Subgroups of Alzheimer's disease associated with diabetes mellitus based on brain imaging.

BACKGROUND/AIMS: We attempted to define possible subgroups of Alzheimer's disease (AD) associated with diabetes mellitus (DM) based on brain imaging. METHODS: We classified 175 patients with clinically diagnosed AD and type 2 DM into 4 subgroups on the basis of the presence or absence of cerebrovascular disease (CVD) on MRI (CVD or no CVD) and posterior cerebral hypoperfusion on SPECT (AD pattern or no AD pattern). Differences in the clinical characteristics among the subgroups were examined. RESULTS: The subgroup showing neither a CVD pattern nor an AD pattern had significantly older age, higher hemoglobin A1c level, longer duration of diabetes, higher frequency of insulin therapy, lower frequency of apolipoprotein E4 carriers, less severe medial temporal lobe atrophy, more impaired attention, less impaired word recall, and slower progression of cognitive impairment than the subgroup showing an AD pattern. We found no characteristic features of other subgroups. CONCLUSION: The clinical features of subjects with AD associated with DM may differ depending on brain imaging patterns. Among them, there may be a dementia subgroup with characteristics predominantly associated with DM-related metabolic abnormalities.

[Screening test for overactive bladder in a newly developed comprehensive geriatric assessment initiative].

PURPOSE: Lower urinary tract symptoms, particularly in overactive bladder (OAB), are frequently observed among elderly patients. The impact of OAB on their quality of life is so strong that the assessment of OAB is necessary in comprehensive geriatric assessment (CGA). As CGA takes time to complete, we established a convenient instrument consisting of 2 questions on OAB and assessed its utility. METHOD: We recruited 123 elderly patients with various diseases (mean age: 83.2 years, 63 men), in whom 2 questions on nocturia (Q1) and urinary incontinence at night (Q2) were asked. Thereafter, overactive bladder symptom scores (OABSS) were obtained to diagnose OAB based on the OAB criteria. Statistical analyses for Q1 and Q2 were performed using the OABSS criterion as a gold standard. To elucidate the clinical characteristics of the elderly patients, they were divided into 2 groups on the basis of the presence or absence of nocturia: nocturia (+) and nocturia (-) groups. The nocturia (+) group was subdivided into 2 subgroups: with or without incontinence. RESULTS: Nocturia (Q1) was observed in 82 elderly patients and urinary incontinence (Q2) in 23, whereas OAB was diagnosed in 22. The sensitivity, specificity, and positive predictive value (PPV) of Q1 (Q1+Q2) were 100% (68.2%), 40.6% (92.1%), and 26.8% (65.2%), respectively. The nocturia (+) group patients were characterized as predominantly composed of men with cerebrovascular disease, disturbed activities of daily living, interrupted sleep, delayed wake-up time, and treatment with diuretics. Furthermore, Parkinson disease, depressive state, sedentary life style, and treatment without diuretics were frequently observed in patients in the incontinence (+) subgroup. CONCLUSION: A low PPV with a high sensitivity of Q1 was improved by using Q1+Q2, where both Q1 and Q2 enable better assessment of OAB resulting in being a useful screening test for OAB.

[Leg edema detected on comprehensive geriatric assessment for elderly outpatients and its associated risk factors].

