Insights into the pathological basis of dementia from population-based neuropathology studies.

The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.

Two-decade change in prevalence of cognitive impairment in the UK.

Identification of individuals at high risk of dementia has usually focused attention on the clinical concept of mild cognitive impairment (MCI), which captures an intermediate state between normal cognitive ageing and dementia. In many countries age specific risk of dementia has declined, but whether this is also the case for subclinical cognitive impairment is unknown. This has important implications for prevention, planning and policy. Here we describe subclinical cognitive impairment and mild dementia prevalence changes, in the UK, over 2 decades. The Cognitive Function and Ageing Studies have examined the full spectrum of cognition, from normal to dementia, in representative populations of people aged ≥ 65 years in the UK over the last 2 decades 7635 participants were interviewed in CFAS I in Cambridgeshire, Newcastle, and Nottingham in 1991, with 1457 being diagnostically assessed. In the same geographical areas, the CFAS II investigators interviewed 7796 individuals in 2011. Using established criteria, the population was categorised into seven groups: no cognitive impairment, Mild cognitive Impairment (defined using consensus criteria), other cognitive impairment no dementia without functional impairment, OCIND with functional impairment, cognitive impairment (MMSE < 24 and no functional impairment), mild dementia (MMSE < 24 with functional impairment, not captured by CFAS dementia criteria), and CFAS dementia criteria. Multinomial logistic regression, adjusted for age and sex, was used to estimate the prevalence of impairment in both studies. Results were standardized to the age-sex specific UK and global population. There is a clear increase in the prevalence of other cognitive Impairment no Dementia (without functional impairment), with the purer MCI remaining stable. In the UK, mild dementia is estimated to fall from 520,704 cases (5.7%, 95% CI 3.8, 8.1) in 1991 to 315,142 (3.0%, 95% CI 2.4, 3.8) in 2011, cognitive impairment, has fallen from 1,225,984 (13.5%, 95% CI 10.1, 17.5) to 654,436 (6.3%, 95% CI 5.4, 7.3) cases. Using additional categories which reflect the continuum of cognitive decline and impairment in populations we see that the mildest dementia declines, but that there is stability in estimates of those who meet MCI criteria. Increases were found in the Other Cognitive Impairment no Dementia group. The decline observed in severe impairment thus seems to have resulted in larger proportions of the population in milder forms, seen alongside physical illnesses.

Comparison of Clostridium difficile isolates from individuals with recurrent and single episode of infection.

PURPOSE: Recurrent Clostridium difficile infection (CDI) is an increasing problem, yet reasons for this are poorly understood. Attention has been paid to the role of strain, with conflicting association of ribotype 027 and recurrences. METHODS: Stool samples and medical records data were collected from 60 patients: 27 with recurrent CDI and 33 with single episode CDI. C. difficile was isolated and ribotyped, and minimum inhibitory concentrations of metronidazole and vancomycin were determined by Etest. RESULTS: Twenty-seven ribotypes were identified, but only four (027, 014 and two internally designated strains) were found in more than one patient. Ribotype 027 predominated and was significantly over-represented in the recurrent CDI group (70%) versus the single episode CDI group (30%) (P = 0.004). Female gender and the presence of ribotype 027 were significantly associated with recurrent CDI in the multivariable model. Metronidazole MICs for recurrent isolates were significantly higher compared to single episode isolates (P ≤ 0.024). A general linear model indicated that the difference in MIC was associated with ribotype 027 (P = 0.0023), not whether the isolate was from recurrent or single episode disease (P = 0.25). CONCLUSIONS: Ribotype 027 was associated with recurrent disease. While there was no difference in the prevalence of metronidazole resistance, isolates from recurrent CDI patients had significantly higher metronidazole MICs, because of higher MICs in ribotype 027. This study provides further support to the clinical importance of ribotype 027 and raises questions about the potential impact of decreased metronidazole susceptibility on the pathophysiology of recurrent CDI.

Relationships of brain cholesterol and cholesterol biosynthetic enzymes to Alzheimer's pathology and dementia in the CFAS population-derived neuropathology cohort.

Altered cholesterol metabolism is implicated in brain ageing and Alzheimer's disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer's disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.

Impact of COVID-19 policies on perceptions of loneliness in people aged 75 years and over in the cognitive function and aging study (CFAS II).

