Septal E/e' Ratio Is Associated With Cerebral White Matter Hyperintensity Progression in Young-Old Hypertensive Patients.

Background: The incidence of hypertension increases with age, as does that of brain abnormalities associated with cerebral pathologic and functional degeneration. Little is known about the relationship between hypertension-related cardiac changes and cerebral pathologic degeneration. We examined the relationship between left ventricular (LV) diastolic dysfunction and cerebral white matter hyperintensity (WMH) progression in young-old hypertensive patients. Methods and Results: This single-center prospective longitudinal observational study included 156 individuals aged 65-75 years with well-controlled hypertension, normal LV contraction, and no history of symptomatic heart failure. WMH was quantified on brain magnetic resonance imaging (MRI). The primary outcome was the rate of WMH volume progression between the baseline and follow-up MRI (∆WMH). Participants were classified into tertiles on the basis of ∆WMH (small, medium, and large ∆WMH). The mean (±SD) age at recruitment was 69.6±2.8 years, and the mean follow-up period was 4.6 years. The ratio of early diastolic mitral inflow velocity to early diastolic septal mitral annulus velocity (septal E/e') was significantly higher in the large ∆WMH group than in the small and medium ∆WMH groups. On multiple regression analysis, septal E/e' was significantly positively associated with square-root-transformed ∆WMH (ß=0.457, P<0.001). Conclusions: Septal E/e' was significantly positively associated with the rate of progression of WMH volume, suggesting that LV diastolic dysfunction is associated with the progression of abnormal brain aging.

Quantitative Analysis of White Matter Hyperintensity: Comparison of Magnetic Resonance Imaging Image Analysis Software.

OBJECTIVE: White matter hyperintensity (WMH), defined as abnormal signals on magnetic resonance imaging (MRI), is an important clinical indicator of aging and dementia. Although MRI image analysis software can automatically detect WMH, the quantitative accuracy of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) is unknown. MATERIALS AND METHODS: This study was a sub-analysis of MRI data from an ongoing hospital-based prospective cohort study (the Gimlet study). Between March 2016 and March 2017, we enrolled patients who visited our memory clinic and agreed to undergo medical assessments of cognitive function and fecal examination to study the gut microbiome. Participants with a history of stroke were excluded. WMH was independently quantitatively analyzed using two MRI imaging analysis software modalities: SNIPER and FUSION. Intraclass correlation coefficients and the mean difference in volume were calculated and compared between modalities. RESULTS: The data of 87 patients (49 women, mean age 74.8 ± 7.9 years) were analyzed. Both total WMH and DWMH volumes obtained using FUSION were greater (p < 0.001), and PVH volume was smaller (p < 0.001) than those obtained using SNIPER. Intraclass correlation coefficients for the lesion measurements of WMH, PVH, and DWMH between the different software were 0.726 (p < 0.001), 0.673 (p < 0.001), and 0.048 (p = 0.231), respectively. CONCLUSIONS: There were significant differences in the quantitative data of WMH between the two MRI imaging analysis software modalities. Thus, care should be taken for quantitative assessments of WMH.

Impact of regional white matter hyperintensities on specific gait function in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Gait disturbance and musculoskeletal changes are evident in persons living with Alzheimer's disease (AD). Because complex gait control requires the integration of neural networks, cerebral small vessel disease (SVD), which is highly prevalent in persons with AD, might have an additional impact on gait disturbance. This study investigated whether white matter hyperintensities (WMH) are more predominantly associated with gait disturbance in persons with AD than in individuals with mild cognitive impairment (MCI) and normal cognition (NC) and further identified the regional impact of WMH on specific gait changes. METHODS: This study included 396 subjects (aged 65 to 86 years, 63.9% female) diagnosed with AD (n = 187), MCI (n = 118), or NC (n = 91). WMH, lacunes, perivascular spaces, and cerebral microbleeds were assessed as markers of SVD. The volume of WMH was quantified in each brain lobe (frontal, temporal, occipital, and parietal) and sublobar regions in the basal ganglia and thalamus. Gait function was assessed using an electronic walkway. We investigated the association between regional WMH and gait disturbance in individuals with AD, MCI, and NC, adjusted for classical and musculoskeletal confounders. RESULTS: Among markers of SVD, WMH were most associated with gait disturbance. In AD subjects, periventricular WMH in the frontal and parietal lobes were associated with slow gait speed (rs  = -0.21, P = 0.007 and rs  = -0.18, P = 0.019, respectively). These lesions were also associated with changes in stride time, double-leg support time, and walking angle (all rs  > 0.20, P < 0.01). Lesions in the basal ganglia and thalamus were associated with slow gait speed (rs  = -0.16, P = 0.034 and rs  = -0.18, P = 0.023, respectively) and greater gait speed variability (rs  = 0.16, P = 0.034 and rs  = 0.20, P = 0.010, respectively). MCI subjects showed only associations between sublobar lesions and shorter stride length (rs  = -0.24, P = 0.016) and increased walking angle (rs  = 0.32, P = 0.002). NC subjects did not show associations between WMH and gait parameters. MCI and NC subjects were more affected by muscle weakness than WMH for global gait function (rs  = 0.42, P < 0.001 and rs  = 0.23, P = 0.046, respectively). CONCLUSIONS: Persons with AD showed a predominant association between WMH and gait disturbance compared with MCI and NC subjects, and regional WMH had a detrimental effect on specific gait changes.

