BACKGROUND: Although white matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary-to-transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether connectome gradient structure is altered as WMH progresses and how this alteration is associated with WMH-related cognitive decline remain unknown.
METHODS: A total of 758 WMH individuals completed cognitive assessment and resting-state functional MRI (rs-fMRI). The functional connectome gradient was reconstructed based on rs-fMRI by using a gradient decomposition framework. Interrelations among the spatial distribution of WMH, functional gradient measures, and specific cognitive domains were explored.
RESULTS: As the WMH volume increased, the executive function (r = -0.135, p = 0.001) and information-processing speed (r = -0.224, p = 0.001) became poorer, the gradient range (r = -0.099, p = 0.006), and variance (r = -0.121, p < 0.001) of the primary-to-transmodal gradient reduced. A narrower gradient range (r = 0.131, p = 0.001) and a smaller gradient variance (r = 0.136, p = 0.001) corresponded to a poorer executive function. In particular, the relationship between the frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary-to-transmodal gradient.
CONCLUSIONS: These findings indicated that WMH volume, the primary-to-transmodal gradient, and cognition were interrelated. The detrimental effect of the frontal/occipital WMH on executive function was partly mediated by the decreased differentiation of the connectivity pattern between the primary and transmodal areas.

UNASSIGNED: Research suggests that the neighborhood in which people live can be a risk or protective factor for various health outcomes, including cognitive decline to Alzheimer\'s disease. Similar to the impact of neighborhood on health outcomes, sleep difficulties have been linked to cognitive function in older adults. However, few studies have examined how neighborhood physical disorders moderate the effects of sleep on subjective cognitive decline (SCD).
UNASSIGNED: The study examined the moderating effect of neighborhood factors on the relationship between sleep difficulties and SCD.
UNASSIGNED: Data were obtained from 2,494 respondents (1,065 males and 1,429 females) from Wave 11 of the National Health and Aging Trends (NHATS) data. Sleep difficulties were operationalized as the presence of difficulties in falling and staying asleep. Neighborhood physical disorder (e.g., vandalism, graffiti) was based on interviewer observations of respondents\' neighborhoods. SCD was operationalized as subjective reports of increasing or worse memory loss in the past 12 months and present memory rating. We utilized Linear regression to test neighborhood physical disorder as a moderator of the relationship between sleep difficulties and SCD.
UNASSIGNED: We found a significant interaction between sleep difficulties and neighborhood physical disorder on SCD (β=0.03, SE = 0.01, 95% CI[0.00,0.51], p < 0.001). Participants who reported higher average sleep difficulties and higher levels of neighborhood physical disorder were more likely to report SCD.
UNASSIGNED: Our findings add to inform future health interventions and policy recommendations that address modifiable sources of cognitive decline and risk of Alzheimer\'s disease.

