Anti-epileptic drug use and subsequent degenerative dementia occurrence.

INTRODUCTION: The use of anti-epileptic drugs (AEDs) in degenerative dementia (DD) remains uncertain. We aimed to evaluate the association of early AED administration with subsequent DD occurrence. METHODS: Using a large nationwide database, we enrolled patients newly diagnosed with epilepsy from 2014 to 2019 (n = 104,225), and using propensity score matching, we divided them into treatment (those prescribed AEDs in 2014) and control groups. The primary outcome was subsequent DD occurrence in 2019. RESULTS: Overall, 4489 pairs of patients (2156 women) were matched. The odds ratio (treatment/control) for DD occurrence was 0.533 (95% confidence interval: 0.459-0.617). The DD proportions significantly differed between the treatment (340/4489 = 0.076) and control (577/4489 = 0.129) groups. DISCUSSION: Among patients newly diagnosed with epilepsy, compared to non-use, early AED use was associated with a lower occurrence of subsequent DD. Further investigations into and optimization of early intervention for epilepsy in DD are warranted. Highlights: Anti-epileptic drug (AED) use before epilepsy diagnosis was linked with a lower subsequent degenerative dementia (DD) occurrence.Identifying the epileptic phenotype was crucial for justifying early AED use in DD.AED use with an epilepsy diagnosis did not pose an additional risk of DD.The potential contribution of combination drug therapy to the strategy was noted.

[Disease-modifying Drugs for non-Alzheimer Dementias].

Neurodegenerative diseases represent the most common cause of dementia. Protein aggregation is upstream in the pathological mechanisms and is a therapeutic target in the development of disease-modifying drugs in this patient population. Notably, α-synuclein or DNA-binding protein of 43kDa (TDP-43) is commonly involved in the pathomechanisms that contribute to non-Alzheimer neurodegenerative diseases. Several immunotherapy clinical trials on α-synuclein have progressed to phase 2, and small-molecule therapeutics are ongoing. With regard to TDP-43, immunotherapies that target protein aggregates are currently being developed, and research is underway to investigate several drugs that target the associated causative gene. Further research is warranted for deeper insight into both disease-modifying drugs; biomarker tests need to be developed to determine their efficacy. However, both proteins aggregate and accumulate in the brain in many neurodegenerative diseases and dementia; therefore, they are therapeutically significant, and future progress is expected in research and development.

Effect of matcha green tea on cognitive functions and sleep quality in older adults with cognitive decline: A randomized controlled study over 12 months.

OBJECTIVE: Lifestyle habits after middle age significantly impact the maintenance of cognitive function in older adults. Nutritional intake is closely related to lifestyle habits; therefore, nutrition is a pivotal factor in the prevention of dementia in the preclinical stages. Matcha green tea powder (matcha), which contains epigallocatechin gallate, theanine, and caffeine, has beneficial effects on cognitive function and mood. We conducted a randomized, double-blind, placebo-controlled clinical study over 12 months to examine the effect of matcha on cognitive function and sleep quality. METHODS: Ninety-nine participants, including 64 with subjective cognitive decline and 35 with mild cognitive impairment were randomized, with 49 receiving 2 g of matcha and 50 receiving a placebo daily. Participants were stratified based on two factors: age at baseline and APOE genotype. Changes in cognitive function and sleep quality were analyzed using a mixed-effects model. RESULTS: Matcha consumption led to significant improvements in social acuity score (difference; -1.39, 95% confidence interval; -2.78, 0.002) (P = 0.028) as evaluated by the perception of facial emotions in cognitive function. The primary outcomes, that is, Montreal Cognitive Assessment and Alzheimer's Disease Cooperative Study Activity of Daily Living scores, showed no significant changes with matcha intervention. Meanwhile, Pittsburgh Sleep Quality Index scores indicated a trend toward improvement with a difference of 0.86 (95% confidence interval; -0.002, 1.71) (P = 0.088) between the groups in changes from baseline to 12 months. CONCLUSIONS: The present study suggests regular consumption of matcha could improve emotional perception and sleep quality in older adults with mild cognitive decline. Given the widespread availability and cultural acceptance of matcha green tea, incorporating it into the daily routine may offer a simple yet effective strategy for cognitive enhancement and dementia prevention.

