amyloid-beta-peptides and Dementia--Vascular

To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.. The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).. Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.. The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Biomarkers; Case-Control Studies; Chemokine CCL2; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Lobar Degeneration; Humans; Hydrocephalus, Normal Pressure; Male; Middle Aged; Multiple System Atrophy; Neurofilament Proteins; Parkinson Disease; Peptide Fragments; Phosphoproteins; Sensitivity and Specificity; Supranuclear Palsy, Progressive; tau Proteins

Although it is known that Alzheimer's disease (AD) is associated with the progressive accumulation of amyloid β-peptide (Aβ) in the human brain, its pathogenic role has to be completely clarified. Aβ moves from the bloodbrain barrier to the plasma and an increased Aβ production in brain could be associated with higher Aβ concentrations in blood. A recent study has evaluated Aβ40 and Aβ42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aβ concentration in RBCs.. The aim of the study was to investigate if erythrocyte associated Aβ (iAβ) levels could be different in subjects affected by dementia in comparison with controls and according to the patient's cognitive impairment or different dementia subtypes.. To answer these questions we assessed iAβ40 and iAβ42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD.. In this population we found significant differences in iAβ42 between controls and cognitive impaired patients. Moreover, iAβ42 significantly differed between dementia vs MCI. AD also showed different iAβ42 levels as compared to VaD. Conversely, no differences were found for iAβ40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAβ42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found.. Our findings support the evidence that iAβ42 could be an instrument to early recognize dementia and predict cognitive impairment.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Cognitive Dysfunction; Correlation of Data; Dementia, Vascular; Erythrocytes; Female; Humans; Male; Mental Status Schedule; Peptide Fragments

Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-β (Aβ), possibly indicating improved Aβ clearance from brain to blood.. We measured and compared plasma concentrations of Aβ42, Aβ40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia.. Plasma Aβ42 levels and Aβ42/Aβ40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10).. This study is the first to show an association between ACE-I use and increased plasma Aβ42 level and Aβ42/Aβ40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aβ42 indicates improved Aβ42 clearance from brain that contributes to protection from cognitive decline.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Amyloid beta-Peptides; Angiotensin-Converting Enzyme Inhibitors; Cognitive Dysfunction; Creatine; Dementia, Vascular; Female; Humans; Hypertension; Male; Peptide Fragments

To observe the influence of electroacupuncture (EA) stimulation with different electrical current intensities and therapeutic intervals on learning-memory ability and expression of β-amyloid peptide Aβ 1-40 and arginine vasopressin (AVP) genes in the hippocampal CA 1 region in vascular dementia (VD) rats, so as to provide evidence for treatment of VD.. In comparison with the sham group, the average escape latency of place navigation task, and the duration for crossing the target-platform for the 1. EA can improve the learning-memory ability of VD rats, which Feb be related to its effects in inhibiting the expression of Aβ 1-40 mRNA and up-regulating the expression of AVP mRNA in hippocampal CA 1 region; and the therapeutic effects of higher stimulating intensity and higher intervention frequency are obviously better than those of lower stimulating intensity and lower therapeutic frequency.

Topics: Acupuncture Points; Amyloid beta-Peptides; Animals; Arginine Vasopressin; CA1 Region, Hippocampal; Dementia, Vascular; Disease Models, Animal; Electroacupuncture; Humans; Learning; Male; Memory; Peptide Fragments; Rats; Rats, Sprague-Dawley

Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better insights into changes in brain metabolism. We performed cytokine profiling and measured levels of the cellular prion protein (PrP(C)) in serum and cerebrospinal fluid (CSF) samples from patients with VD and with vascular encephalopathy (VE). Significant changes were observed for interleukin (IL)-1β, IL-4, IL-5, tumor necrosis factor alpha, interferon gamma, granulocyte-colony stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta in serum and for IL-6 and granulocyte macrophage colony-stimulating factor in CSF of VD and VE patients, suggesting that most of immune markers depend on vascular lesions, while only IL-6 was related to dementia. In VD patients, the severity of dementia as defined by the Mini-Mental Status Test or Cambridge Cognitive Examination battery test was significantly correlated with the levels of IL-8 (CSF) and macrophage inflammatory protein 1 beta (serum and CSF). Additionally, in CSF of VD patients, our data revealed a correlation between immune and neurodegenerative marker proteins. Both indicate an association of neuroinflammation and cognitive decline. Levels of PrP(C) were regulated differentially in VD and VE patients compared with Alzheimer's disease patients and controls. Moreover, we observed a significant negative correlation between cytokine levels and PrP(C) in VD patients in CSF and serum, as well as a correlation between PrP(C) expression with levels of neurodegenerative marker proteins in CSF (in VD and VE patients). Our data suggest that immunological modifiers play a role in VD and VE patients and provide evidence for an association of PrP(C) with immune and neurodegenerative markers.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Cerebrovascular Disorders; Cohort Studies; Cytokines; Dementia, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Linear Models; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Peptide Fragments; Prions; tau Proteins

Cerebral microbleeds (MBs) may relate to amyloid in dementia. We selected 26 probable Alzheimer's disease (AD) patients with MBs, 26 age- and sex-matched AD patients without MBs, 11 vascular dementia (VaD) patients, and 22 patients with subjective complaints. We measured amyloid beta 1-42 (Aβ42) and 1-40 (Aβ40) in cerebrospinal fluid (CSF) and plasma, and blood-brain barrier (BBB) function using albumin ratios. CSF Aβ42 was lowest in AD with MBs, whereas Aβ40 was selectively decreased in VaD. In plasma, amyloid-beta was nonsignificantly elevated in VaD compared with controls. Higher albumin ratios in VaD suggested blood-brain barrier dysfunction. A MB pattern suggestive of cerebral amyloid angiopathy (CAA) related to lower CSF Aβ42, while a non-cerebral amyloid angiopathy specific MB distribution related to higher plasma Aβ40. Amyloid-beta is differentially implicated in AD with MBs and VaD. MB distribution related to different amyloid profiles, supporting distinct etiologies. Our results suggest that Aβ42 is retained in cerebrovasculature of AD patients with MBs, while in contrast, VaD patients may possibly drain amyloid.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Dementia, Vascular; Female; Humans; Male; Middle Aged; Peptide Fragments

Amyloid beta(40) (Abeta(40)) is the most abundant Abeta peptide in the brain. The cerebrospinal fluid (CSF) level of Abeta(40) might therefore be considered to most closely reflect the total Abeta load in the brain. Both in Alzheimer's disease (AD) and in normal aging the Abeta load in the brain has a large inter-individual variability. Relating Abeta(42) to Abeta(40) levels might consequently provide a more valid measure for reflecting the change in Abeta metabolism in dementia patients than the CSF Abeta(42) concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).. To investigate the diagnostic value of the CSF Abeta(42)/Abeta(40) ratio in differentiating AD from controls, VaD, DLB and FTD.. We analysed the CSF Abeta(42)/Abeta(40) ratio, phosphorylated tau(181) and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls.. Mean Abeta(40) levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Abeta(40) levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Abeta(42)/Abeta(40) ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) concentrations alone (p<0.01) The Abeta(42)/Abeta(40) ratio performed equally well as the combination of Abeta(42), phosphorylated tau(181) and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) alone.. The CSF Abeta42/Abeta40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Abeta42 alone, and is a more easily interpretable alternative to the combination of Abeta42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Dementia; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Middle Aged; Peptide Fragments