The increasing burden of Alzheimer\'s disease (AD) emphasizes the need for effective diagnostic and therapeutic strategies. Despite available treatments targeting amyloid beta (Aβ) plaques, disease-modifying therapies remain elusive. Early detection of mild cognitive impairment (MCI) patients at risk for AD conversion is crucial, especially with anti-Aβ therapy. While plasma biomarkers hold promise in differentiating AD from MCI, evidence on predicting cognitive decline is lacking. This study\'s objectives were to evaluate whether plasma protein biomarkers could predict both cognitive decline in non-demented individuals and the conversion to AD in patients with MCI. This study was conducted as part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a prospective, community-based cohort. Participants were based on plasma biomarker availability and clinical diagnosis at baseline. The study included MCI (n = 50), MCI-to-AD (n = 21), and cognitively unimpaired (CU, n = 40) participants. Baseline plasma concentrations of six proteins-total tau (tTau), phosphorylated tau at residue 181 (pTau181), amyloid beta 42 (Aβ42), amyloid beta 40 (Aβ40), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP)-along with three derivative ratios (pTau181/tTau, Aβ42/Aβ40, pTau181/Aβ42) were analyzed to predict cognitive decline over a six-year follow-up period. Baseline protein biomarkers were stratified into tertiles (low, intermediate, and high) and analyzed using a linear mixed model (LMM) to predict longitudinal cognitive changes. In addition, Kaplan-Meier analysis was performed to discern whether protein biomarkers could predict AD conversion in the MCI subgroup. This prospective cohort study revealed that plasma NFL may predict longitudinal declines in Mini-Mental State Examination (MMSE) scores. In participants categorized as amyloid positive, the NFL biomarker demonstrated predictive performance for both MMSE and total scores of the Korean version of the Consortium to Establish a Registry for Alzheimer\'s Disease Assessment Packet (CERAD-TS) longitudinally. Additionally, as a baseline predictor, GFAP exhibited a significant association with cross-sectional cognitive impairment in the CERAD-TS measure, particularly in amyloid positive participants. Kaplan-Meier curve analysis indicated predictive performance of NFL, GFAP, tTau, and Aβ42/Aβ40 on MCI-to-AD conversion. This study suggests that plasma GFAP in non-demented participants may reflect baseline cross-sectional CERAD-TS scores, a measure of global cognitive function. Conversely, plasma NFL may predict longitudinal decline in MMSE and CERAD-TS scores in participants categorized as amyloid positive. Kaplan-Meier curve analysis suggests that NFL, GFAP, tTau, and Aβ42/Aβ40 are potentially robust predictors of future AD conversion.

UNASSIGNED: We have shown that genetic factors associating with motor progression of Parkinson\'s disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better.
UNASSIGNED: Data were obtained from the Parkinson\'s Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD.
UNASSIGNED: SDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323.
UNASSIGNED: SDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.

BACKGROUND: Spatial extent-based measures of how far amyloid beta (Aβ) has spread throughout the neocortex may be more sensitive than traditional Aβ-positron emission tomography (PET) measures of Aβ level for detecting early Aβ deposits in preclinical Alzheimer\'s disease (AD) and improve understanding of Aβ\'s association with tau proliferation and cognitive decline.
METHODS: Pittsburgh Compound-B (PIB)-PET scans from 261 cognitively unimpaired older adults from the Harvard Aging Brain Study were used to measure Aβ level (LVL; neocortical PIB DVR) and spatial extent (EXT), calculated as the proportion of the neocortex that is PIB+.
RESULTS: EXT enabled earlier detection of Aβ deposits longitudinally confirmed to reach a traditional LVL-based threshold for Aβ+ within 5 years. EXT improved prediction of cognitive decline (Preclinical Alzheimer Cognitive Composite) and tau proliferation (flortaucipir-PET) over LVL.
CONCLUSIONS: These findings indicate EXT may be more sensitive to Aβ\'s role in preclinical AD than level and improve targeting of individuals for AD prevention trials.
CONCLUSIONS: Aβ spatial extent (EXT) was measured as the percentage of the neocortex with elevated Pittsburgh Compound-B. Aβ EXT improved detection of Aβ below traditional PET thresholds. Early regional Aβ deposits were spatially heterogeneous. Cognition and tau were more closely tied to Aβ EXT than Aβ level. Neocortical tau onset aligned with reaching widespread neocortical Aβ.