Comparison of Depressive Symptoms between International and Domestic Students in a Japanese University: Pre- and Post-COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic led to significant lifestyle changes and uncertainties, triggering a secondary wave of mental health issues in society. University students are especially susceptible to mental disorders. International students are considered more vulnerable due to limited emotional and financial support from their families and difficulties accessing community support. Hence, we conducted a longitudinal analysis to compare depressive symptoms among international students before and during the pandemic. METHODS: Data from depression screenings conducted at the University of Tsukuba in 2019 and 2020 were utilized. We included all students enrolled in 2019 who underwent health check-ups in both 2019 and 2020. Participants completed the Patient Health Questionnaire-9 (PHQ-9), enabling a comparison of item scores between domestic and international students. Psychopathological network analysis was employed to examine relationships among the items. RESULTS: Prior to the pandemic, international students generally exhibited relatively good mental health compared with domestic students. During the 2020 pandemic, no significant difference was observed, but international students tended to demonstrate better mental health. However, network analysis revealed intergroup variations in the relationships among PHQ-9 items, with concentration problems and suicidal thoughts being more prominent among international students. CONCLUSION: This study's findings suggest that young people studying abroad experience mental health crises similar to their domestic counterparts. Nevertheless, the patterns of these crises may differ between the two groups.

Brain Healthcare Quotient as a Tool for Standardized Approach in Brain Healthcare Interventions.

In addressing the challenge of assessing healthy brain aging across diverse interventions, this study introduces the use of MRI-derived Brain Healthcare Quotients (BHQ) for comprehensive evaluation. We analyzed BHQ changes in 319 participants aged 24-69, who were allocated into dietary (collagen peptide, euglena, matcha, isohumulone, xanthophyll) and physical activity (hand massage with lavender oil, handwriting, office stretching, pink lens, clinical art) groups, alongside a control group, over a month. These interventions were specifically chosen to test the efficacy of varying health strategies on brain health, measured through BHQ indices: GM-BHQ for gray matter volume, and FA-BHQ for white matter integrity. Notably, significant improvements in FA-BHQ were observed in the collagen peptide group, with marginal increases in the hand massage and office stretching groups. These findings highlight BHQ's potential as a sensitive tool for detecting brain health changes, offering evidence that low-intensity, easily implemented interventions can have beneficial effects on brain health. Moreover, BHQ allows for the systematic evaluation of such interventions using standard statistical approaches, suggesting its value in future brain healthcare research.

Vocal expression of emotions discriminates dementia with Lewy bodies from Alzheimer's disease.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), the two most common neurodegenerative dementias, both exhibit altered emotional processing. However, how vocal emotional expressions alter in and differ between DLB and AD remains uninvestigated. We collected voice data during story reading from 152 older adults comprising DLB, AD, and cognitively unimpaired (CU) groups and compared their emotional prosody in terms of valence and arousal dimensions. Compared with matched AD and CU participants, DLB patients showed reduced overall emotional expressiveness, as well as lower valence (more negative) and lower arousal (calmer), the extent of which was associated with cognitive impairment and insular atrophy. Classification models using vocal features discriminated DLB from AD and CU with an AUC of 0.83 and 0.78, respectively. Our findings may aid in discriminating DLB patients from AD and CU individuals, serving as a surrogate marker for clinical and neuropathological changes in DLB. Highlights: DLB showed distinctive reduction in vocal expression of emotions.Cognitive impairment was associated with reduced vocal emotional expression in DLB.Insular atrophy was associated with reduced vocal emotional expression in DLB.Emotional expression measures successfully differentiated DLB from AD or controls.

Distinct eye movement patterns to complex scenes in Alzheimer's disease and Lewy body disease.

Background: Alzheimer's disease (AD) and Lewy body disease (LBD), the two most common causes of neurodegenerative dementia with similar clinical manifestations, both show impaired visual attention and altered eye movements. However, prior studies have used structured tasks or restricted stimuli, limiting the insights into how eye movements alter and differ between AD and LBD in daily life. Objective: We aimed to comprehensively characterize eye movements of AD and LBD patients on naturalistic complex scenes with broad categories of objects, which would provide a context closer to real-world free viewing, and to identify disease-specific patterns of altered eye movements. Methods: We collected spontaneous viewing behaviors to 200 naturalistic complex scenes from patients with AD or LBD at the prodromal or dementia stage, as well as matched control participants. We then investigated eye movement patterns using a computational visual attention model with high-level image features of object properties and semantic information. Results: Compared with matched controls, we identified two disease-specific altered patterns of eye movements: diminished visual exploration, which differentially correlates with cognitive impairment in AD and with motor impairment in LBD; and reduced gaze allocation to objects, attributed to a weaker attention bias toward high-level image features in AD and attributed to a greater image-center bias in LBD. Conclusion: Our findings may help differentiate AD and LBD patients and comprehend their real-world visual behaviors to mitigate the widespread impact of impaired visual attention on daily activities.