Relationships between overactive bladder and cerebral white matter hyperintensity in outpatients at a memory clinic.

AIM: Cerebral small vessel disease and lower urinary tract symptoms are common in older people. However, the association between white matter hyperintensity (WMH) and overactive bladder (OAB) is not fully understood. We aimed to identify the relationship between WMH and OAB. METHODS: We carried out neuropsychological testing and head magnetic resonance imaging (T2-weighted and fluid-attenuated inversion recovery) of 72 outpatients at a memory clinic and evaluated their Overactive Bladder Symptom Score. WMH was assessed using the Fazekas scale, and WMH volumes were determined using Software for Neuro-Image Processing in Experimental Research. OAB was diagnosed based on a urinary urgency score (the third question of the Overactive Bladder Symptom Score) of two or higher and a total Overactive Bladder Symptom Score of three or higher. Multivariate logistic analysis was carried out, with the presence/absence of overactive bladder as the outcome variable, and age, sex, body mass index and diabetes mellitus as covariates. RESULTS: Of the 72 participants, 17 (24%) were diagnosed with OAB. WMH assessed by the visual rating scale was not associated with OAB. However, participants with OAB showed significantly higher WMH volume than those without OAB. Regionally, participants with OAB showed high WMH volume in the frontal, occipital and parietal lobes. Multiple logistic regression analysis showed that WMH was significantly associated with OAB (OR 1.82, 95% CI 1.11-2.98), after adjustment for clinically important confounders. CONCLUSIONS: Cerebral WMH volume is associated with OAB, independent of age, sex, body mass index and diabetes mellitus. Geriatr Gerontol Int 2021; 21: 996-1002.

Association of Glucose Fluctuations with Sarcopenia in Older Adults with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus accelerates loss of muscle mass and strength. Patients with Alzheimer's disease (AD) also show these conditions, even in the early stages of AD. The mechanism linking glucose management with these muscle changes has not been elucidated but has implications for clarifying these associations and developing preventive strategies to maintain functional capacity. This study included 69 type 2 diabetes patients with a diagnosis of cognitive impairment (n = 32) and patients with normal cognition (n = 37). We investigated the prevalence of sarcopenia in diabetes patients with and without cognitive impairment and examined the association of glucose alterations with sarcopenia. Daily glucose levels were evaluated using self-monitoring of blood glucose, and we focused on the effects of glucose fluctuations, postprandial hyperglycemia, and the frequency of hypoglycemia on sarcopenia. Diabetes patients with cognitive impairment displayed a high prevalence of sarcopenia, and glucose fluctuations were independently associated with sarcopenia, even after adjusting for glycated hemoglobin A1c (HbA1c) levels and associated factors. In particular, glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed. Our observation suggests the importance of glucose management by considering glucose fluctuations to prevent the development of disability.

Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus is associated with neurodegeneration and cerebrovascular disease. However, the precise mechanism underlying the effects of glucose management on brain abnormalities is not fully understood. The differential impacts of glucose alteration on brain changes in patients with and without cognitive impairment are also unclear. This cross-sectional study included 57 older type 2 diabetes patients with a diagnosis of Alzheimer's disease (AD) or normal cognition (NC). We examined the effects of hypoglycemia, postprandial hyperglycemia and glucose fluctuations on regional white matter hyperintensity (WMH) and brain atrophy among these patients. In a multiple regression analysis, postprandial hyperglycemia was independently associated with frontal WMH in the AD patients. In addition, postprandial hyperglycemia was significantly associated with brain atrophy, regardless of the presence of cognitive decline. Altogether, our findings indicate that postprandial hyperglycemia is associated with WMH in AD patients but not NC patients, which suggests that AD patients are more susceptible to postprandial hyperglycemia associated with WMH.