BACKGROUND: The COVID-19 pandemic and associated social distancing measures have profoundly impacted society and social contact patterns, with older people disproportionately affected. Concerns have been raised about a resulting pandemic of loneliness in older people, although the current evidence is mixed. This study provides a unique perspective on the prevalence of loneliness in a population cohort of older people before the pandemic, followed up after the introduction of social restrictions. METHODS: Data analysis was conducted using Wave 3 of the longitudinal Cognitive Function and Aging Study II (2018-2019) and a sub-study focusing on experiences during the COVID-19 pandemic (2020). The sample comprised 379 adults aged over 75 living in Cambridge, Newcastle, and Nottingham. Multivariable binary logistic regression was conducted to identify correlates of prevalent loneliness, adjusted for confounding covariates, during the pandemic. The prevalence of loneliness during the pandemic was compared to loneliness in 2018-2019. RESULTS: Prevalence of loneliness in this sample during the pandemic was 25.1% (95% CI 20.9%-29.7%) compared to 17.2% (95% CI 13.7%-21.3%) in 2018-2019 (χ2  = 14.1, p < 0.01). Variables associated with increased odds of prevalent loneliness included: prior loneliness, living alone, female gender, living in an area of higher deprivation, frequent pre-pandemic social contact at community groups, and separation from family during the pandemic, adjusted for age and sex. Weekly technology-mediated contact using telephone or video calls was associated with lower odds of loneliness. CONCLUSIONS: COVID-19 recovery plans should address loneliness in older people. Target groups should include those who have previously been lonely, people who live alone, those living in deprived areas, and those who had previously been socially active through community groups.

Secular Trends in Dementia Free Cognitive Function in Older Adults: A Systematic Review.

BACKGROUND: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. OBJECTIVE: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. METHODS: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 28 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. RESULTS: 28,101 studies were identified and 15 selected covering the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. RESULTS: Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. CONCLUSION: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising.

Dementia in the older population is associated with neocortex content of serum amyloid P component.

Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones in vitro and in experimental animals in vivo. The neocortical content of serum amyloid P component was immunoassayed in 157 subjects aged 65 or more with known dementia status at death, in the large scale, population-representative, brain donor cohort of the Cognitive Function and Ageing Study, which avoids the biases inherent in studies of predefined clinico-pathological groups. The serum amyloid P component values were significantly higher in individuals with dementia, independent of serum albumin content measured as a control for plasma in the cortex samples. The odds ratio for dementia at death in the high serum amyloid P component tertile was 5.24 (95% confidence interval 1.79-15.29) and was independent of Braak tangle stages and Thal amyloid-ß phases of neuropathological severity. The strong and specific association of higher brain content of serum amyloid P component with dementia, independent of neuropathology, is consistent with a pathogenetic role in dementia.

Prevalence and Risk of Mild Cognitive Impairment in Low and Middle-Income Countries: A Systematic Review.

BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. OBJECTIVE: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. METHODS: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs and were included as long as MCI was clearly defined. RESULTS: 5,568 articles were screened, and 78 retained. In total, n = 23 different LMICs were represented; mostly from China (n = 55 studies). Few studies were from countries defined as lower-middle income (n = 14), low income (n = 4), or from population representative samples (n = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n = 26). Prevalence of amnesic MCI (aMCI) (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. CONCLUSION: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning.

Heterogeneity of cellular inflammatory responses in ageing white matter and relationship to Alzheimer's and small vessel disease pathologies.

White matter lesions (WML) are common in the ageing brain, often arising in a field effect of diffuse white matter abnormality. Although WML are associated with cerebral small vessel disease (SVD) and Alzheimer's disease (AD), their cause and pathogenesis remain unclear. The current study tested the hypothesis that different patterns of neuroinflammation are associated with SVD compared to AD neuropathology by assessing the immunoreactive profile of the microglial (CD68, IBA1 and MHC-II) and astrocyte (GFAP) markers in ageing parietal white matter (PARWM) obtained from the Cognitive Function and Ageing Study (CFAS), an ageing population-representative neuropathology cohort. Glial responses varied extensively across the PARWM with microglial markers significantly higher in the subventricular region compared to either the middle-zone (CD68 p = 0.028, IBA1 p < 0.001, MHC-II p < 0.001) or subcortical region (CD68 p = 0.002, IBA1 p < 0.001, MHC-II p < 0.001). Clasmatodendritic (CD) GFAP+ astrocytes significantly increased from the subcortical to the subventricular region (p < 0.001), whilst GFAP+ stellate astrocytes significantly decreased (p < 0.001). Cellular reactions could be grouped into two distinct patterns: an immune response associated with MHC-II/IBA1 expression and CD astrocytes; and a more innate response characterised by CD68 expression associated with WML. White matter neuroinflammation showed weak relationships to the measures of SVD, but not to the measures of AD neuropathology. In conclusion, glial responses vary extensively across the PARWM with diverse patterns of white matter neuroinflammation. Although these findings support a role for vascular factors in the pathogenesis of age-related white matter neuroinflammation, additional factors other than SVD and AD pathology may drive this. Understanding the heterogeneity in white matter neuroinflammation will be important for the therapeutic targeting of age-associated white matter damage.

Consumer attitudes toward entomophagy before and after evaluating cricket (Acheta domesticus)-based protein powders.

