Dementia without cholinergic deficit

We examined the role of cholinergic system in multi-infarct dementia (MID) by measuring acetylcholinesterase (AChE) activities in cerebrospinal fluid (CSF) of clinically diagnosed MID patients, Alzheimer's disease (AD) patients and controls. In spite of the similar clinical severity of dementia, MID patients had unaltered AChE levels, whereas AD patients had significantly reduced AChE levels in CSF when compared to controls. In the autopsy study we analyzed choline acetyltransferase (ChAT) levels in four cortical brain areas from clinically and neuropathologically studied AD patients, demented non-AD patients and controls. ChAT activities in the cerebral cortex in non-AD patients were on the same level as in controls, but AD patients had a marked loss of ChAT activity in all four cortical brain areas studied. Although cholinergic deficit is a usual phenomenon associated with cognitive failure, severe dementia can exist without cholinergic dysfunction.     

CSF biomarkers for mild cognitive impairment

A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.     

Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is a severe chronic neurodegenerative disorder of the brain. A probable diagnosis of AD can be obtained by cerebrospinal fluid levels of 3 biomarkers: beta-amyloid (1–42), total tau and phospho-tau181. Researchers are interested in finding additional biomarkers in CSF to improve the specificity and sensitivity of diagnosis, including also other forms of dementia, such as mild cognitive impairment (MCI). In addition, less invasive diagnostic methods using blood or blood-derived cells are being investigated. This mini-review (in concert with the other reviews of this special issue) summarizes the usefulness of growth factors and cytokines/chemokines as putative surrogate biomarkers for diagnosing AD and MCI in CSF and blood. Briefly, the expression levels of growth factors and cytokines/chemokines are very heterogenous, indicating the pathological diversity of these diseases. At present, no single growth factor or cytokine alone stands out as a useful biomarker for diagnosing AD or MCI. However, the combined “patients profile signature” of several selected growth factors and/or cytokines/chemokines may allow to diagnose AD and MCI with higher selectively and specificity.     

Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia

BACKGROUND: The differentiation of Alzheimer's disease (AD) from vascular dementia (VaD) is hampered by clinical diagnostic criteria with disappointing sensitivity and specificity. The objective of this study was to investigate whether cerebrospinal fluid (CSF) levels of total tau protein (t-tau), amyloid beta42 protein (Abeta42), and tau phosphorylated at threonine 181 (p-tau181) are useful biomarkers to distinguish AD patients from VaD patients. METHODS: We measured CSF levels of p-tau181, Abeta42, and t-tau in 86 patients with a clinical diagnosis of AD or VaD and in 30 control participants. RESULTS: Optimal differentiation between AD and VaD was achieved by using the ratio of the CSF levels of Abeta42 and p-tau181 (Q Abeta42/p-tau) with sensitivity, specificity, positive and negative predictive values all > or = 85%. CONCLUSIONS: Our results support further efforts to prospectively validate the use of Q Abeta42/p-tau as a biomarker to discriminate between AD and VaD.     

脑脊液磷酸化tau蛋白的检测对阿尔茨海默病的诊断价值

目的通过对阿尔茨海默病(AD)患者脑脊液磷酸化tau蛋白检测的研究,探讨其对AD的诊断价值。方法采用ELISA法检测11例AD患者(AD组)、13例血管性痴呆患者(血管性痴呆组)及29例非神经系统疾病患者(正常对照组)的脑脊液磷酸化tau蛋白。结果与血管性痴呆组和正常对照组比较,AD组患者脑脊液中磷酸化tau蛋白含量明显增高(P<0.05)。血管性痴呆组患者脑脊液中磷酸化tau蛋白水平与正常对照组比较无明显差异(P>0.05)。结论检测脑脊液磷酸化tau蛋白含量可作为AD诊断的辅助指标。     

