyse the available evidence on the effect of probiotics on MCI and dementia. Methods A systematic search and meta-analysis were performed on Cochrane Library, ProQuest, Web of Science, PubMed-Medline, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, ScienceDirect and Open Grey. Search terms included diagnoses of interest (dementia and MCI) and the intervention of interest (probiotic, lactobacillus and bifidobacterium). Original articles reporting the use of probiotics supplementation for the treatment of dementia and MCI were screened and studied independently by two researchers. After that, a random and fixed effects model was used at the meta-analysis stage of the results to determine its effect size. Results A total of 16 articles (10 preclinical and 6 clinical) that met the inclusion criteria for the systematic review, and 15 articles (10 preclinical and 5 clinical) for meta-analysis were finally included. In humans, the administration of probiotics improved general cognitive function after the treatment period. Similarly, an improvement in memory and spatial/non-spatial learning was identified in the probiotic group of animals compared to the control group. On the other hand, the results showed an increase in the levels of the brain-derived neurotrophic factor, an improvement in the inflammatory profile and regulation of cellular biomarkers after probiotics administration. Conclusion Probiotics supplementation could be an adequate therapeutic strategy both in dementia and CI based on clinical and preclinical evidence. However, it is therefore important to translate preclinical data into clinical data where the evidence is more limited

Promoting the adoption of assistive technologies to aid with spatial orientation in dementia care

Introduction: In dementia care, locating technologies are a type of assistive technology that hold the potential to improve the quality of life of persons with dementia and their care partners by assisting in the management of spatial orientation impairments and wandering. Although many products are commercially available, their adoption remains low. To better understand how to promote their adoption, we examined user experience and clinical effectiveness resulting from product use and explored barriers to their adoption. Methods: In a first user experience study, a prototype locating technology was tested for four weeks by 17 dyads composed of persons with dementia and their care partners. In a second user experience study, two similar commercially available locating technologies were tested for four weeks each by another 17 dyads. User experience was examined with ratings of product usability, product functions and product features. Clinical effectiveness, frequency of use, purchase willingness, and product satisfaction were assessed with various scales. In a third qualitative focus group interview study with 22 interdisciplinary professional stakeholders, we explored views on the barriers to their adoption, as well as views on services and information dissemination strategies. Results: In the first study, the prototype was rated fairly in terms of usability, product functions and product features. However, usability ratings significantly decreased after four weeks. In the second study, ratings of usability, as well as of several product functions and product features were significantly more favourable for one of the two tested commercial products. Clinical effectiveness was not found in either study. In the third study, the main adoption barriers were based on unclear benefits and ethical concerns, as well as limitations in awareness, technology, product characteristics, and capital investments. Key services and information dissemination strategies centred on digital autonomy support, emergency support, information dissemination actors, product acquisition, and product advertising. Discussion: Results from both user experience studies indicate that focusing on specific product functions and features might substantially improve user experience. This might translate to measurable clinical effectiveness and higher adoption rates. Results from our qualitative study indicate that not only product characteristics and the technology itself impact adoption. Indeed, focusing on services and information dissemination strategies around products warrants closer attention as they might markedly improve adoption.Einleitung: Ortungssysteme in der Demenzversorgung gelten als eine vielversprechende Art von assistierender Technologie, um die Lebensqualität von Menschen mit Demenz und ihren Pflegepartnern zu verbessern, indem sie dabei helfen räumliche Orientierungsstörungen und Wanderungen zu bewältigen. Ihre Verwendung bleibt jedoch trotz der Verfügbarkeit vieler kom-merzieller Produkte gering. Um besser zu verstehen, wie ihre Verwendung gefördert werden kann, haben wir die Nutzererfahrung und klinische Wirksamkeit, die sich aus der Produktnutzung ergeben sowie die Barrieren für ihre Einführung untersucht. Methoden: In einer ersten Nutzererfahrungsstudie wurde ein Prototyp Ortungssystem vier Wo-chen lang von 17 Dyaden bestehend aus Menschen mit Demenz und ihren Pflegepartnern ge-testet. In einer zweiten Nutzererfahrungsstudie wurden zwei ähnliche kommerziell erhältliche Or-tungssysteme jeweils vier Wochen lang von weiteren 17 Dyaden getestet. Die Nutzererfahrung wurde mit Bewertungen der Benutzerfreundlichkeit, Produktfunktionen und Produkteigenschaften untersucht. Klinische Wirksamkeit, Nutzungshäufigkeit, Kaufbereitschaft und Produktzufrieden-heit wurden mit verschiedenen Skalen bewertet. In einer dritten qualitativen Fokusgruppeninter-viewstudie mit 22 interdisziplinären professionellen Stakeholdern untersuchten wir Ansichten zu den Barrieren für ihre Verwendung sowie zu Dienstleistungen und Strategien zur Informationsverbreitung. Ergebnisse: In der ersten Studie waren die Bewertungen der Benutzerfreundlichkeit, Produkt-funktionen und Produkteigenschaften mittelmäßig. Die Bewertung der Benutzerfreundlichkeit ging jedoch nach vier Wochen deutlich zurück. In der zweiten Studie fielen die Bewertungen der Benutzerfreundlichkeit sowie einiger Produktfunktionen und Produkteigenschaften bei einem der beiden getesteten Produkte deutlich besser aus. Klinische Wirksamkeit wurde in keiner der Studien gefunden. In der dritten Studie konzentrierten sich die wichtigsten Einführungsbarrieren auf unklare Vorteile und ethische Bedenken sowie auf bewusstseins-, technologisch-, produktmerkmal- und kapitalinvestitionsbasierte Einschränkungen. Dienstleistungen und Strategien zur Informationsverbreitung konzentrierten sich auf Unterstützung von digitaler Autonomie, Notfallunterstützung, Akteure der Informationsverbreitung, Produktakquisition und Produktwerbung. Diskussion: Die Ergebnisse beider Studien zur Nutzererfahrung zeigen, dass die Nutzererfah-rung durch die Optimierung bestimmter Produktfunktionen und Produkteigenschaften erheblich verbessert werden kann. Dies könnte zu einer messbaren klinischen Wirksamkeit und höheren Verwendung führen. Die Ergebnisse unserer qualitativen Studie zeigen, dass die Verwendung durch mehr als die Produktemerkmale und die Technologie selbst bestimmt wird. Deshalb ist eine gezielte Fokussierung auf Dienstleistungen und Strategien zur Informationsverbreitung rund um Ortungssysteme notwendig, da sie die Verwendung deutlich verbessern könnte