The underlying mechanisms of small vessel disease (SVD) subtypes are diffuse arteriopathy (diffuse-SVD) or microatheroma (focal-SVD). Endothelial dysfunction by beta-amyloid peptide (Abeta) deposition has been associated with lacunar infarcts and leukoaraiosis, but its specific relationship with SVD subtypes is unknown. We hypothesized that plasma Abeta levels can play a different role in SVD subtypes in patients with acute lacunar stroke.. We studied 149 patients with acute ischemic stroke of SVD etiology according to Trial Of Org 10172 In Acute Stroke Treatment criteria and 25 age-matched control subjects. Patients were classified into focal-SVD: 39 patients with isolated lacunar infarct without leukoaraiosis and diffuse-SVD: 110 patients with an isolated lacunar infarct with leukoaraiosis or with multiple lacunar infarcts with or without leukoaraiosis. Baseline data included vascular risk factors and extensive laboratory tests, including plasma Abeta levels.. Median [quartiles] Abeta(1-40) levels (40.4 [35.1, 50.5] versus 55.1 [42.3, 69.6] pg/mL), but not Abeta(1-42) levels, were significantly higher in the diffuse-SVD group than in focal-SVD group (P<0.001) and control subjects (P<0.001). No differences in Abeta(1-40) levels were found between focal-SVD and control subjects. Logistic regression analysis showed that age (OR, 1.06; 95% CI, 1.01 to 1.12), history of hypertension (OR, 3.5; 95% CI, 1.3 to 9.2), and plasma beta-amyloid(1-40) levels over the median value (OR, 17.3; 95% CI, 3.0 to 99 for the third quartile and OR, 6.0; 95% CI, 1.6 to 23 for the fourth quartile) were independently associated with the diffuse-SVD subtype.. Plasma beta-amyloid(1-40) levels are independently associated with the diffuse-SVD subtype. These results are consistent with the pathophysiological role of fraction Abeta(1-40) in disrupting endothelial vascular function.

Topics: Acute Disease; Aged; Amyloid beta-Peptides; Arterioles; Brain Infarction; Causality; Cerebral Arteries; Cohort Studies; Dementia, Vascular; Endothelial Cells; Female; Humans; Leukoaraiosis; Male; Microcirculation; Middle Aged; Peptide Fragments; Predictive Value of Tests

Vascular dysfunction and inflammatory processes may be early events in the pathology of Alzheimer's disease (AD). Even though amyloid beta-peptides (Abeta) play a prominent role in the initiation and progression of cellular dysfunction in AD, the precise in vivo actions of various Abeta-peptides has not been established. The cerebrovascular actions of the major Abeta-peptides (1-40) and (1-42) in live animals were investigated using an open cranial window technique. We show here that the Abeta-peptides cause vascular lesions, especially in the arterioles. In one set of experiments, leukocytes and platelets were tagged with Rhodamine 6G, soluble Abeta(1-40) infused intravenously for 2 minutes, and the vasculature video recorded for 90 minutes. In a second set of experiments, soluble Abeta(1-40) infusion was followed 30 minutes later by an infusion of soluble Abeta(1-42) and the vasculature recorded for 90 minutes. Fluorescent and transmission electron microscopic examinations demonstrated the following cerebrovascular action of Abeta-peptides: endothelial cell damage, leukocyte adhesion, platelet activation, thrombus formation, impeded blood flow, and smooth muscle cell damage. The vascular disruption observed were similar to those observed in the brains of some AD patients and may represent the initial phase of a vascular inflammatory response associated with cerebral amyloid angiopathy. The combination of Abeta(1-40) and (1-42) produced significantly more vascular disruption than Abeta(1-40) alone. Oral administration of conjugated estrogens in ovariectomized female rats protected them from the deleterious actions of Abeta-peptides. The reported protective effect of estrogen against AD may be mediated in part through prevention of cerebrovascular Abeta toxicity.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Adhesion; Cerebral Amyloid Angiopathy; Dementia, Vascular; Endothelium, Vascular; Estrogens, Conjugated (USP); Female; Humans; Intracranial Embolism; Leukocytes; Microscopy, Electron; Peptide Fragments; Platelet Activation; Rats