Frontal White Matter Hyperintensity Is Associated with Verbal Aggressiveness in Elderly Women with Alzheimer Disease and Amnestic Mild Cognitive Impairment.

BACKGROUND/AIMS: Behavioral and psychological symptoms of dementia (BPSD) are exhibited in most patients with Alzheimer disease (AD). Although white matter hyperintensity (WMH) is often observed with AD, the precise role of WMH in BPSD remains unclear. The current study aimed to identify the impact of regional WMH on specific features of BPSD in persons with mild to moderate AD and amnestic mild cognitive impairment (aMCI). METHODS: A sample of 256 female outpatients with AD (n = 217) and aMCI (n = 39) were recruited. We assessed BPSD using the Dementia Behavior Disturbance Scale. WMH and brain atrophy were evaluated using an automatic segmentation program. Regional WMH was evaluated as periventricular hyperintensity (PVH) and deep WMH in frontal, temporal, occipital, and parietal lobes. RESULTS: Whole-brain WMH was associated with verbal aggressiveness. In multivariate analysis, PVH in the frontal lobe was independently associated with verbal aggressiveness after adjustment for brain atrophy and clinical confounders. CONCLUSION: The current results indicated that PVH in the frontal lobe was independently associated with verbal aggressiveness.

Impact of frontal white matter hyperintensity on instrumental activities of daily living in elderly women with Alzheimer disease and amnestic mild cognitive impairment.

BACKGROUND: Instrumental activities of daily living (IADL) start to decline during the progression of amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD). Cognitive and physical decline are involved in the loss of functional independence. However, little is known about AD-related neural change that leads to IADL impairment. The purpose of this study was to clarify the effects of regional white matter hyperintensity (WMH) on IADL impairment in persons with AD and aMCI. METHODS: The participants were 347 female subjects aged 65-85 years diagnosed with AD (n = 227), aMCI (n = 44) or normal cognition (n = 76). IADL was assessed by the Lawton Index. Cognition, mood and mobility function were evaluated by comprehensive geriatric assessment batteries. WMH and brain atrophy were analyzed with brain magnetic resonance imaging, using an automatic segmentation program. Regional WMH was measured in the frontal, temporal, occipital and parietal lobes. RESULTS: Ability to carry out IADL of shopping, food preparation, mode of transportation, responsibility for own medication, and ability to handle finances was obviously impaired in the early stage of AD. Frontal WMH was specifically associated with disability to do shopping and food preparation even after adjusting for several confounders including brain atrophy. CONCLUSIONS: IADL subcategories were differentially impaired along with cognitive status in persons with AD and aMCI. Frontal WMH was an important predictor of impaired ability to do shopping and food preparation. A preventive strategy for WMH might lead to suppression of IADL disability and slow the progression of AD.

Frontal white matter hyperintensity predicts lower urinary tract dysfunction in older adults with amnestic mild cognitive impairment and Alzheimer's disease.

AIM: Lower urinary tract symptoms often limit activities of daily life and impair quality of life in the elderly. The purpose of the present study was to determine whether regional white matter hyperintensity (WMH) can predict lower urinary tract symptoms in elderly with amnestic mild cognitive impairment or Alzheimer's disease. METHODS: The participants were 461 patients aged 65-85 years diagnosed with amnestic mild cognitive impairment or Alzheimer's disease. Patients and their caregivers were asked about symptoms of lower urinary tract symptoms (urinary difficulty, frequency and incontinence). Cognition, behavior and psychological symptoms of dementia and medication were evaluated. WMH and brain atrophy were analyzed using an automatic segmentation program. Regional WMH was evaluated in the frontal, parietal, temporal and occipital lobes. RESULTS: Patients with urinary incontinence showed significantly greater volume of WMH. WMH increased with age, especially in the frontal lobe. WMH in the frontal lobe was closely associated with urinary incontinence after adjustment for brain atrophy and classical confounding factors. CONCLUSIONS: Frontal WMH was a predictive factor for urinary incontinence in older adults with amnestic mild cognitive impairment or Alzheimer's disease. Urinary incontinence in demented older adults is not an incidental event, and careful insight into regional WMH on brain magnetic resonance imaging might greatly help in diagnosing individuals with a higher risk of urinary incontinence.

White matter hyperintensities and geriatric syndrome: An important role of arterial stiffness.