In recent years, the use of insects in food products has increased. Insects are a sustainable ingredient that is high in protein. However, consumption in Western countries is low, and this may be due to poor sensory qualities, expense, availability, and food neophobia. The objectives of this study were to determine Atlantic Canadian consumers' attitudes toward entomophagy and to assess consumers' perception of cricket-based protein powders. There were two phases to this study: in phase one, participants (n = 107) completed a survey about their attitudes toward consuming insects (Specific Beliefs and Attitudes about Insect Consumption Scale created by Ruby, Rozin, & Chan 2015), and in the second phase, participants (n = 102) were asked to evaluate four different protein powders (two contained crickets) using 9-point hedonic scales and a CATA questionnaire. Then, the participants were again asked to complete the aforementioned survey. Before consuming cricket protein powder, most participants thought that insects were a sustainable protein source, but also thought that the consumption of insects was undesirable. However, after consuming cricket protein powder, the participants were willing to buy cricket powder and were willing to recommend it to their friends. For insect consumption to become acceptable in the Western world, it will need to be integrated slowly to reduce consumers' fear and negative attitudes. Protein powders are consumed by many people in the Western world and are an excellent candidate to allow for the integration of insects into their diets. PRACTICAL APPLICATION: This study demonstrated that consumers in Atlantic Canada are more willing to eat insects after having tried them in protein powders. Additionally, protein powders represent a familiar context for consumers and allow for the acceptable integration of cricket powder. Consumers are willing to buy and recommend crickets to their friends after consuming them (in a processed form); however, they still have concerns that insects may carry harmful microbes and toxins.

Advanced Glycation End Product Formation in Human Cerebral Cortex Increases With Alzheimer-Type Neuropathologic Changes but Is Not Independently Associated With Dementia in a Population-Derived Aging Brain Cohort.

Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aß phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's.

Is There a Link Between Cognitive Reserve and Cognitive Function in the Oldest-Old?

Background: The oldest-old (aged ≥85 years) are the fastest growing age group, with the highest risk of cognitive impairment and dementia. This study investigated whether cognitive reserve applies to the oldest-old. This has implications for cognitive interventions in this age group. Methods: Baseline and 5-year follow-up data from the Newcastle 85+ Study were used (N = 845, mean age = 85.5, 38% male). A Cognitive Reserve Index (CRI) was created, including: education, social class, marital status, engagement in mental activities, social participation, and physical activity. Global (Mini-Mental State Examination) and domain specific (Cognitive Drug Research Battery subtests assessing memory, attention, and speed) cognitive functions were assessed. Dementia diagnosis was determined by health records. Logistic regression analysis examined the association between CRI scores and incident dementia. Mixed effects models investigated baseline and longitudinal associations between the CRI scores and cognitive function. Analyses controlled for sex, age, depression, and cardiovascular disease history. Results: Higher reserve associated with better cognitive performance on all baseline measures, but not 5-year rate of change. The CRI associated with prevalent, but not incident dementia. Conclusions: In the oldest-old, higher reserve associated with better baseline global and domain-specific cognitive function and reduced risk of prevalent dementia; but not cognitive decline or incident dementia. Increasing reserve could promote cognitive function in the oldest-old. The results suggest there would be little impact on trajectories, but replication is needed. Development of preventative strategies would benefit from identifying the role of each factor in building reserve and why rate of change is not affected.

A three-dimensional atlas of human dermal leukocytes, lymphatics, and blood vessels.

Dendritic cells (DCs), macrophages (Mφ), and T cells are major components of the skin immune system, but their interstitial spatial organization is poorly characterized. Using four-channel whole-mount immunofluorescence staining of the human dermis, we demonstrated the three-dimensional distribution of CD31(+) blood capillaries, LYVE-1(+) lymphatics, discrete populations of CD11c(+) myeloid DCs, FXIIIa(+) Mφ, and lymphocytes. We showed phenotypic and morphological differences in situ between DCs and Mφ. DCs formed the first dermal cellular layer (0-20 µm beneath the dermoepidermal junction), Mφ were located deeper (40-60 µm), and CD3(+) lymphocytes were observed throughout (0-60 µm). Below this level, DCs, T cells, and the majority of Mφ formed stable perivascular sheaths. Whole-mount imaging revealed the true extent of dermal leukocytes previously underestimated from cross-section views. The total area of apical dermis (0-30 µm) contained approximately 10-fold more myeloid DCs than the entire blood volume of an average individual. Surprisingly, <1% of dermal DCs occupied lymphatics in freshly isolated skin. Dermal DCs rapidly accumulated within lymphatics, but Mφ remained fixed in skin explants cultured ex vivo. The leukocyte architecture observed in normal skin was distorted in inflammation and disease. These studies illustrate the micro-anatomy of dermal leukocytes and provide further insights into their functional organization.