Near a biological diagnosis of Alzheimer's disease and related disorders

PURPOSE: To review the current concepts in the biological diagnosis of Alzheimer's disease (AD) and related disorders. CURRENT KNOWLEDGE AND KEY POINTS: As new therapeutics specific of AD may be available soon, early diagnosis of AD in the context of mild cognitive impairment (MCI) or dementia appears to be challenging. The high amount of atypical clinical forms of AD leads to develop new tools allowing in vivo diagnosis. New CerebroSpinal Fluid (CSF) biomarkers seem to reflect specific aspects of deep neuropathological changes observed in AD, i.e. amyloid deposits and neurofibrillary tangles. Amyloid beta-peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tubulin associated unit (tau) isoforms appear to be the most sensitive and specific CSF biomarkers, the combination of these biomarkers depicting the best diagnosis value for AD. These molecules are also efficient in the prediction of the conversion from the MCI state to the dementia state of AD. Combined to clinical and neuro-imaging information, CSF biomarkers appear thus to be highly relevant in improving the early etiological diagnosis of dementia. FUTURE PROSPECTS AND PROJECTS: The current research focalises on the development of new molecules coming from Abeta and tau protein families, in the CSF and in the serum, as well as molecules reflecting other pathological metabolism changes, as alpha-synuclein in Lewy Body Disease. The diagnosis value of CSF biological markers is so promising that they have been recently included in the research diagnosis criteria of AD.     

Clinical studies of the cholinergic deficit in Alzheimer's disease. I. Neurochemical and neuroendocrine studies

Autopsy studies indicating that cholinergic neurons are selectively lost in patients with Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT) suggest that peripheral markers for central cholinergic activity would be useful in diagnosis. The present studies found that cerebrospinal fluid (CSF) concentrations of acetylcholine (ACh) correlated with the degree of cognitive impairment (r = .70) in a sample of carefully diagnosed patients with AD/SDAT, but metabolites of other neurotransmitters were not related to cognitive state; this suggests that CSF ACh may be a valid measure of cholinergic degeneration. Cortisol and growth hormone were measured in plasma samples drawn from patients and controls every 30 minutes from 2100 to 1100 hours the next day. Mean plasma cortisol concentrations were higher in patients with AD/SDAT than in controls and correlated inversely with CSF methoxy-hydroxyphenylglycol (MHPG) (r = .61) and positively with degree of cognitive impairment (r = +.53); as anticholinergic drugs suppress cortisol this finding indicates that cortisol dysregulation may be a marker for abnormalities in other neurotransmitter systems, particularly the noradrenergic system. Growth hormone secretion was not different in patients and controls but was positively correlated with CSF MHPG (r = +.63).     

Cerebrospinal fluid antimicroglial antibodies in Alzheimer disease: a putative marker of an ongoing inflammatory process

Immunocompetent microglia play an important role in the pathogenesis of Alzheimer's disease (AD). Antimicroglial antibodies in the cerebrospinal fluid (CSF) in clinically diagnosed AD patients have been previously recorded. Here, we report the results of the analysis of the CSF from 38 autopsy cases: 7 with definite AD; 14 with mild and 10 with moderate Alzheimer's type pathology; and 7 controls. Antimicroglial antibodies were identified in 70% of patients with definite AD, in 80% of patients with moderate and in 28% of patients with mild Alzheimer's type pathology. CSF antimicroglial antibodies were not observed in any of the control cases. The results show that CSF antimicroglial antibodies are present in the majority of patients with definite AD and also in cases with moderate Alzheimer's type changes. They may also indicate dysregulation of microglial function. Together with previous observations, these findings indicate that compromised immune defense mechanisms play an important role in the pathogenesis of AD.     

Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease

Plasma Aβ42 and Aβ40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Aβ42 and Aβ40 increase with age but subsequently decrease when Aβ begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Aβ levels in elderly populations, we investigated how plasma Aβ42, Aβ40, and a protofibrillar subspecies of Aβ42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Aβ42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Aβ42, a decreased Aβ42/Aβ40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Aβ42 levels. Our results suggest individuals with elevated plasma Aβ42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Aβ may reflect compartmentalization of Aβ peptides in the brain.     

Glycemia and Levels of Cerebrospinal Fluid Amyloid and Tau in Patients Attending a Memory Clinic

OBJECTIVES: To determine the association between markers of glycemia and cerebrospinal fluid (CSF) amyloid β 1–42 (Aβ42) and tau levels in patients attending a memory clinic. DESIGN: Cross‐sectional study. SETTING: Memory clinic. PARTICIPANTS: Two hundred forty‐five consecutive patients attending a memory clinic. Clinical diagnoses were subjective cognitive complaints (n=91), mild cognitive impairment (n=62), Alzheimer's disease (n=58), and other dementia (n=34). Twenty‐one patients had diabetes mellitus. MEASUREMENTS: Glycosylated hemoglobin (HbA1c); fasting blood glucose levels; and CSF levels of Aβ42, total tau, and p‐tau 181. RESULTS: In regression analyses across the whole study sample adjusted for age, sex, and diagnostic group, there was no relationship between HbA1c or fasting glucose and CSF tau, p‐tau 182, or Aβ42 levels. Stratification for diabetes mellitus did not change the results. CONCLUSION: These observations do not support the hypothesis that the association between dysglycemia and impaired cognitive functioning is mediated through aberrant amyloid or tau metabolism.     

Distinction between preclinical Alzheimer's disease and depression

OBJECTIVE: To assess the prevalence of depression in subjects with preclinical Alzheimer's disease (AD) and to investigate the possibility of differentiating subjects with preclinical AD and depression from subjects with depression-related cognitive impairment. DESIGN: A prospective, observational cohort study. SETTING: An outpatient memory clinic of a university-affiliated hospital. PARTICIPANTS: Nondemented subjects with cognitive impairment older than 55 years (n = 111) without neurological or somatic causes for the cognitive impairment. MEASUREMENTS: At baseline, data were collected on patient characteristics, the severity of depression, and cognitive functioning. The course of the cognitive impairment and the presence of dementia were assessed after 2 and 5 years. RESULTS: Twenty-five subjects had preclinical dementia with Alzheimer's type dementia at follow-up. Sixty percent of these subjects (n = 15) were depressed at baseline. Subjects with depression and preclinical AD had at baseline a poorer performance on the cognitive tasks and were older than the subjects with depression-related cognitive impairment. Logistic regression with backward step selection selected age and memory performance as the best predictors for Alzheimer's type dementia in the depressed subjects. The specificity of these predictors for the diagnosis of future Alzheimer's type dementia in depressed subjects was 94%, sensitivity was 90%, positive predictive value was 90%, and negative predictive value was 94%. CONCLUSIONS: Depression is common in preclinical AD. Depressed subjects with preclinical AD can be accurately differentiated from subjects with depression-related cognitive impairment by age and the severity of the memory impairment. Research that aims to investigate preclinical AD should not exclude a priori subjects with depression inasmuch as preclinical AD is often accompanied by depression.     

阿尔茨海默病和帕金森痴呆患者脑脊液中tau蛋白和β淀粉样蛋白水平的研究

目的探讨在阿尔茨海默病(AD)和帕金森痴呆(PDD)患者脑脊液(CSF)中tau蛋白和β淀粉样蛋白(Aβ1-42)的水平及临床意义。方法同时将符合美国国立神经病、语言障碍和脑卒中研究所-老年性痴呆及相关性疾病协会的“很可能AD”标准的22例AD组患者与20例PDD组患者和21例性别、年龄相匹配的无中枢神经系统疾患、无痴呆表现的心理疾病患者作为对照组(NC组)进行研究。结果3组CSF中tau蛋白平均浓度比较,AD组明显高于NC组(P<0.05);AD组与PDD组差异无显著性意义(P>0.05)。3组CSF中A1β-42平均浓度比较,AD组明显低于NC组(P<0.05),PDD组与NC组差异无显著性意义(P>0.05)。结论AD患者CSF中tau蛋白和Aβ1-42浓度变化是其重要的实验室表现,可以作为AD的辅助诊断指标和与PDD早期鉴别诊断的可能生物学指标。     

轻度认知功能障碍向阿尔茨海默病转化的预测研究进展

轻度认知功能障碍（MCI）是介于正常衰老与痴呆之间的认知功能缺损状态,MCI进展为阿尔茨海默病（AD）的危险性较高,故MCI阶段可能是进行AD预防性治疗的最合适阶段,因而成为研究的焦点。本文就近年来MCI向AD的转化预测研究做一综述,主要包括五个方面：神经心理学测试、生物标志物检查、神经影像学检查、脑电生理学检查及其治疗进展。     

Relation between aerobic fitness and brain structures in amnestic mild cognitive impairment elderly

Mild cognitive impairment (aMCI) is a clinical condition, with high risk to develop Alzheimer’s disease. Physical exercise may have positive effect on cognition and brain structure in older adults. However, it is still under research whether these influences are true on aMCI subjects with low Ab_42 and high total tau in cerebrospinal fluid (CSF), which is considered a biomarker for AD. Therefore, we aimed to investigate a possible relation between aerobic fitness (AF) and gray matter (GM) volume and AF and white matter (WM) integrity in aMCI with a CSF biomarker. Twenty-two participants with aMCI acquired the images on a 3.0-T MRI. AF was assessed by a graded exercise test on a treadmill. Voxel-based morphometry and tract-based spatial statistic methods were used to analyze the GM volume and WM microstructural integrity, respectively. We correlated AF and GM volume and WM integrity in aMCI (p < 0.05, FWE corrected, cluster with at least five voxels). There was a positive relation between AF and GM volume mostly in frontal superior cortex. In WM integrity, AF was positively correlated with fractional anisotropy and negatively correlated with mean diffusivity and radial diffusivity, all in the same tracts that interconnect frontal, temporal, parietal, and occipital areas (longitudinal fasciculus, fronto-occipital fasciculus, and corpus callosum). These results suggest that aerobic fitness may have a positive influence on protection of brain even in aMCI CSF biomarker, a high-risk population to convert to AD.     

阿尔茨海默病患者脑脊液中葡萄糖、真胰岛素水平与载脂蛋白E基因的关系

目的 检测阿尔茨海默病(AD)患者脑脊液中葡萄糖、真胰岛素水平,探讨AD患者脑脊液中胰岛素异常及与载脂蛋白E(ApoE)基因的关系.方法 随机选择35例对照组、48例AD患者,留取脑脊液检验其葡萄糖、真胰岛素水平,将AD按轻、中重度和不同ApoE基因型分组后与相应的对照组进行比较.结果 AD患者各组脑脊液中葡萄糖与相应对照组比较,无显著性差异(P> 0.05);轻度AD组脑脊液真胰岛素较对照组无显著性差异(P> 0.05),中重度AD组真胰岛素较对照组降低,有显著性差异(P< 0.05);无ApoEε4 AD组较对照组真胰岛素降低,有显著性差异(P< 0.05).结论 AD患者脑脊液中胰岛素水平降低,与疾病的严重程度和ApoEε4基因型相关.     

Vitamin B12, folate, homocysteine and dementia: are they really related?

Dementia is an acquired impairment of intellectual and memory functioning. There are numerous factors affecting neurocognitive functions like vascular factors, Vitamin B12 and folate and homocysteine levels. The aim of this study is to determine whether there is a relationship between the serum levels of these metabolites and diagnosis of dementia and mild cognitive impairment (MCI). A total of 1249 patients admitted to Hacettepe University Hospital Department of Internal Medicine, Division of Geriatric Medicine Outpatient Clinic between 1 February 2002 and 30 June 2003 were included in this study. Vitamin B12, folate and homocysteine levels were measured in all patients, and they were evaluated also for their cognitive abilities. In this study pool, 121 cases were diagnosed as Alzheimer's disease (AD), 60 patients were diagnosed as having non-Alzheimer dementia (NAD), 273 had MCI. When patients with AD, NAD, MCI and patients without dementia were compared according to their median values of folate, Vitamin B12 and homocysteine, there were no significant differences. Results of studies searching for a correlation between Vitamin B12, folate and homocysteine levels and their relation with cognitive status of the elderly are controversial in various studies from different countries. In this study (with 1249 elderly patients) we were unable to find any correlation between homocysteine, Vitamin B12 and folate levels and cognitive functioning in contrast with some literary data. Nevertheless, these metabolites should be measured routinely in the examination of any elderly patient, since they can play important roles in geriatric patients.     

Assessing adipokines as potential biomarkers of dementia,Alzheimer's disease,and mild cognitive impairment: A systematic review and meta-analysis

Midlife obesity and late-life weight loss confer a greater risk for developing dementia and Alzheimer's disease (AD), but the exact mechanisms behind this phenomenon are currently unknown. The answer could lie on the involvement of gastrointestinal factors, such as adipokines (e.g., leptin, adiponectin, and resistin) and ghrelin. In this context, we conducted a pre-registered systematic review and meta-analysis of 42 cross-sectional and 13 longitudinal studies targeting the associations between leptin, adiponectin, resistin, and ghrelin and the prevalence of general dementia, AD, and mild cognitive impairment (MCI). We also examined the relationship between the four gastrointestinal factors and neurocognitive outcomes and AD-related cerebrospinal fluid biomarkers. Patients with AD had lower blood leptin and higher resistin levels than cognitively normal participants. Lower leptin and higher resistin were associated with higher degree of cognitive impairment. Additionally, lower late-life leptin levels might be associated with higher prospective risk of dementia and AD, although more studies are needed to corroborate this. Results in ghrelin and adiponectin were not conclusive, with age, sex distribution, obesity, and severity of dementia seemingly acting as moderators across several analyses. Our work might contribute to the identification of new preclinical blood markers of MCI and AD.     

Longitudinal course of behavioral problems during Alzheimer's disease: linear versus curvilinear patterns of decline

BACKGROUND: Patients with Alzheimer's Disease (AD) are commonly assumed to experience a linear decline in behavioral functioning that parallels progressive cognitive decline. However, some researchers have suggested that specific behavioral problems either decline at different rates or improve in late dementia. METHODS: The present analyses examined 150 AD patients at an initial assessment, 61 of whom were also evaluated annually on two additional occasions. Measures of cognitive impairment and behavioral problems were obtained. RESULTS: Cross-sectional results indicated curvilinear associations between dementia severity and certain behavioral problems (forgetful behaviors, and emotional and impulsive behaviors). Longitudinal analyses further indicated trends for curvilinear rates of behavioral disturbance across time, with some problem areas showing improvement as AD progresses through the most severe stages. CONCLUSIONS: Even though Alzheimer's disease is a progressive dementia characterized by increasing cognitive deterioration, it appears to be inaccurate to expect behavioral functioning to show the same linear decline across time.     

Plasma β-amyloid peptides in canine aging and cognitive dysfunction as a model of Alzheimer's disease

Aging dogs naturally demonstrate cognitive impairment and neuropathology that model early Alzheimer's disease (AD). In particular, there is evidence that canine cognitive dysfunction syndrome (CDS) in aged dogs is accompanied by cortical deposition of Aβ peptides and neurodegeneration. Plasma Aβ levels have been examined in humans as putative biomarkers for AD, but to date, no similar studies have been conducted for canine dementia. The aim of the present study was to assess plasma Aβ1-42 and Aβ1-40 levels in a blind study using pet dogs that were either successfully aging or exhibiting CDS. The severity of cognitive impairment was assessed using an owner-based questionnaire. On average, young dogs presented significantly higher plasma levels of Aβ1-42 and Aβ1-40 than aged, cognitively unimpaired dogs. Notably, among aged dogs, the levels of Aβ1-42 and the Aβ42/40 ratio were significantly higher in those showing mild cognitive impairment than in either cognitively unimpaired or severely affected dogs. These results suggest that increased plasma Aβ1-42 levels and Aβ42/40 ratio could be a biomarker for canine cognitive dysfunction, which is considered an excellent natural model of early AD.     

探讨补体受体1基因与脑脊液中相关蛋白的关系

目的探讨补体成分(3b/4b)受体1基因[the complement component (3b/4b) receptor 1gene,CR1]多态性与脑脊液相关蛋白的关系。方法从美国国立老年研究所组织建立的阿尔茨海默病(AD)神经影像学研究数据库中选择812例受试者,其中48例AD患者为AD组,483例轻度认知障碍(MCI)患者为MCI组,281例正常对照(NC)者为NC组。用免疫分析试剂盒和xMAP Luminex试剂盒检测入选者脑脊液中β淀粉样蛋白(Aβ)、总tau(t-tau)蛋白和磷酸化tau(p-tau)蛋白水平。结果 AD组rs61522287位点基因突变后,GA基因型较GG基因型脑脊液Aβ42水平增加[(193.20±79.05)ng/L vs(137.90±37.28)ng/L,P=0.03762]。8个CR1的单核苷酸多态性(SNP)位点可以调节AD患者脑脊液中t-tau蛋白和p-tau蛋白水平。11个CR1的SNP突变位点参与调节MCI组患者tau蛋白水平。3个CR1的SNP位点基因突变增加MCI组脑脊液中Aβ42水平。rs41274776和rs12567945位点突变同时增加NC组脑脊液中p-tau和Aβ42水平。结论本研究率先明确了CR1的SNP位点与脑脊液蛋白(Aβ42,t-tau和p-tau)之间的关系,这对未来寻找AD的早期诊断,早期筛查提供了新思路。