The effect of bright light on rest-activity rhythms and behavioural and psychological symptoms of dementia

De fleste som lever med demens har også atferdsmessige- og psykologiske symptomer ved demens (APSD) som for eksempel depresjon, angst, agitasjon, og søvnforstyrrelser. APSD påvirker livskvalitet og pleiebehov. Aktivitetsrytmen er ofte endret hos personer med demens. For eksempel kan søvn og våkenhet forekomme uregelmessig, med rastløshet og atferdsforstyrrelser på kvelds- og nattestid, og søvn på dagtid. Forstyrrelser i søvn og våkenhet har negative konsekvenser for daglig fungering, kognisjon, og affekt. I tillegg er det trolig at denne typen problemer gjenspeiler forstyrrelse av den endogene cirkadiane rytmen. APSD, inkludert søvnproblemer, behandles ofte medikamentelt, på tross av at slik behandling har begrenset effekt og kan medføre alvorlige bivirkninger. Lys påvirker den cirkadiane rytmen, og kan i tillegg ha en innvirkning på våkenhet og humør. Disse omtales som ikke-visuelle effekter av lys. Lysterapi er en ikke-medikamentell behandling som ifølge noen tidligere studier kan ha en positiv effekt på affekt, agitasjon, søvnforstyrrelser og aktivitetsrytmer hos personer med demens, men resultatene fra ulike studier har ikke vært entydige. Målet med denne avhandlingen var å undersøke effekten av lysterapi på APSD og aktivitetsrytmer, gjennom en klynge-randomisert placebo-kontrollert studie over 24 uker – DEM.LIGHT studien. Et sekundært mål, og et forarbeid til hovedstudien, var å undersøke lysforholdene ved demensenheter på sykehjem. Artikkel 1 presenterte en undersøkelse av lys på 15 demensenheter i Bergen kommune, gjennomført ved to årstider og med lysmålinger i ulike retninger. Lysmålingene ble sammenlignet med grenseverdier basert på anbefalinger og tidligere forskning. Lysverdiene ble oppgitt i måleenheter som er relevante for ikkevisuelle effekter av lys. Artikkel 2 og 3 rapporterte resultater fra DEM.LIGHTstudien, gjennomført på 8 sykehjem med 69 deltagere. Intervensjonen besto av takmonterte LED-lys i fellesstuen på 4 demensenheter, som gav lys av ulik styrke og fargetemperatur gjennom dagen. Maksimalt nivå for intervensjonen var ~1000 lx og 6000 K, mellom kl. 10:00 og 15:00, målt vertikalt 1.2 m over gulvet. Kontrollgruppen (4 demensenheter) hadde standard innendørsbelysning (~150–300 lx, 3000 K). Data ble innhentet ved baseline, og etter 8, 16 og 24 uker. Artikkel 2 undersøkte effekten av lysbehandlingen på aktivitetsrytmer registrert med aktigrafi, og artikkel 3 undersøkte effekten på proxy-vurderte APSD-mål (Cornell Scale for Depression in Dementia, CSDD og Neuropsychiatric Inventory – Nursing Home Version, NPI-NH). Effekten av behandlingen ble analysert ved bruk av blandede regresjonsmodeller (multilevel models), med demensstadium (Functional Assessment Staging Tool, FAST skåre) ved baseline som en a priori bestemt kovariat. I tillegg ble baselineskårer på utfallsmålene inkludert som kovariater i analysene til artikkel 3. I artikkel 1 fant vi at de fleste målingene av lyset på demensenhetene var under terskelverdiene, uavhengig av årstid og måleretning. I artikkel 2 fant vi ingen forbedring av aktivitetsrytmen etter BLT hos personer med demens når vi korrigerte for multippel testing. Uten slik korreksjon var akrofasen (tidspunktet for aktivitetrytmens makspunkt) signifikant mindre forsinket (med en time) i uke 16 i intervensjonsgruppen sammenlignet med kontrollgruppen. Artikkel 3 rapporterte blandede resultater for effekten av lysintervensjonen på APSD. Det var en signifikant effekt på underskalaer som måler affektive symptomer i uke 16, men ikke i uke 8 eller 24, etter korreksjon for multippel testing. Det var en signifikant effekt på CSDD og NPI-NH total-skårer i uke 16 før, men ikke etter, korreksjon for multippel testing. Det var ingen signifikant effekt på andre underskalaer. Oppsummert peker funnene fra artikkel 1 mot at lyset på demensenheter er utilstrekkelig sett opp mot terskelverdier for ikke-visuelle effekter av lys. Likevel var resultatene fra DEM.LIGHT-studien, som økte belysningen på demensenheter, blandede. Basert på disse resultatene kan vi ikke anbefale takmontert lysterapi ved demensenheter. Det er imidlertid flere metodologiske utfordringer og karakteristikker ved utvalget som begrenser generaliserbarheten til disse funnene.Most people living with dementia have behavioural