Nucleus accumbens degeneration in spinocerebellar ataxia type 2: a preliminary study.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) exhibits mainly cerebellar and oculomotor dysfunctions but also, frequently, cognitive impairment and neuropsychological symptoms. The mechanism of the progression of SCA2 remains unclear. This study aimed to evaluate longitudinal structural changes in the brains of SCA2 patients based on atrophy rate. METHODS: The OpenNeuro Dataset ds001378 was used. It comprises the demographic data and two magnetic resonance images each of nine SCA2 patients and 16 healthy controls. All structural images were preprocessed using FreeSurfer software, and each region's bilateral volume was summed. Atrophy rates were calculated based on the concept of symmetrised percent change and compared between SCA2 patients and healthy controls using non-parametric statistics. As post hoc analysis, correlation analysis was performed between infratentorial volume ratio and the accumbens area atrophy rates in SCA2 patients. RESULTS: There were no significant differences between groups for age, gender, and the time between scans. Statistical analysis indicated a significantly larger atrophy rate of the accumbens area in SCA2 patients than in controls. Additionally, the infratentorial volume ratio and accumbens area atrophy rates showed moderate negative correlation. CONCLUSIONS: This study found that nucleus accumbens (NAc) atrophy was significantly accelerated in SCA2 patients. Anatomically, the NAc is densely connected with infratentorial brain regions, so it is reasonable to posit that degeneration propagates from the cerebellum and brainstem to the NAc and other supratentorial areas. Functionally, the NAc is essential for appropriate behaviour, so NAc degeneration might contribute to neuropsychological symptoms in SCA2 patients.

Evaluation of Cognitive and Physical Function Among Older Adults by Their Physical Activity: A Cross-Sectional Kasama Study, Japan.

BACKGROUND: The amyloid-ß1-42 (Aß42) level is a biomarker that is widely used to evaluate individual cognitive dysfunction early in neurodegenerative diseases, as well as differentiate between normal cognitive function, mild cognitive impairment, Alzheimer's disease, and vascular cognitive impairment. OBJECTIVE: Our cross-sectional study evaluated the association between daily exercise and physical and cognitive function and Aß42 levels among a subsample of 325 older adults from the Kasama Study. METHODS: Participants (age: 74.5 [range 65-90] years) were classified into three exercise groups: the dual-task (DEG, n = 128), single-task (SEG, n = 122), and non-exercise (NEG, n = 75) groups. The main outcomes were the plasma Aß42 levels and the scores of the five cognitive (5-COG) tests and five cognition-related physical function (5-PHYS) tests. RESULTS: The Aß42 levels and 5-COG and 5-PHYS scores were higher in the SEG and DEG than in the NEG. The Aß42 levels were higher in the DEG than in the NEG (p = 0.008). CONCLUSIONS: Physical activities such as regular exercise may benefit older adults, improving their cognitive and physical function.

Feasibility study of Internet video-based speech-language activity for outpatients with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia is a clinical dementia syndrome secondary to neurodegenerative disease characterized by language-related difficulties. Currently, there is no effective treatment for language impairment in primary progressive aphasia. In the present study, we investigated the feasibility of Internet video-based speech-language activities for this condition. METHODS: Twenty-three people with primary progressive aphasia (pwPPA) participated in the study and were provided with twelve speech-language activity videos on a dedicated website, with three sessions per week. The group that chose to continue with participation after three months of intervention received Internet activities for one year. Cognitive domains associated with persistence, treatment motivation, and video difficulty settings were statistically analyzed. RESULTS: After three months, 17 out of 23 participants opted to continue with the activities. The ability to follow oral commands which was measured pre intervention was higher in the group that continued compared with those participants who discontinued activity. The scores of two Standard Language Test of Aphasia subtests, sentence repetition and narrative writing-associated with the ability to comprehend and produce sentence structure-were highly correlated with motivation, interest and concentration in activity. Participants with different levels of primary progressive aphasia progression could participate in the same video-based activities when high-frequency words were used in the video. CONCLUSIONS: Internet video-based speech-language activity at home has potential as a useful tool for future primary progressive aphasia treatment because it provides a cost-effective approach to intensive intervention and overcomes barriers associated with traditional therapy approaches.

New balance capability index as a screening tool for mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is not just a prodrome to dementia, but a very important intervention point to prevent dementia caused by Alzheimer's disease (AD). It has long been known that people with AD have a higher frequency of falls with some gait instability. Recent evidence suggests that vestibular impairment is disproportionately prevalent among individuals with MCI and dementia due to AD. Therefore, we hypothesized that the measurement of balance capability is helpful to identify individuals with MCI. METHODS: First, we developed a useful method to evaluate balance capability as well as vestibular function using Nintendo Wii balance board as a stabilometer and foam rubber on it. Then, 49 healthy volunteers aged from 56 to 75 with no clinically apparent cognitive impairment were recruited and the association between their balance capability and cognitive function was examined. Cognitive functions were assessed by MoCA, MMSE, CDR, and TMT-A and -B tests. RESULTS: The new balance capability indicator, termed visual dependency index of postural stability (VPS), was highly associated with cognitive impairment assessed by MoCA, and the area under the receiver operating characteristic (ROC) curve was more than 0.8, demonstrating high sensitivity and specificity (app. 80% and 60%, respectively). CONCLUSIONS: Early evidence suggests that VPS measured using Nintendo Wii balance board as a stabilometer helps identify individuals with MCI at an early and preclinical stage with high sensitivity, establishing a useful method to screen MCI.

Initial symptoms of early-onset dementia in Japan: nationwide survey.

AIM: The aim of this study was to investigate initial symptoms of early-onset dementia (EOD) for each dementia subtype. METHOD: We conducted a nationwide, population-based EOD prevalence study in Japan. Data were collected through service providers for people with EOD. Initial symptoms were assessed in six domains: loss of memory, difficulty in word generation, irritability, loss of motivation, increased mistakes in the workplace or domestically, and unusual behaviours or attitudes other than those listed. RESULTS: Participants were 770 people with EOD. Characteristic initial symptoms were observed for each EOD subtype. Loss of memory was more common in early-onset Alzheimer's disease (75.7%, P < 0.001), difficulty in word generation was more common in early-onset vascular dementia (41.3%, P < 0.001), and loss of motivation, increased mistakes in the workplace or domestically, and unusual behaviours or attitudes other than those listed were more common in early-onset frontotemporal dementia (34.9%, P < 0.001; 49.4%, P < 0.001; 34.9%, P < 0.001, respectively). In addition, we observed gender differences whereby loss of memory was more common among women and irritability was more common among men. More than half of the participants were employed at symptom onset, and 57.2% of those who were employed at the onset had initial symptoms of increased mistakes in the workplace or domestically. CONCLUSION: This report reveals differences in the frequency of initial symptoms by EOD subtype. The results contribute to increasing public awareness of the initial symptoms of EOD, which will facilitate early diagnosis and social support.

Relationship between hippocampal subfields volume and balance function in healthy older adults.

BACKGROUND: The volume of the hippocampus and its subfields is known to be affected by aging, disease, and physical training. In regard to training, the differential effects of aerobic exercise and dance training on the subfield volume suggest that balance function may be involved. However, the relationship between balance function and the volume of the hippocampus and its subfields remains unclear. METHODS: Subjects were 30 cognitively intact individuals. They underwent balance tests, cognitive tests and structural MRI scans. The balance index measured was the index of postural stability (IPS) under a visual block condition and/or a proprioception block condition. MR images acquired using a 3-tesla system and three-dimensional T1-weighted images were segmented in the hippocampal subfield with Freesurfer 6.0.0. The relationship between the IPS and hippocampal volume was evaluated. RESULTS: A positive correlation was observed only between the IPS closed eyes/soft surface condition and whole hippocampal volume ratio. In the subfields, positive correlations were found between the IPS and molecular layer of the hippocampus, granule cell layer of the dentate gyrus (GC-ML-DG), and cornu ammonis areas (CA)3 and CA4. These correlations were stronger under the closed eyes/soft surface condition than under the other conditions. CONCLUSIONS: A correlation between balance function and the volume of the hippocampus and subfields was found in healthy elderly subjects. The balance function may be involved in the volume of the whole hippocampus and specific subfields. The IPS closed eyes/soft surface condition is considered to reflect vestibular function. Thus, IPS may be useful in evaluations of the relationship between the vestibular system function via the hippocampus and balance.

Screening of Mild Cognitive Impairment Through Conversations With Humanoid Robots: Exploratory Pilot Study.

BACKGROUND: The rising number of patients with dementia has become a serious social problem worldwide. To help detect dementia at an early stage, many studies have been conducted to detect signs of cognitive decline by prosodic and acoustic features. However, many of these methods are not suitable for everyday use as they focus on cognitive function or conversational speech during the examinations. In contrast, conversational humanoid robots are expected to be used in the care of older people to help reduce the work of care and monitoring through interaction. OBJECTIVE: This study focuses on early detection of mild cognitive impairment (MCI) through conversations between patients and humanoid robots without a specific examination, such as neuropsychological examination. METHODS: This was an exploratory study involving patients with MCI and cognitively normal (CN) older people. We collected the conversation data during neuropsychological examination (Mini-Mental State Examination [MMSE]) and everyday conversation between a humanoid robot and 94 participants (n=47, 50%, patients with MCI and n=47, 50%, CN older people). We extracted 17 types of prosodic and acoustic features, such as the duration of response time and jitter, from these conversations. We conducted a statistical significance test for each feature to clarify the speech features that are useful when classifying people into CN people and patients with MCI. Furthermore, we conducted an automatic classification experiment using a support vector machine (SVM) to verify whether it is possible to automatically classify these 2 groups by the features identified in the statistical significance test. RESULTS: We obtained significant differences in 5 (29%) of 17 types of features obtained from the MMSE conversational speech. The duration of response time, the duration of silent periods, and the proportion of silent periods showed a significant difference (P<.001) and met the reference value r=0.1 (small) of the effect size. Additionally, filler periods (P<.01) and the proportion of fillers (P=.02) showed a significant difference; however, these did not meet the reference value of the effect size. In contrast, we obtained significant differences in 16 (94%) of 17 types of features obtained from the everyday conversations with the humanoid robot. The duration of response time, the duration of speech periods, jitter (local, relative average perturbation [rap], 5-point period perturbation quotient [ppq5], difference of difference of periods [ddp]), shimmer (local, amplitude perturbation quotient [apq]3, apq5, apq11, average absolute differences between the amplitudes of consecutive periods [dda]), and F0cov (coefficient of variation of the fundamental frequency) showed a significant difference (P<.001). In addition, the duration of response time, the duration of silent periods, the filler period, and the proportion of fillers showed significant differences (P<.05). However, only jitter (local) met the reference value r=0.1 (small) of the effect size. In the automatic classification experiment for the classification of participants into CN and MCI groups, the results showed 66.0% accuracy in the MMSE conversational speech and 68.1% accuracy in everyday conversations with the humanoid robot. CONCLUSIONS: This study shows the possibility of early and simple screening for patients with MCI using prosodic and acoustic features from everyday conversations with a humanoid robot with the same level of accuracy as the MMSE.

Association between behavioural and psychological symptoms of dementia and residence status in patients with Alzheimer's disease.

BACKGROUND: Examining the relationship between the behavioural and psychological symptoms of dementia (BPSD) and residence status is crucial to improving BPSD and reducing the burden on caregivers. However, studies on how BPSD differ between individuals living at home and those in institutional settings are lacking. We conducted a questionnaire survey among healthcare providers (HCPs) involved in dementia care and nursing to clarify the characteristics of BPSD by residence status in patients with Alzheimer's disease (AD) living at home or in facilities. METHODS: We sent questionnaires to HCPs and asked them to answer questions on up to five cases that needed treatment for BPSD and who received long-term care insurance services from 1 April 2016 to 31 March 2017. Responses were received for 371 cases, of which 130 diagnosed with AD were analyzed. The patients were divided into two groups: patients with AD living at home (home care group) and patients with AD living in facilities (facility care group). A Chi-square test was used to identify differences between the two groups. A binomial logistic regression analysis was also conducted to clarify the association between residence status and BPSD. RESULTS: Of the 130 patients, 72 lived at home (home care group) and 58 resided in facilities (facility care group). None of the background factors was significantly different between the two groups. The Chi-square test indicated that sleep disturbance was significantly more common in the facility care group (60.3% in the facility care group vs. 33.3% in the home care group, P = 0.003), while the logistic regression analysis indicated that sleep disturbance was significantly associated with residence status (odds ratio: 2.529, P = 0.038). CONCLUSIONS: Sleep disturbances were more frequently observed among patients with AD living in institutions than among those living in their homes.