AIM: Leg edema, observed on comprehensive geriatric assessment (CGA) of 142 elderly outpatients with a variety of chronic diseases, was studied clinically to clarify its incidence and its associated risk factors. METHODS: The severity of pitting edema was assessed at 3 points, namely, the pretibial edge, medial malleolus, and the dorsum of the foot. On palpation, edema was graded as 0 to 3 for each point on one leg, the sum of which was used as the edema score. According to the edema score, subjects were divided into 3 groups; the moderate to severe (MS) group, the slight to mild (SM) group, and the group without pitting edema. The MS group was defined as having an edema score of 4 or more or edema of grade 2 or more, while the SM group was defined as having an edema score of 2 to 3 points without edema of grade 2 or more. The status of underlying disease, vascular risks, varicose veins, medications, daily activity, nutrition, total protein (TP), albumin, brain natriuretic peptide (BNP), and the estimated glomerular filtration rate (eGFR) were compared among the 3 groups. RESULTS: There were 36 subjects in the MS group and 19 subjects in the SM group. Diabetes, atrial fibrillation, varicose veins, and polypharmacy were more frequent in the MS group than in the control group. Sedentary life style, house-bound, and gait trouble were significantly more frequent in the MS and SM groups. There were no significant differences in the scores of the Mini-Nutritional Assessment Short Form among the groups, although both the body weight and calf circumference in the MS group were significantly greater than those in the group without pitting edema. Low serum TP, albumin and eGFR were seen in the MS group as well as high BNP levels. Multiple regression analysis revealed diabetes, varicose veins, sedentarism, and hypoalbuminemia as risk factors associated with leg edema (R(2)=0.365, p<0.0001). CONCLUSION: Leg edema was frequent in the elderly outpatients and was associated strongly with diabetes, varicose veins, sedentarism, and hypoalbuminemia. These findings suggest that advising against a sedentary life style could help the resolution of edema, and also indicates the clinical usefulness of CGA. Furthermore, leg edema should be seriously considered along with nutritional assessment because edema could influence various anthropometric parameters.

Accumulation of phosphorylated alpha-synuclein in aging human brain.

Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy dots); and axons in the white matter (Lewy axons). This novel pathology was abundantly present around LBs and also involved the limbic subcortical white matter, the cerebral cortical molecular layer, and the spongiform changes of the medial temporal lobe associated with cases of dementia with LBs (DLB). The phosphorylated alpha-synuclein was limited to the temporal lobe in cases of Parkinson disease, spread from the temporal lobe to the frontal lobe in cases of DLB transitional form and further spread to the parietal and occipital lobes in DLB neocortical form. Our findings suggest that LB-related pathology initially involves the neuronal perikarya, dendrites, and axons, causes impairment of axonal transport and synaptic transmission, and later leads to the formation of LBs, a hallmark of functional disturbance long before neuronal cell death.

Changes in carotid atherosclerosis patterns detected by ultrasonography in Japanese elderly patients with aortic aneurysm.

To clarify current changes in the patterns of carotid atherosclerosis in Japan, carotid ultrasonographic findings in Japanese male patients with aortic aneurysm were compared between two groups examined in different periods. The first group was recruited from 42 consecutively examined patients in 1997, while the second group consisted of 40 consecutive patients from September, 2001 to January, 2002. Carotid lesions were analyzed by computer, and classified into three types based on the texture: echolucent, hyperechoic, and heterogeneous types. The mean age of the first group was 72 years, similar to that of the second group. In the first group, cigarette smoking was frequently noted, while the mean BMI was greater and IHD and CVD were frequent in the second group. Fifty carotid lesions were seen in each group. Severe stenosis and hypoechoic type lesions were more frequent in the second group than in the first group. These findings indicated that hypoechoic-type lesions, which are considered to be lipid deposition, hemorrhage, or loose fibrous tissue, and severe stenosis, were increased in the more recent group. This predicted that circulatory disturbance due to unstable atherosclerotic lesions may increase in the future among the elderly because carotid lesions reflect vascular change in other organs.

[Marked decrease of intracranial atherosclerosis in contrast with unchanged coronary artery stenosis in Japan].

We conducted comparative studies on intracranial atherosclerosis and coronary artery stenosis over the past 28 years. Two-year consecutive autopsy case studies from an urban geriatric hospital between 1974-1975 (Group I. 484 cases). 1986-1987 (Group II, 504 cases) and 2000-2001 (Group III, 273 cases) were employed. Atherosclerotic changes of the bilateral middle cerebral arteries and basilar artery were semiquantitatively evaluated as none (0), mild (1), moderate (2) and severe (3) and values of the 3 arteries were totalled to give a value of 0-9 which was taken as the intracranial atherosclerotic index (ICAI). The coronary stenotic index was calculated as previously reported (Sugiura et al 1969). ICAI and CSI were directly compared with each other, together with risk factors for each, including mean blood pressure (BP), serum level of total cholesterol (Tch) and the history of diabetes mellitus (DM+). Chronologically ICAI decreased dramatically but CSI did not change at all. There was continuous lowering of BP, elevation of Tch and increased incidence of DM+. There was a significant positive correlation in BP in relation to both ICAI and CSI (p < 0.01). DM+ vs. CSI (p < 0.01) and ICAI (p < 0.05), and Tch vs. CSI (p < 0.01) but not ICAI. Regression analysis highlighted age and BP as major risk factors for ICAI. Our study provides the first morphological confirmation of marked decrease of the intracranial atherosclerosis in the recent 28 years, in contrast with unchanged coronary stenosis in Japanese elderly subjects.

Endovascular treatment of ruptured intracranial aneurysms in patients 70 years of age and older.

BACKGROUND: An increasing number of elderly patients present with intracranial aneurysms. In addition to female gender, an older age is associated with a higher risk of developing a subarachnoid hemorrhage (SAH), and these patients often fare poorly in terms of long-term outcome. It is often thought that elderly patients would especially benefit from endovascular aneurysm treatment. We assessed the clinical outcomes in elderly patients with ruptured intracranial aneurysms (RIAs) who were treated by endovascular procedures. METHODS: We performed a retrospective review of a prospective database of elderly patients treated with coil embolization for RIAs. The clinical outcomes were assessed using the modified Glasgow Outcome Scale. The rates of procedural complications and adverse events were also recorded. RESULTS: During a period of 5 years, 162 patients with 183 intracranial aneurysms were treated in our hospital by means of an endovascular approach. Among them, 51 patients (31.5%) with a ruptured aneurysm were aged 70 years or older. These patients aged 70-91 years (mean age, 74 years) were treated by coil embolization for RIAs. Among them, seven had a Hunt and Hess (HH) grade of I or II, 42 had an HH grade of III or IV, and 2 had an HH grade of V. Endovascular treatment resulted in 32 complete occlusions (62.7%), 15 neck remnants (22%), and 4 body fillings (7.9%). Procedural complications occurred in five patients (9.8%). The outcomes were good or excellent in 17 patients (33.3%). Three patients (5.8%) who died had an HH grade of IV or V. Rebleeding occurred during follow-up in one patient (1.9%). CONCLUSIONS: Coil embolization of intracranial aneurysms is safe and effective in the elderly. However, the morbidity and mortality rates are higher in patients with high HH grades. This finding suggests that the timing of treatment should be based on the patient's initial clinical status.

Preoperative prediction of macrophage infiltration by 3-D tomographic ultrasound in endoarterectomized carotid plaques in elderly patients.

AIM: Assessment of plaque characteristics is important for the optimal treatment of carotid stenosis, particularly in elderly patients. Macrophage infiltration is reported to be involved in carotid plaque instability. However, immunohistochemical assessment of the detailed localization of macrophage infiltration in carotid plaques remains limited. We attempted to elucidate this using 3-D ultrasonography (3D-US). We compared findings of the detailed localization of macrophage infiltration with findings from the newly developed tomographic ultrasound imaging (TUI). METHODS: We obtained specimens of carotid arteries from 18 patients undergoing carotid endarterectomy (CEA), and investigated the localization of macrophages and vascular smooth muscle cells. Their localization obtained from 11 patients was compared with their preoperative TUI findings. RESULTS: We classified the localization of macrophage infiltration into four types: (i) focal infiltration in the thick fibrous cap (12 cases); (ii) subendothelial zonal infiltration (2 cases); (iii) peripheral infiltration around the lipid core (8 cases); and (iv) local infiltration near the shoulder of the fibrous cap (2 cases). Among them, preoperative TUI was available in 11 CEA cases for histological comparison. We identified two sites of focal macrophage infiltration that corresponded to local echogenic lesions without an acoustic shadow on TUI. The proliferation of smooth muscle cells failed to show an apparent echogenicity. CONCLUSIONS: TUI could not only evaluate the morphological features, but also showed the two types of focal macrophage infiltration relevant to plaque instability as an echogenic focus. TUI carried out by 3D-US is an easily applicable and non-invasive method that is considered useful for evaluating carotid plaques in elderly patients.

Isoform-specific immunolocalization of 14-3-3 proteins in atherosclerotic lesions of human carotid and main cerebral arteries.

14-3-3 proteins are now recognized to have a wide range of potential functions and pathological relevance, such as regulating the intercellular signal processes of differentiation, the development and growth of cells, or preventing or mediating cell apoptosis and survival by controlling the localization of potential signaling molecules. We investigated the immunolocalization of 14-3-3 proteins in atherosclerotic lesions of human cerebral and carotid arteries using 14-3-3 isoform-specific antibodies to distinguish 7 isoforms, and confirmed the cell type localization using double immunofluorolabeling. 14-3-3 common (COM)-like immunoreactivity (IR) was intense, mainly in the foam cells and multinucleated giant cells of the carotid artery. The beta, gamma, epsilon, tau, eta, and zeta (6/7) isoform-specific antibodies showed similar results to those with anti-14-3-3 COM antibody. However, among these isoform-specific antibodies, the anti-eta isoform antibody most intensely immunolabeled multinucleated giant cells and foam cells, and the anti-zeta isoform antibody most intensely immunolabeled infiltrating vascular smooth muscle cells (VSMCs), in carotid plaques. Zeta IR was also observed in one part of the mural thrombus and in the nuclei of foam cells. Gamma isoform-like IR was relatively limited in cell components, but extracellular lesions were partly positive for this isoform. In the main cerebral arteries, the anti-epsilon isoform antibody most intensely immunolabeled infiltrating VSMCs in the intima of thickened fibrous cap plaques. Endothelial cells were also positive for the epsilon isoform. These findings may provide a basis for understanding the isoform-specific role associated with atherosclerotic lesions of the cerebral and carotid arteries.

Association between ApoE phenotypes and telomere erosion in Alzheimer's disease.

Although several reports suggest that Alzheimer's disease (AD) is associated with shortened telomere length, the clinical relevance of this has not yet been fully elucidated. This study was conducted to clarify the correlation of telomere length with clinical characteristics and ApoE phenotypes in 74 AD patients. Telomere length was determined from genomic DNA extracted from whole blood by quantitative real-time polymerase chain reaction. We found no significant difference in telomere length between the AD and non-dementia elderly control (n = 35) groups. Furthermore, no significant correlation was found among telomere length and the severity of cognitive decline and disease duration, age, or gender difference. However, telomere length was significantly shorter in AD patients with the ApoE4 homozygote than in those with the ApoE4 heterozygote (p < .001) and noncarriers (p < .001). These findings suggest that shortened telomere length may be associated with the ApoE4 homozygote in AD patients.

Plasma brain natriuretic peptide levels indicating thromboembolism in very elderly patients with non-valvular atrial fibrillation.

BACKGROUND: Assessment of left atrial (LA) function by transesophageal echocardiography is useful for detecting patients with a high risk thromboembolism secondary to atrial fibrillation (AF). A recent study showed that the atrium is the main source of brain natriuretic peptide (BNP) in AF patients without overt heart failure. The purpose of this study was to assess the possible relationship between LA function and plasma BNP levels in very elderly patients with non-valvular AF. METHODS AND RESULTS: Seventy-four consecutive patients with chronic non-valvular AF (aged, 82+/-6 years) underwent transthoracic and transesophageal echocardiography and measurement of plasma BNP. Thirteen AF patients who had a history of cerebral embolism or echocardiographic evidence of thrombus (TE+ group) were compared with 61 AF patients who had no such complications (TE- group). The TE+ group demonstrated a lower LA appendage (LAA) velocity and higher plasma BNP level than the TE- group. Assessment of variables by multiple logistic regression analysis revealed that BNP was a significant predictor of thromboembolism. There was a significant negative correlation between the plasma BNP level and the LAA peak flow velocity. CONCLUSIONS: The present findings would suggest the usefulness of measuring plasma BNP to detect very elderly non-valvular AF patients at high risk for thromboembolism.