and psychological symptoms of dementia (BPSD), such as depression, anxiety, agitation, and disturbed sleep, that strongly affect well-being and care needs. The rest-activity rhythm (RAR), i.e., the diurnal pattern of activity, is often altered in individuals with dementia. Sleep and wakefulness may, for instance, occur at irregular intervals, characterised by restlessness and behavioural disturbances at night, and napping during the day. This disruption of the sleep-wake pattern is detrimental to functioning and well-being. It is also thought to reflect deterioration of the endogenous circadian rhythm. Pharmacotherapy is often used to treat BPSD, including sleep disturbances, but has limited efficacy and is associated with severe side effects. Light influences the circadian rhythm, and can also have effects on alertness and mood. These are collectively referred to as non-image forming (NIF) effects of light. Bright light treatment (BLT) is a non-pharmacological intervention that has been found to improve affective symptoms, agitation, sleep disorders, and RARs in people with dementia in some studies, but results have been mixed. The main aim of this thesis was to investigate the effect of BLT on RARs and BPSD in a 24-week cluster randomised controlled trial - the DEM.LIGHT trial (ClinicalTrials.gov identifier: NCT03357328). A secondary aim, and preparation for the trial, was to investigate the illumination in nursing home dementia units. Paper 1 was a field study investigating nursing home illumination in 15 dementia units across seasons and gaze directions. Measured illuminances were compared to thresholds suggested by industry standards and research, and measurement units relevant to NIF effects of light were used. Paper 2 and 3 reported results from the DEM.LIGHT trial, conducted at 8 dementia units, with 69 participants. In the intervention group (4 units), ceiling mounted LED-panels provided ambient light of varying illuminance and correlated colour temperature throughout the day, with a peak of ~1000 lx and 6000 K (measured vertically at 1.2 m) between 10:00 and 15:00. In the control group (4 units), standard indoor light of ~150–300 lx, 3000 K was used. Data were collected at baseline and at 8, 16, and 24 weeks. Paper 2 investigated the effect of the intervention on actigraphy-measured RARs, and paper 3 investigated the effect on proxy-rated BPSD measures: the Cornell Scale for Depression in Dementia (CSDD) and the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Treatment effects were analysed using multilevel regression models, with dementia stage (score on the Functional Assessment Staging Tool, FAST) at baseline as a pre-determined covariate. In addition, baseline scores on the outcome measures were included as covariates in the models in paper 3. In paper 1 we found that, regardless of season and gaze direction, nearly all measured illuminances in dementia units fell below the thresholds. In paper 2, we found that there was no effect of BLT on RAR outcomes in people with dementia when controlling for multiple testing. Without controlling for multiple testing, the acrophase (i.e., timing of the activity peak) was significantly less delayed (by one hour) in the intervention group compared to the control group, in week 16. Paper 3 found mixed results for the effect of BLT on BPSD. There was a significant reduction of scores on affective subscales in the intervention group in week 16, but not at other follow-ups, after controlling for multiple testing. There was a significant effect on the NPI-NH and CSDD total scores in week 16 before, but not after, controlling for multiple testing. There were no significant effects on other subscales. In conclusion, the findings in paper 1 suggest that illumination in dementia units is inadequate compared to thresholds suggested for NIF effects of light. However, the results of the DEM.LIGHT trial, which increased the indoor illumination in dementia units, were mixed. Based on our results, we cannot make clear recommendations regarding the use of ambient BLT in dementia units. Several methodological challenges and sample characteristics may limit the generalisability of these results.Doktorgradsavhandlin

Reproducibility in the absence of selective reporting: An illustration from large-scale brain asymmetry research.

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes