Association between Gray and White Matter Lesions and Its Involvement in Clinical Symptoms of Alzheimer's-Type Dementia.

BACKGROUND: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer's disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a concerted effect of both GML and WML. OBJECTIVE: This study aimed to investigate the association between GML and WML and how they are involved in the symptoms of CI and BPSD in dementia patients by means of imaging technology. METHODS: Patients in our memory clinic, who were diagnosed with AD-type dementia or amnestic mild cognitive impairment (aMCI) and had undergone both single-photon emission computed tomography (SPECT) and brain MRI, were consecutively enrolled (n = 156; 61 males and 95 females; 79.8 ± 7.4 years old). Symptoms of CI and BPSD were obtained from patients' medical records. For the analysis of GMLs and WMLs, SPECT data and MRI T1-weighted images were used, respectively. This study followed the Declaration of Helsinki, and all procedures were approved by the institutional ethics committee. RESULTS: According to a multivariate analysis, disorientation and disturbed attention demonstrated a relationship between the precuneus and WMLs in both hemispheres. Hyperactivity in BPSD showed multiple correlations between GMLs on both sides of the frontal cortex and WMLs. Patients with aMCI presented more multiple correlations between GMLs and WMLs compared with those with AD-type dementia regarding dementia symptoms including BPSD. CONCLUSION: The interaction between GMLs and WMLs may vary depending on the symptoms of CI and BPSD. Hyperactivity in BPSD may be affected by the functional relationship between GMLs and WMLs in the left and right hemispheres. The correlation between GMLs and WMLs may be changing in AD-type dementia and aMCI.

Impact of hs-CRP concentration on brain structure alterations and cognitive trajectory in Alzheimer's disease.

Introduction: Present study was to investigate hs-CRP concentration, brain structural alterations, and cognitive function in the context of AD [Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD]. Methods: We retrospectively included 313 patients (Mean age = 76.40 years, 59 SCD, 101 MCI, 153 AD) in a cross-sectional analysis and 91 patients (Mean age = 75.83 years, 12 SCD, 43 MCI, 36 AD) in a longitudinal analysis. Multivariable linear regression was conducted to investigate the relationship between hs-CRP concentration and brain structural alterations, and cognitive function, respectively. Results: Hs-CRP was positively associated with gray matter volume in the left fusiform (ß = 0.16, pFDR = 0.023) and the left parahippocampal gyrus (ß = 0.16, pFDR = 0.029). Post hoc analysis revealed that these associations were mainly driven by patients with MCI and AD. The interaction of diagnosis and CRP was significantly associated with annual cognitive changes (ß = 0.43, p = 0.008). Among these patients with AD, lower baseline CRP was correlated with greater future cognitive decline (r = -0.41, p = 0.013). Conclusion: Our study suggests that increased hs-CRP level may exert protective effect on brain structure alterations and future cognitive changes among patients already with cognitive impairment.

Impact of atrial fibrillation on the cognitive decline in Alzheimer's disease.

BACKGROUND: Atrial fibrillation (AF) is a strong risk factor for Alzheimer's disease (AD) independent of ischemic stroke. However, the clinicopathological impact of AF on the severity of AD has not been well elucidated. We aimed to investigate the clinical differences between dementia patients with AF and those without AF by means of imaging data. METHODS: Following approval from the institutional ethics committee, patients with newly diagnosed AD or amnestic mild cognitive impairment (aMCI) were retrospectively screened (n = 170, 79.5 ± 7.4 years old). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on the MRI data, the cerebral volume, cerebral microbleeds (CMBs), periventricular white matter lesions (WMLs), and deep WMLs were evaluated. The regional cerebral blood flow (rCBF) was measured using 123I-IMP SPECT. RESULTS: Of the patients, 14 (8.2%) and 156 (91.8%) had AF (AF group) and sinus rhythm (SR group), respectively. The AF group had significantly lower MMSE scores than the SR group (average [standard deviation (SD)]: 19.4 [4.4] and 22.0 [4.4], respectively; p = 0.0347). Cerebral volume and CMBs did not differ between the two groups. The periventricular WMLs, but not the deep WMLs, were significantly larger in the AF group than in the SR group (mean [SD] mL: 6.85 [3.78] and 4.37 [3.21], respectively; p = 0.0070). However, there was no significant difference in rCBF in the areas related to AD pathology between the two groups. CONCLUSION: AD and aMCI patients with AF showed worse cognitive decline along with larger periventricular WMLs compared to those with SR, although the reduction of rCBF was not different between patients with AF and SR. The white matter lesions may be a more important pathology than the impairment of cerebral blood flow in dementia patients with AF. A larger study is needed to confirm our findings in the future.

Impact of constipation on progression of Alzheimer's disease: A retrospective study.

BACKGROUND AND PURPOSE: In terms of the gut-brain axis, constipation has been considered to be an important factor of neurodegenerative diseases, although the exact mechanism is still controversial. Herein, we aimed to investigate the contribution of constipation to the progression of dementia in a retrospective study. METHODS: Patients of Alzheimer's disease(AD) and amnestic mild cognitive impairment were consecutively screened between January 2015 and December 2020, and those of whom brain MRI and neuropsychological tests were performed twice were enrolled in this study. Participants were classified into with constipation (Cons[+], n = 20) and without constipation (Cons[-], n = 64) groups. Laboratory data at the first visit were used. Regression analysis was performed in MMSE, ADAS-Cog, and the volumes of hippocampus on MRI-MPRAGE images and deep white matter lesions (DWMLs) on MRI-FLAIR images obtained at two different time points. RESULTS: The main finding was that the Cons[+] group showed 2.7 times faster decline in cognitive impairment compared with the Cons[-] group, that is, the liner coefficients of ADAS-Cog were 2.3544 points/year in the Cons[+] and 0.8592 points/year in the Cons[-] groups. Ancillary, changes of DWMLs showed significant correlation with the time span (p < 0.01), and the liner coefficients of DWMLs were 24.48 ml/year in the Cons[+] and 14.83 ml/year in the Cons[-] group, although annual rate of hippocampal atrophy was not different between the two groups. Moreover, serum homocysteine level at baseline was significantly higher in the Cons[+] group than Cons[-] group (14.6 ± 6.4 and 11.5 ± 4.2 nmol/ml, respectively: p = 0.03). CONCLUSION: There is a significant correlation between constipation and faster progression of AD symptoms along with expansion of DWMLs.

Perceived social isolation is correlated with brain structure and cognitive trajectory in Alzheimer's disease.

Both objective and perceived social isolations were associated with future cognitive decline and increase risk of Alzheimer's disease (AD). However, the impacts of perceived social isolation depending on different clinical stages of AD have not been elucidated. The aim of this study was to investigate the influence of perceived social isolation or loneliness on brain structure and future cognitive trajectories in patients who are living with or are at risk for AD. A total of 176 elderly patients (mean age of 78 years) who had complaint of memory problems (39 subjective cognitive decline [SCD], 53 mild cognitive impairment [MCI], 84 AD) underwent structural MRI and neuropsychological testing. Loneliness was measured by one binary item question "Do you often feel lonely?." Voxel-based morphometry was conducted to evaluate regional gray matter volume (rGMV) difference associated with loneliness in each group. To evaluate individual differences in cognitive trajectories based on loneliness, subgroup analysis was performed in 51 patients with AD (n = 23) and pre-dementia status (SCD-MCI, n = 28) using the longitudinal scores of Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog). Whole brain VBM analysis comparing lonely to non-lonely patients revealed loneliness was associated with decreased rGMV in bilateral thalamus in SCD patients and in the left middle occipital gyrus and the cerebellar vermal lobules I - V in MCI patients. Annual change of ADAS-Jcog in patients who reported loneliness was significantly greater comparing to these non-lonely in SCD-MCI group, but not in AD group. Our results indicate that perceived social isolation, or loneliness, might be a comorbid symptom of patients with SCD or MCI, which makes them more vulnerable to the neuropathology of future AD progression.

Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer's disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-ß accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.

Alzheimer's Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

Alzheimer's disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it-i.e., specialized pro-resolving lipid mediators (SPMs)-attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.

Voxel-Based Morphometry Reveals a Correlation Between Bone Mineral Density Loss and Reduced Cortical Gray Matter Volume in Alzheimer's Disease.

Background: Decreased bone mineral density (BMD) was associated with poorer cognitive function and increased risk of Alzheimer's disease (AD). However, objective evidence for the relationship between osteoporosis and AD in humans has not been extensively described. Objectives: We aimed to evaluate the relationships between BMD and the cortical volumes of brain regions vulnerable to AD; hippocampus, parahippocampal gyrus, precuneus, posterior cingulate, and angular gyrus, using voxel-based morphometry (VBM), to investigate the association between bone loss and AD. Methods: A cohort of 149 consecutive elderly participants who complained of memory disturbance underwent high-resolution structural brain magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA). We used SPM12 software to conduct a voxel-based multiple regression analysis to examine the association between femoral neck BMD values and regional gray matter volume (rGMV) on structural T1-weighted MRI. Results: After adjusting for subject age, gender, total brain volume (TBV), and mini-mental state examination (MMSE) scores, the multiple regression analysis showed significant correlations between BMD loss and rGMV decline in the left precuneus, which is an important neural network hub vulnerable to AD. Conclusion: These data suggest that the bone and brain communicate with each other, as in "bone-brain crosstalk," and that control of BMD factors could contribute to cognitive function and help prevent AD.

Hypoperfusion in the posterior cingulate cortex is associated with lower bone mass density in elderly women with osteopenia and Alzheimer's disease.

Accelerated bone loss is closely associated with Alzheimer's disease (AD), but the relationship between bone mineral density (BMD) and imaging markers of neurodegeneration remains uncertain. We examined the effect of low bone mass (osteopenia) on regional cerebral blood flow (rCBF) in patients with AD (n = 19) and non-demented aging (n = 12). We enrolled 31 female outpatients diagnosed with osteopenia (age ≥ 65 years) who had both a single-photon emission computed tomography brain scan and dual-energy X-ray absorptiometry bone scan taken at their initial investigation. We analyzed the relationship between osteopenia (-2.5 < T-score < -1) and rCBF in 62 cortical areas measured using the stereotactic extraction estimation analysis on single-photon emission computed tomography (SPECT) (mean Z-scores). We found that the mean Z-scores of 14 cerebral subregions, most of which are often affected early in AD, were significantly lower in the AD group than the non-demented group (P < .001). The age-stratified multivariate regression analysis showed that the decreased rCBF in the left posterior cingulate cortex (PCC) was an independent predictor of osteopenia (r = -0.395; P = .005). BMD and rCBF in the left PCC were significantly correlated in the overall population (r = -0.54; P = .001), as well as the AD group (r = -0.514; P = .02). These imaging data suggest that osteopenia may contribute to neurodegeneration of a brain network hub associated with AD.

Clinical Utility of a Semiquantitative Method Using Lumbar Radiography as a Screening Tool for Osteoporosis in Elderly Subjects.

BACKGROUND Osteoporosis is a major global public health problem in the current aging era. Osteoporosis is often diagnosed only after patients have a fracture that causes a severe decline in ability to perform activities of daily life. Although the current criterion standard for diagnosing osteoporosis is dual-energy X-ray absorptiometry (DXA), this modality remains less prevalent among general practitioners in geriatric medicine. The aim of this study was to determine the diagnostic utility of visual inspection of lumbar radiography in detecting bone mineral density (BMD) decline. MATERIAL AND METHODS We retrospectively reviewed medical data of 78 patients who underwent both lateral lumbar radiography and DXA. Board-certified radiologists determined the clinical grade of each patient's condition according to the semiquantitative (SQ) method of lumbar fracture assessment. We compared the grades and young adult means of BMD in the lumbar spine and hips as measured using DXA. RESULTS BMD of the femoral neck was significantly lower in patients with severe osteoporosis (grades 2 and 3 as classified using the SQ method) than in those with mild osteoporosis (grades 0 and 1; P<0.05). A receiver operating characteristic curve analysis showed that the SQ method can help predict the decrease in BMD (young adult mean score of <70%) in the femoral neck with moderate accuracy (sensitivity, 0.621; specificity, 0.829; area under the curve, 0.742). CONCLUSIONS These results suggest that lateral lumbar radiography can provide useful information about bone mineral status and can serve as a tool for osteoporosis screening by general practitioners.

Assessment of Gait Symmetry in Elderly Women with Low Bone Mineral Density Using a Portable Trunk Accelerometer: A Pilot Study.

BACKGROUND Convincing evidence regarding gait and balance function in elderly women with low bone mineral density (BMD) and/or osteoporosis is limited. In the present study, we aimed to compare the gait characteristics in elderly women with and without low BMD and to analyze plausible parameter(s) for predicting low BMD. MATERIAL AND METHODS We retrospectively analyzed prospectively collected data of 26 consecutive postmenopausal women aged >65 years who were admitted to our geriatric outpatient service. They were assigned to 2 groups, with (n=14) and without (n=12) low BMD based on T-score (0.05). Receiver operating characteristic curve analysis demonstrated that LI can predict low BMD in the femur neck with moderate accuracy (area under the curve=0.75, 95% confidence interval 0.55-0.95; P=0.031). The optimal cut-off value was 17%, with 67% specificity and 86% sensitivity. CONCLUSIONS These results suggest that elderly women with low BMD may walk with asymmetrical trunk movement, but they are able to generate gait patterns similar to healthy peers. The LI may provide valuable quantitative information for preventing fractures in subjects with osteoporosis.

Isolated Fornix Infarction with Damage to the Limbic System as a Cause of Persistent Amnesia: A Case Report.

BACKGROUND The fornix is a white matter tract bundle that acts as the major output of the hippocampus and is an important component of the Papez circuit. We present an instructive imaging case of sudden onset of persistent amnesia due to selective ischemic damage of the anterior fornix. CASE REPORT A 54-year-old Japanese male came to our attention for a sudden onset of retrograde amnesia, associated with severe anterograde amnesia. The brain magnetic resonance imaging demonstrated a bright diffusion restriction, which was associated with swollen fornices bilaterally. His symptoms gradually improved, but episodic memory impairment still persisted after 1 month. The coronal T1-weighted MPRAGE (magnetization-prepared rapid acquisition with gradient echo) sequence clearly showed disruption of the left anterior fornix. Diffusion tensor tracking showed decrease in the density of entire fiber tracts on the Papez circuit as well as location of the left fornix. CONCLUSIONS When dealing with sudden, persistent amnesia associated with small fornix infarction, it is prudent to consider the possibility of tract damage along with limbic system damage using MPRAGE sequence.

Posterior Associative and Cingulate Cortex Involvement of Brain Single-Photon Emission Computed Tomography (SPECT) Imaging in Semantic Dementia with Probable Alzheimer Disease Pathology: A Case Report.

BACKGROUND Semantic dementia (SD) is a type of primary progressive aphasia with prominent language dysfunction, mostly within the spectrum of frontotemporal lobar degeneration (FTLD). Although there is an overlap in clinical manifestations of SD attributable to FTLD and neuropathologically proven Alzheimer disease (AD), clinical diagnostic clues are not readily available. We present a characteristic finding based on a single-photon emission computed tomography (SPECT)-based regional cerebral blood flow study and its statistical imaging analysis for a rare case of SD with AD-like pathology. CASE REPORT A 61-year-old male was referred to our hospital due to difficulties in self-management and impaired comprehension of word meaning suggestive of SD. Although his brain MRI revealed mild frontal lobe atrophy, his SPECT with three-dimensional stereotactic surface projections (3D-SSP) analysis showed left-sided hypo-perfusion that was more prominent in the inferior temporal gyrus and the inferior parietal lobule, with bilateral frontal lobe hypo-perfusion. The SPECT scan also showed involvement of the right inferior parietal area and, in medial aspects, the posterior cingulate cortex and adjacent precuneus; these finding were compatible with early hypo-perfused areas seen in AD. The lumbar cerebrospinal fluid biomarker findings seemed to fit SD in association with probable AD pathology. CONCLUSIONS This is the first reported case to use SPECT with 3D-SSP statistical analysis as a potential, useful imaging modality for the diagnosis of SD with probable AD pathology.

Preceding functional tooth loss delays recovery from acute cerebral hypoxia and locomotor hypoactivity after murine subarachnoid haemorrhage.

Tooth loss and related changes in the functionality may lead to worse outcome of stroke patients, but the effect on hemorrhagic stroke remains unclear. This study aimed to determine the impact of impaired masticatory function on acute cerebral oxygenation and locomotor activity after experimental subarachnoid haemorrhage (SAH). Twenty C57BL/6 mice with (MC-treated group) or without (control group) prior treatment of cutting off the upper molars were subjected to SAH by endovascular perforation. Grading of SAH and acute cerebral infarction were assessed by MR images. Brain tissue oxygen saturation (SbtO2 ) by photoacoustic imaging and parameters related to locomotor activity by open-field test were analyzed serially after SAH. In all mice, global SbtO2 depression was notable immediately after SAH induction (P <.001), which recovered close to the baseline levels until day 3. However, MC-treated mice demonstrated a prolonged relative cerebral hypoxia (<40% of the baseline SbtO2) as compared to the control (3 ± 1 vs 1 ± 1 days; P <.05). The average distance travelled on day 7 and the ratio of central-area distance/total travelled distance by open-field test between days 7 and 14 were significantly lower in MC-treated mice than in the control mice (P <.05), although the occurrences of new infarction were not statistically different (P >.05). These data suggest a possible link between preceding masticatory impairment and early brain injury to deteriorate neurobehavioural function in patients after SAH.