Possible association of limbic tau pathology with psychosis or behavioral disturbances: Studies of two autopsied psychiatric patients.

Tauopathies, including Alzheimer's disease and primary age-related tauopathy (PART), present heterogeneous clinico-pathological phenotypes that include dementia, aphasia, motor neuron diseases, and psychiatric symptoms. PART is neuropathologically characterized by the presence of neurofibrillary tangles in limbic regions without significant Aß deposition, but its clinical features have not yet been fully established. Here, we present two patients with distinct psychosis and behavioral symptoms. At autopsy, these patients showed tau pathologies that could not be classified as typical PART, although PART-like neurofibrillary tangles were present in limbic regions. Clinically, both patients were admitted to mental hospitals due to severe delusions or other neuropsychiatric/behavioral symptoms. The first case presented with hallucination, delusion, and apathy at age 70, and died of pancreatic cancer at age 75. He had neuronal cytoplasmic inclusions with selective accumulation of 3Rtau in the striatum and thorn-shaped astrocytes in the amygdala. The second case, who presented with abnormal behaviors such as wandering, agitation and disinhibition, exhibited limbic neurodegeneration with massive 4R tau-positive oligodendroglial inclusions in the medial temporal white matter. His age at onset was 73, and the duration of disease was 15 years. These findings support the notion that distinct limbic tau pathology with concomitant degeneration of the related neural circuits might induce specific psychosis and behavioral symptoms. This underlines the importance of neuropathological evaluation for both clinical education and practice in the fields of neuropathology and neuropsychiatry.

Structural Cerebral Network Differences in Prodromal Alzheimer's Disease and Prodromal Dementia with Lewy Bodies.

INTRODUCTION: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have long prodromal phases without dementia. However, the patterns of cerebral network alteration in this early stage of the disease remain to be clarified. METHOD: Participants were 48 patients with mild cognitive impairment (MCI) due to AD (MCI-AD), 18 patients with MCI with DLB (MCI with Lewy bodies: MCI-LB), and 23 healthy controls who underwent a 1.5-Tesla magnetic resonance imaging scan. Cerebral networks were extracted from individual T1-weighted images based on the intracortical similarity, and we estimated the differences of network metrics among the three diagnostic groups. RESULTS: Whole-brain analyses for degree, betweenness centrality, and clustering coefficient images were performed using SPM8 software. The patients with MCI-LB showed significant reduction of degree in right putamen, compared with healthy subjects. The MCI-AD patients showed significant lower degree in left insula and bilateral posterior cingulate cortices compared with healthy subjects. There were no significant differences in small-world properties and in regional gray matter volume among the three groups. CONCLUSIONS: We found the change of degree in the patients with MCI-AD and with MCI-LB, compared with healthy controls. These findings were consistent with the past single-photon emission computed tomography studies focusing on AD and DLB. The disease-related difference in the cerebral neural network might provide an adjunct biomarker for the early detection of AD and DLB.

Dark Chocolate Intake May Reduce Fatigue and Mediate Cognitive Function and Gray Matter Volume in Healthy Middle-Aged Adults.

Background: Dark chocolate has attracted attention for its potential for cognitive improvement. Though some reports indicate that dark chocolate is good for cognitive function, others raise doubts. This inconsistency in past results reflecting the relationship between dark chocolate and cognitive function indicates the potential existence of factors that mediate between dark chocolate intake and cognitive function. Methods: With the hypothesis that fatigue may be one such mediating factor, we performed a four-week randomized control study to seek a link between dark chocolate consumption, cognitive function, fatigue, and the brain in middle-aged adults. Results: We found that dark chocolate reduced mental and physical fatigue, and a path analysis revealed that it enhanced vitality, executive function, memory, and gray matter volume both directly and indirectly. Fatigue reduction was also associated with an improvement in physical function, which had a positive impact on emotional functioning, relief of bodily pain, and social functioning. Conclusions: Our results suggest that dark chocolate may help reduce fatigue in individuals, leading to improvements in brain health and various cognitive functions as well as in quality of life.