Vitamin B12 deficiency can present with a variety of neurological and cognitive symptoms. Especially in elderly patients, vitamin B12 deficiency can be easily overlooked because symptoms may be attributed to comorbid conditions or solely to the aging process. In this case study, we present two patients, a 71-year-old man and a 74-year-old female, with vitamin B12 deficiency. The male patient had a history of (partial) resection of the ileum/jejunum/colon because of intestinal ischemia. The female patient had a history of hypothyroidism, type 2 diabetes with complications (including peripheral neuropathy), mitochondrial myopathy, and chronic lymphocytic leukemia. Both patients presented with severe fatigue, cognitive impairment, and impaired walking. Next to this, the male patient suffered from depressive symptoms and mild disorientation, and the female patient experienced neuropathic pain. She also mentioned a positive family history for B12 deficiency. The first patient had normal to high B12 levels because he was already on B12 injections (once every three weeks) because of an earlier diagnosed B12 deficiency. The female patient had B12 levels within normal range (holotranscobalamin 54 pmol/L) and her diagnosis was confirmed by elevated homocysteine and methylmalonic acid levels. Treatment with frequent hydroxocobalamin injections and other supplements significantly improved their cognitive, emotional, and motor functions. These cases underscore the need for a high level of clinical suspicion in elderly patients, also in cases of normal B12 levels but with clinical signs of deficiency and a positive risk factor, such as stomach or small bowel surgery or positive family history.
Plain language titleA case study of two elderly patients with vitamin B12 deficiency and neurological and cognitive complaintsPlain language summaryVitamin B12 deficiency in elderly patients can be easily overlooked as symptoms can also be caused by other age-related diseases or the aging process. In our article we present two elderly patients, a 71-year-old male and a 74-year-old female, with neurological complaints, such as severe fatigue, cognitive decline, and walking impairment. The male patient had a history of small bowel surgery, and the female patient mentioned that she had several siblings with B12 deficiency. Additionally, the male patient suffered from depressive symptoms and mild disorientation, and the female had severe pain in her legs. The male patient already received B12 injections because of an earlier B12 diagnosis, but with a relatively low frequency. The B12 levels of the female patients were within the normal range. However, her diagnoses could be confirmed with additional laboratory measurements, such as homocysteine and methylmalonic acid. Treatment with frequent B12 injections and other supplements significantly improved their cognitive, emotional, and motor functions. Our study shows that clinicians should carefully consider the possibility of B12 deficiency in elderly patients with cognitive and neurological complaints, also in patients with B12 levels within the normal range, but with risk factors such as family members with B12 deficiency or conditions that may impair the vitamin B12 uptake, such as previous stomach or small bowel surgery.

The objective of the present study was to retrospectively evaluate hair mercury (Hg) content in reproductive-age women living in Central Russia (Moscow and Moscow region), and to calculate the potential costs of the potential Hg-induced IQ loss in a hypothetical national birth cohort.
METHODS: A total of 36,263 occupationally non-exposed women aged between 20 and 40 years living in Moscow (n = 30,626) or Moscow region (n = 5637) in the period between 2005 and 2021 participated in this study. Hair Hg content was evaluated with inductively coupled plasma-mass spectrometry (ICP-MS). Hair Hg levels in reproductive-age women were used for assessment of the potential IQ loss and its costs.
RESULTS: The results demonstrate that hair Hg content in the periods between 2010 and 2015, and 2016-2021 was significantly lower than that in 2005-2009 by 26 % and 51 %, respectively. The highest hair Hg level was observed in women in 2005 (0.855 µg/g), being more than 2.5-fold higher than the lowest value observed in 2020 (0.328 µg/g). Multiple regression analysis revealed a significant inverse association between the year of analysis and hair Hg content (β = -0.288; p < 0.001). The calculations demonstrate that in 2005 the costs of IQ loss in children exceeded 1.0 (1.6) billion USD, whereas in 2020 the costs of IQ loss accounted to approximately 0.15 (0.28) billion USD.
CONCLUSIONS: Taken together, our data demonstrate that Hg accumulation in reproductive-age women reduced significantly in Russia from 2005 to 2021 resulting in predicted economic benefits by decreasing the costs of Hg-induced IQ loss.