White matter hyperintensities (WMH) are defined as cerebral white matter changes presumed to be of vascular origin, bilateral and mostly symmetrical. They can appear as hyperintense on T2-weighted and fluid-attenuated inversion recovery sequences, and as isointense or hypointense on T1-weighted magnetic resonance imaging of the brain. WMH have been focused on because of their clinical importance as a risk factor for cerebrovascular diseases and cognitive impairment. WMH are associated with geriatric syndrome, which is defined by clinical symptoms characteristic of older adults, including cognitive and functional impairment and falls. Cerebral small vessel diseases, such as WMH, might play an important role as risk factors for cerebrovascular diseases, cognitive impairment and geriatric syndrome through the mechanism of arterial stiffness. However, the vascular, physiological and metabolic roles of arterial stiffness remain unclear. Basically, arterial stiffness indicates microvessel arteriosclerosis presenting with vascular endothelial dysfunction. These changes might arise from hemodynamic stress as a result of a "tsunami effect" on cerebral parenchyma. In the present article, we review the clinical characteristics of WMH, focusing particularly on two associations: (i) those between cerebral small vessel diseases including WMH and arterial stiffness; and (ii) those between WMH and geriatric syndrome.

Factors associated with increased caregivers' burden in several cognitive stages of Alzheimer's disease.

AIM: To investigate factors associated with caregiver burden (CB) in persons caring for older adults with various cognitive stages of Alzheimer's disease (AD). METHODS: Participants were 1127 outpatients and their caregivers. Participants comprised 120 older adults with normal cognition (NC), 126 with amnestic mild cognitive impairment (aMCI) and 881 with AD. AD patients were subclassified into four groups by Mini-Mental State Examination (MMSE) score: AD29-24 (n = 117), AD23-18 (n = 423), AD17-12 (n = 254) and AD11-0 (n = 87). Participants and their caregivers underwent comprehensive geriatric assessment batteries including Zarit Burden Interview (ZBI) Barthel Index, Lawton Index, Dementia Behavior Disturbance Scale (DBD) to evaluate CB, Instrumental and Basic Activity of Daily Living (IADL/BADL), and Behavioral and Psychological Symptoms of Dementia (BPSD). The comorbidity of geriatric syndrome and the living situation of the patient/caregiver were also assessed. RESULTS: ZBI score was higher in patients with lower MMSE score. Multivariate regression analysis identified that DBD was consistently associated with CB in all patients; symptoms related to memory deficit were related to CB in aMCI; differential IADL, such as inability to use a telephone, use transportation, manage finances, shop, cook and take responsibility for own medication, were related to CB in AD29-24, AD23-18 and AD17-12, and geriatric syndrome including falls and motor disturbance, sleep problems, urinary incontinence, and fatigue was related to CB in AD23-18 and AD17-12. CONCLUSIONS: Multiple factors including BPSD, impaired life function and geriatric syndrome were cognitive stage-dependently associated with CB. Preventive treatment of BPSD and comorbidity, and effective assistance for IADL deficits could contribute to alleviation of CB.

Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVES: Preventive strategy for falls in demented elderly is a clinical challenge. From early-stage of Alzheimer's disease (AD), patients show impaired balance and gait. The purpose of this study is to determine whether regional white matter lesions (WMLs) can predict balance/gait disturbance and falls in elderly with amnestic mild cognitive impairment (aMCI) or AD. DESIGN: Cross-sectional. SETTINGS: Hospital out-patient clinic. PARTICIPANTS: One hundred sixty-three patients diagnosed with aMCI or AD were classified into groups having experienced falls (n = 63) or not (n = 100) in the previous year. MEASUREMENTS: Cognition, depression, behavior and psychological symptoms of dementia, medication, and balance/gait function were evaluated. Regional WMLs were visually analyzed as periventricular hyperintensity in frontal caps, bands, and occipital caps, and as deep white matter hyperintensity in frontal, parietal, temporal, and occipital lobes, basal ganglia, thalamus, and brain stem. Brain atrophy was linearly measured. RESULTS: The fallers had a greater volume of WMLs and their posture/gait performance tended to be worse than nonfallers. Several WMLs in particular brain regions were closely associated with balance and gait impairment. Besides polypharmacy, periventricular hyperintensity in frontal caps and occipital WMLs were strong predictors for falls, even after potential risk factors for falls were considered. CONCLUSIONS: Regional white matter burden, independent of cognitive decline, correlates with balance/gait disturbance and predicts falls in elderly with aMCI and AD. Careful insight into regional WMLs on brain magnetic resonance may greatly help to diagnose demented elderly with a higher risk of falls.