Cerebrospinal fluid tau, phospho-tau181 and β-amyloid1−42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease

The aim of the present study was the quantitation of total tau protein ( τ _T), tau phosphorylated at threonine 181 ( τ _P-181) and β -amyloid₁₋₄₂ (A β 42) in the cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH), Alzheimer's disease (AD) and controls. Double sandwich ELISAs (Innogenetics) were used for the measurements. Total tau was significantly increased in iNPH and highly increased in AD as compared with the control group, whilst A β 42 was decreased in both diseases. CSF τ _P−181 levels were significantly increased only in AD, but not in iNPH as compared with the controls. A cut-off level for τ _T at 300 pg/ml, successfully discriminated AD from normal aging with a 95.8% specificity and 91% sensitivity; whilst the τ _P-181/ τ _T ratio (cut-off value 0.169) was more specific (100%) but less sensitive (92.5%). For the discrimination of iNPH from AD τ _T achieved low specificity (77.8%) but high sensitivity (92.5%), whilst τ _P-181 (cut-off value 47.4) was both sensitive and specific (88.7% and 86.7% respectively) for the discrimination of these disorders. The present study, despite being clinical, supports the notion that CSF τ _P-181 alone or in combination with τ _T may be a useful marker in the discrimination of iNPH from AD.     

Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.     

Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia

INTRODUCTION: Cystatin C, a cysteine protease inhibitor, has been implicated in the neurodegenerative and repair processes of the nervous system, and the deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different types of dementias. OBJECTIVE AND METHODS: Because of the differential diagnostic importance, serum and cerebrospinal fluid (CSF) cystatin C levels of 24 late onset Alzheimer's demented (AD) and 16 ischemic type of vascular demented (VD) probands were compared with 17 aged control (AC) persons. RESULTS: The serum and CSF cystatin levels were found in the normal range in all groups. The ischemic VD probands had the tendency to have higher cystatin C levels than the AD. No correlation has been found with the severity and duration of dementia and with the other measured parameters. CONCLUSION: These results indicate that lower than normal CSF cystatin C level is not a diagnostic marker in ischemic VD and CAA related to AD.     

CSF tau protein and β-amyloid (1–42) in Alzheimer''s disease diagnosis: discrimination from normal ageing and other dementias in the Greek population

Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's disease (AD). In order to evaluate their diagnostic potential in clinical practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15 patients with non-AD neurodegenerative dementias (NAND), six patients with vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and a sensitivity of 82% in differentiating AD from normal ageing, whilst the corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67 and 82%, respectively. Tau was better in differentiating AD, from normal ageing (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values comparable or even better than tau for differentiating AD from normal ageing (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and definitely better than any of the candidate markers alone, for differentiating AD from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful adjuvant to clinical criteria for dementia diagnosis.     

听觉P300对血管性痴呆早期诊断及鉴别诊断的价值

目的探讨P300对血管性痴呆(VD)的早期诊断及与Alzheimer病(AD)鉴别的价值.方法分别对20名正常人(NC)、20例VD患者、24例无痴呆脑梗死患者(CI)及20例AD患者进行神经心理学量表长谷川智力量表(HDS)评分,并选用听觉oddball序列分别对上述各组进行P300测试.结果 (1)VD组与CI组及NC组比较,N2、P3潜伏期(PL)明显延长(均P<0.05);P3PL与HDS评分呈负相关(r=-0.686,P＜0.01),且较HDS更为敏感;梗死部位与P300变化有一定关系,梗死位于颞叶、额叶的患者与其他梗死部位的患者相比,P3PL异常率明显增高(P＜0.05).(2)AD组与VD组相比,N1 PL更长,差异有显著性(P<0.05).结论 (1)P300对VD的早期诊断具有重要意义.(2)N1PL在VD与AD的鉴别诊断中有一定的意义.     

Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia

Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.     

Olfactory dysfunction in dementia of Alzheimer's type and vascular dementia

Background: Olfactory function in vascular dementia has not been extensively investigated to date. We studied olfactory function in vascular dementia (VD) and dementia of Alzheimer's type (DAT). Methods: We studied olfactory functioning in 12 patients suffering from dementia of Alzheimer's type, 11 patients with vascular dementia and 30 normal subjects. For these subjects we examined a 12‐item version of the Pennsylvania smell identification test and mini‐mental state examinations. These three groups were matched for age, sex and educational level. Results: Although the dementia scores were comparable in the DAT and VD groups, the smell identifications were low in DAT patients compared with VD patients and normal control subjects. Conclusions: These results suggest that the smell identification test may be useful in differential diagnosis between DAT and VD patients     

beta-amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer's disease

Impaired olfaction, hyposmia or anosmia are part of the clinical phenotype in neurodegenerative disorders including Alzheimer's disease (AD). It has been proposed that the most severely affected areas are interconnected with the central olfactory system in contrast to the relative sparing of other sensory areas which lack olfactory connections. The pathology of the first synaptic relay in the olfactory pathway, the olfactory bulb (OB), has been studied in AD, but the results have been inconsistent. In order to define more fully the pathology of the OB, we analysed 15 AD and 15 control cases, using amyloid and tau immunohistochemistry on serial sections. This study demonstrates for the first time that all layers of the OB are severely affected in AD and in normal ageing. The principal effector cells of the OB, the mitral cells, developed neurofibrillary tangles (NFTs) both in AD and in controls. All the cases, with the exception of two of the controls, contained NFTs. Amyloid immunoreactivity was detected in diffuse, primitive, classical and compact deposits in AD, while five control cases contained mainly diffuse deposits. We did not find a correlation between amyloid deposition and NFT formation. Among the control cases, two contained neither amyloid nor NFTs, eight had NFTs but no amyloid and only five had both NFTs and amyloid. All the AD cases had NFT and amyloid deposition. Our data suggest that the earlier pathology in the OB is NFT formation and more than ten NFTs/section is compatible with 93.3% diagnostic accuracy for AD.     

The frequency of apolipoprotein E4 allele is not increased in patients with probable vascular dementia

We used the NINDS-AIREN criteria to diagnose vascular dementia (VD), and compared apolipoprotein E (apoE) allele frequencies and apoE concentrations in serum and cerebrospinal fluid (CSF) between patients with possible (n=19) and probable (n = 33) VD and controls (n=105). There was no difference in apoE4 frequency between patients with probable VD and controls. Serum and CSF apoE concentrations did not differ between VD patients and contols. Our results suggest that apoE plays no role in the development of VD.     

Effect of statins on β-amyloid metabolism in humans: potential importance for the development of senile plaques in Alzheimer's disease

According to the amyloid cascade hypothesis, both familial and sporadic Alzheimer's disease (AD) is caused by the toxic effect of over-production and/or aggregation of β -amyloid (A β ). Recent cell and animal studies have linked the production of A β to high levels of cholesterol and the use of statins, compounds inhibiting the de novo synthesis of cholesterol. Epidemiological studies have also supported such linkage by showing a reduced prevalence of AD for subjects taking statins. A limited number of clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in AD in humans and this review focuses on the current state of these clinical studies. The results are contradictory, but the overall interpretation suggests that statin treatment probably does not have a direct impact through lowering of cholesterol on the APP processing and A β production in humans. To confirm this, further clinical studies needs to be performed with extended treatment periods and where several parameters (lipid profile, lipoproteins, sterols, biomarkers related to AD and APP metabolites) are analyzed, both in the cerebrospinal fluid and plasma. The pleiotropic effects of statins should be investigated further. One approach is presented in this review.     

Oligoclonal immunoglobulin bands in cerebrospinal fluid of patients with Alzheimer''s disease and vascular dementia

We examined serum and cerebrospinal fluid (CSF) of 16 patients with Alzheimer's disease (AD), 28 patients with vascular dementia (VD), their age-matched controls and multiple sclerosis (MS) patients in order to evaluate the humoral immune response within the central nervous system both quantitatively and qualitatively. Intra-blood-brain barrier (BBB) protein synthesis was calculated by CSF IgG index. The presence of oligoclonal banding (OCB) was investigated with agarose isoelectric focusing (IEF) followed by immunoblotting with antihuman IgG. No patient with AD and only 4 patients with VD had slightly elevated IgG indexes, and no statistically significant differences in the indexes were found between the two groups. No bands were found in the CSF of AD patients but 3 VD patients had OCB in both serum and CSF. One VD patient had bands in serum but no bands in CSF. No kappa or lambda free light chains were found in those demented patients with demonstrable bands in the CSF and serum. No OCB were found in control sera and CSF. For comparison, the majority of patients with MS had OCB in CSF. Thus, no consistent increase of intrathecal protein synthesis was found in patients with AD and VD. Methodological differences explain at least part of the conflicting results published earlier.     

Use of cerebrospinal fluid biomarkers in diagnosis of dementia across Europe

Background and purpose:  Cerebrospinal fluid (CSF) biomarkers have been reported to be useful in dementia diagnosis. Not much is known about their use in clinical practice in Europe.
Methods:  We analyzed data from a survey on the use of CSF biomarkers in the diagnosis of dementia across Europe using a questionnaire which was filled out by representatives of the 25 member countries of the European Federation of Neurological Societies (EFNS).
Results:  Cerebrospinal fluid beta-amyloid, total tau, and phosphorylated tau proteins are frequently evaluated in the majority of the countries (in 18 out of 23 countries). No major technical or ethical issues were found that would hamper the procedure's ability to become routine in early and differential diagnostics of Alzheimer's disease. Cut-off values for beta-amyloid (median 500, range 300–849 pg/ml), total tau (367; 195–450 pg/ml) and phosphorylated tau (60; 40–85 pg/ml) varied considerably amongst countries and even within every country.
Conclusions:  Cerebrospinal fluid analysis of beta-amyloid, tau, and phosphorylated tau is frequently used in Europe. However, the use of various cut off values seriously hampers comparability and yields a potential threat to an interpretation and balanced use in clinical practice. We recommend that each laboratory establishes normative data and that multi-centered studies should be organized to explore the reasons for any differences.     

Serum paraoxonase activity changes in patients with Alzheimer's disease and vascular dementia

The prevalence of Alzheimer's disease (AD) and vascular dementia (VAD) increases with aging of the population. The role of lipoproteins in the pathogenesis of AD is unclear: apoE₂ offers protection and apoE₃ is neutral, while apoE₄ promotes the development of the disease. Recently, several studies have confirmed the role of oxidative stress in the pathogenesis of AD and VAD. HDL-associated paraoxonase is one of the antioxidative enzymes that may reduce LDL oxidation. In our study, we investigated the lipid parameters of the sera and the serum paraoxonase activity in patients with AD and VAD. Lipid parameters were determined by an autoanalyzer in 30 AD patients, 40 VAD patients and 40 healthy, age-matched control (C) subjects. Paraoxonase activity was measured spectrophotometrically using paraoxon as the substrate. The phenotypic distribution of paraoxonase was determined by the dual substrate method, using paraoxon and phenylacetate as substrates. In our results, we found that most of the patients with AD had the apoE4 isoform, consistent with other studies. In the VAD and AD patients we found significantly higher total-cholesterol compared to the control group (C: 4.71 ± 0.89, VAD: 6.3 ± 0.8, AD: 6.52 ± 0.7 mmol/l; p < 0.01) and LDL-cholesterol levels (C: 2.6 ± 0.6, VAD: 3.96 ± 0.8, AD: 3.84 ± 0.6 mmol/l; p < 0.001). The HDL-associated antioxidant, paraoxonase activity did not differ significantly in the patient groups, but compared to the healthy control subjects, paraoxonase activity was significantly lower in both of the patient groups (C: 188 ± 55 U/l; AD: 131 ± 37, VAD: 151 ± 50 l; p < 0.05). Our results suggest that the defect in HDL-associated antioxidant capacity plays a role in the pathogenesis of Alzheimer's disease and vascular dementia. Received: 30 November 2001 / Accepted: 24 January 2002     

Defining dementia: clinical criteria for the diagnosis of vascular dementia

The recognition of cerebrovascular disease (CVD) as a contributing factor and a cause of dementia has led to the development of clinical criteria for vascular dementia (VaD). Due to high specificity, the consensus criteria developed by the National Institute for Neurological and Communicative Disorders and Stroke (NINDS)–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) have been used in controlled clinical trials to select patients with pure VaD. VaD is predominantly a subcortical frontal form of dementia with prominent executive dysfunction. In contrast, the criteria of the NINCDS–Alzheimer's Disease and Related Disorders Association (ADRDA) emphasize memory loss as the main feature to distinguish Alzheimer's disease (AD) from VaD and from other forms of dementia. Moreover, CVD may precipitate the clinical expression of AD. Although no criteria have been created specifically for patients having AD with CVD, the ischemic score, the Informant Questionnaire on Cognitive Decline in the Elderly and a history of prestroke mild cognitive impairment (MCI) may be useful for identifying patients with this mixed form of dementia.     

Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia

OBJECTIVES: The study aimed to increase understanding of behavioural changes in frontotemporal dementia (FTD) and identify features that best differentiate FTD from Alzheimer's disease (AD) and cerebrovascular dementia (CvD). METHODS: A semi-structured questionnaire was administered to carers of 30 FTD, 75 AD and 34 CvD patients. RESULTS: Behavioural changes that strongly discriminated FTD from AD and to a lesser extent CvD were loss of emotions and insight, selfishness, disinhibition, personal neglect, gluttony and sweet food preference, wandering, motor and verbal stereotypies, loss of pain, echolalia and mutism. Irritability, hyposexuality and hypersomnia did not discriminate. Emotional, eating and stereotyped behaviours correctly classified 95% of patients using regression analysis. CONCLUSIONS: Behavioural characteristics accurately differentiate FTD from AD and CvD. The findings highlight the particular importance of affective change in FTD, and underline the role of the frontotemporal lobes in emotion.     

Intrathecal synthesis of immunoglobulin G in vascular dementia

Serum and CSF from 53 vascular dementia (VD) patients and 50 controls were analysed to investigate the possibility of an intrathecal synthesis of IgG, defined as an elevated IgG index (greater than or equal to 7) and/or presence of oligoclonal IgG in cerebrospinal fluid (CSF), but not in serum. Five (9%) patients and no controls exhibited an intrathecal synthesis of IgG. The IgG index increased with the degree of dementia (p less than 0.05). It was positively related to presence/absence of hypertension (p less than 0.05) and correlated positively with diastolic blood pressure (p less than 0.05). The findings suggest that immunological factors might be involved in the pathogenesis of VD.     

The role of neuroimaging in the diagnosis of vascular dementia

Vascular dementia (VaD) and Alzheimer's disease share many pathological and clinical characteristics. Whereas clinical criteria can help differentiate VaD from other types of dementia, neuroimaging is required for confirmation of vascular lesions. Neuroimaging also provides information about location and size of vascular lesions that can lead to a better understanding of symptoms and may help guide therapy.     

Acetylcholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type

We have studied, as a possible marker of cholinergic neurons, the acetylcholinesterase (AChE) activity in cerebrospinal fluid (CSF) of 21 SDA patients and 9 controls of similar age with no neurological disease. The AChE activities were significantly lower in the SDA patients compared to the controls. The AChE activities were also lower in the most severely demented patients compared to those who were less severely demented but the difference was not statistically significant. As a potential glia marker, β-glucuronidase activity in CSF was studied, but no significant difference was found in the activities of the SDA patients compared to the controls.
The reduced AChE activities in the CSF of the SDA patients may be related to the loss of cholinergic neurons or disturbed cholinergic metabolism in the brain.     

Qualitative analyses of clock drawings in Alzheimer's disease and vascular dementia

Although quantitative analyses of clock drawings (CD) have achieved widespread clinical use as a cognitive screening, little is known about the qualitative profiles of CD in Alzheimer's disease (AD) and vascular dementia (VD). To address this issue, the present study examined the significance of qualitative analyses of CD in AD and VD. Sixty-seven AD patients, 44 VD patients and eight controls underwent a clock drawing test and took the Mini-Mental State Examinations (MMSE). In the dementia groups, quantitative scores significantly decreased compared with controls and were significantly correlated with MMSE scores. Qualitative analysis demonstrated that in AD patients qualitative error patterns were stable and independent of severity. In contrast, in VD patients the frequency of graphic difficulties and conceptual deficit increased, while the frequency of spatial and/or planning deficit decreased, as severity worsened. In mild dementia groups the frequency of spatial and/or planning deficit was significantly higher in VD. In moderate dementia groups, the frequency of graphic difficulties was significantly higher in VD and the difference in the frequency of spatial and/or planning deficit seen in mild dementia disappeared. The present study suggests that qualitative analyses of clock drawings could demonstrate the neuropsychological profiles of AD and VD and their differences between these dementias.     

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia

Summary The acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (r_s=0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (r_s=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.