Policy Points Education-cognition research overlooks the role of education quality in shaping cognitive function at midlife and older ages, even though quality may be more responsive to federal and state investment in public schooling than attainment. For older US adults who attended school during the early to mid-20th century, the quality of US education improved considerably as federal and state investment increased. Ensuring access to high-quality primary and secondary education may protect against poor cognitive function at midlife and older ages, particularly among Black Americans and persons who complete less education. It may also play an important role in reducing health inequities.
BACKGROUND: Although educational attainment is consistently associated with better cognitive function among older adults, we know little about how education quality is related to cognitive function. This is a key gap in the literature given that the quality of US education improved considerably during the early to mid-20th century as state and federal investment increased. We posit that growing up in states with higher-quality education systems may protect against poor cognitive function, particularly among Black adults and adults who completed fewer years of school.
METHODS: We used prospective data on cognitive function from the Health and Retirement Study linked to historical data on state investment in public schools, restricting our sample to non-Hispanic White and Black adults born between 1914 and 1959 (19,096 White adults and 4,625 Black adults). Using race-stratified linear mixed models, we considered if state-level education quality was associated with level and decline in cognitive function and if these patterns differed by years of schooling and race.
RESULTS: Residing in states with higher-resourced education systems during childhood was associated with better cognitive function, particularly among those who completed less than 12 years of schooling, regardless of race. For White adults, higher-resourced state education systems were associated with higher scores of total cognitive function and episodic memory, but there were diminishing returns as resources increased to very high levels. For Black adults, the relationship between state education resources and cognitive function varied by age with positive associations in midlife and generally null or negative associations at the oldest ages.
CONCLUSIONS: Federal and state investment in public schools may provide students with opportunities to develop important cognitive resources during schooling that translate into better cognitive function in later life, especially among marginalized populations.

Eggs not only contain all the molecules necessary to nurture new life but are also rich in nutrients such as high-quality protein. For example, epidemiologic studies have shown that egg intake is positively correlated with cognitive function. Thus, we specifically examined the effect of ovalbumin, a major protein present in egg whites, on cognitive function. First, we found that an orally administered enzymatic digest of ovalbumin improves cognitive function in mice fed a high-fat diet. Then, we narrowed down candidate peptides based on the prediction of peptide production according to enzyme-substrate specificity and comprehensive peptide analysis of the digest. We found that three peptides, namely ILPEY, LYRGGLEP, and ILELP, improve cognitive function after oral administration. We also showed that ILPEY, LYRGGLEP, and ILELP were present in the digest and named them ovomemolins A (OMA), B, and C, respectively. Notably, ovomemolins are the first peptides derived from egg whites that have been shown to improve cognitive function. The cognitive improvement induced by OMA, the most abundant of the peptides in the digest, was inhibited by methyllycaconitine, an antagonist of α7nAChR, which is known to be related to memory. These results suggest that OMA improves cognitive function through the acetylcholine system. After OMA administration, brain-derived neurotrophic factor (BDNF) mRNA expression and the number of 5-bromo-2\'-deoxyuridine-positive cells suggested that OMA increases hippocampal BDNF expression and neurogenesis.

Brain aging is associated with a decline in cognitive performance, motor function and sensory perception, even in the absence of neurodegeneration. The underlying pathophysiological mechanisms remain incompletely understood, though alterations in neurogenesis, neuronal senescence and synaptic plasticity are implicated. Recent years have seen advancements in neurophysiological techniques such as electroencephalography (EEG), magnetoencephalography (MEG), event-related potentials (ERP) and transcranial magnetic stimulation (TMS), offering insights into physiological and pathological brain aging. These methods provide real-time information on brain activity, connectivity and network dynamics. Integration of Artificial Intelligence (AI) techniques promise as a tool enhancing the diagnosis and prognosis of age-related cognitive decline. Our review highlights recent advances in these electrophysiological techniques (focusing on EEG, ERP, TMS and TMS-EEG methodologies) and their application in physiological and pathological brain aging. Physiological aging is characterized by changes in EEG spectral power and connectivity, ERP and TMS parameters, indicating alterations in neural activity and network function. Pathological aging, such as in Alzheimer\'s disease, is associated with further disruptions in EEG rhythms, ERP components and TMS measures, reflecting underlying neurodegenerative processes. Machine learning approaches show promise in classifying cognitive impairment and predicting disease progression. Standardization of neurophysiological methods and integration with other modalities are crucial for a comprehensive understanding of brain aging and neurodegenerative disorders. Advanced network analysis techniques and AI methods hold potential for enhancing diagnostic accuracy and deepening insights into age-related brain changes.