A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease.

Local inflammatory processes surrounding the amyloid plaques contribute to the progression and acceleration of the Alzheimer's disease (AD)-related neurodegeneration. Interleukin-6 (IL-6) is an inflammatory cytokine with possible involvement in the local immune response occurring in the central nervous system of AD patients. We tested the hypothesis as to whether a genetic polymorphism of the IL-6 gene (IL-6) modifies the age at onset and risk for sporadic AD. Our results support an association of the C allele of the IL-6 genotype with a delayed initial onset and reduced disease risk and indicate that genetically determined alterations of the immune response may modify the course of AD.     

Plasma levels of soluble receptor for advanced glycation end products in Alzheimer's disease

Background: A decreased plasma level of soluble form of the receptor for advanced glycation end products (sRAGE) in patients with Alzheimer's disease (AD) has been reported. However, no evidence has shown whether the sRAGE plasma level of AD patients may differentiate from other types of dementia. Methods: Our study assessed sRAGE concentrations in the following 121 individuals in Chongqing area: 36 patients with AD, 12 with vascular dementia (VaD), 14 with mixed dementia (MD), 24 with other dementia (OD) including Parkinson's disease dementia, frontotemporal dementia, paralytic dementia and 35 cognitively normal controls. The total plasma level of sRAGE was determined using sandwich ELISA method. Results: sRAGE concentration in AD is significantly decreased compared with healthy controls. However, the receiver operating characteristic curve analysis of sRAGE between the AD and the control shows a low diagnostic accuracy. Conclusions: Our results demonstrate that sRAGE may assist the diagnosis of AD from normal individuals, but cannot differentiate AD from VaD, MD or OD.     

Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease

Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.     

5—HT6受体基因多态性与阿尔茨海默病的关联分析

目的探讨中国上海地区汉族人群中5-HT6受体基因多态性与阿尔茨海默病(AD)的相互关系.方法应用聚合酶链式反应(PCR)-限制性片段长度多态性(RFLP)方法,在106例AD患者,87例血管性痴呆(VD)患者和140例正常健康人中观察了5-HT6受体基因多态性的分布,并对5-HT6受体基因多态性与阿尔茨海默病之间的关系进行探讨.结果①阿尔茨海默病与5-HT6受体基因的多态性之间无显著意义的关联(P＞0.05);②在将受试人群进行ApoE基因分型后,ApoEε4型与非ApoEε4型人群中AD与5-HT6受体基因各基因型或等位基因均无关联(P＞0.05);③将AD患者进行ApoE基因分型后,非ApoEε4型AD与5-HT6的267C/T基因型正相关(OR=2.46,95%CI5.43-1.11,P＜0.05).结论中国上海地区汉族人群中5-HT6受体基因多态性与非ApoEε4型阿尔茨海默病相关联,表现为C/T型频率的升高.     

抽动秽语综合征患者血清自身抗体与可溶性白介素-6受体表达

目的探讨抽动秽语综合征（TS）患者疾病过程中免疫损伤的相关机制。方法应用抗脑抗体（ABAb）、抗核抗体（ANA）、可溶性白介素-6受体（sIL-6R）及可溶性gp130（sgp130）的ELISA方法商品试剂盒,检测患者和正常人血清中sIL-6R、sgpl30及相应抗体的含量。结果TS组血清sIL-6R、sgp130含量显著高于正常对照组（44．078±15．777）：（30．290±9．048）,P〈0．01;（69．032±24．604）：（47．309±14．137）,P〈0．01）;TS患儿血清ABAb、ANA检出率显著高于对照组（66．7％：3．6％,P〈0．01;53．3％：25％,P〈0．05）。且ABAb水平与sgpl30负相关（r=-0．451,P=0．046）。结论在TS患者血清中sIL-6R、sgp130水平显著增高表明依赖IL-6信号传导的生理功能上调和反馈抑制的网络机制启动;自身免疫相关的损伤机制参与了疾病发生发展的病理生理过程。     

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer''s disease

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.     

The insulin gene VNTR polymorphism in Alzheimer's disease: results of a pilot study

Summary. Insulin (INS) and insulin-like growth factors include different polypeptides involved in growth and development. Possibly they play a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). A variable number of tandem repeats (VNTR) polymorphism at the human INS 5′-flanking region consisting of three distinct allele classes has been shown to influence the tissue-specific expression of INS and the insulin-like growth factor 2 (IGF-2). Since alterations in the expression of INS or IGF-2 might be relevant in AD, we investigated the association between the INS VNTR polymorphism and the risk for AD. We found no association between the INS VNTR genotype and the risk for AD (p = 0.873). However, survival analysis revealed that class III homozygotes of the INS VNTR polymorphism had an earlier initial onset in patients suffering from early AD (p = 0.002). Our preliminary results suggest, that genetically determined alterations of the INS/IGF-2 metabolism might modify the course of AD. Further studies are warranted to confirm these data in larger study samples. Received June 7, 2001; accepted February 14, 2002     

Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes

The morphological components of cerebral white matter disease (WMD) were studied in 17 cases of clinically diagnosed dementia and neuropathologically verified Alzheimer's disease (AD) with concomitant WMD. The distribution of grey and white matter changes was evaluated and overall as well as regional severity was graded. Total glial numbers in frontal white matter were counted using a light microscope. Oligodendrocyte and astrocyte quantities as well as astrocytic reactivity were assessed from frontal and parietal lobe white matter using a computer assisted morphometric method. The AD-WMD group was compared with 10 nondemented age-matched controls. Astrocyte/oligodendrocyte ratio (AOR) was calculated, total glial counts and AOR were compared with severity of WMD, and Alzheimer encephalopathy grade was subjectively assessed. Astrocytic numbers, AOR and astrocytic reactivity proved to be significantly higher in the demented group, whereas oligodendrocytic and total glial counts were significantly lower. Furthermore, AOR proved to be positively correlated with severity of WMD, whereas no association was found with Alzheimer encephalopathy. We conclude that WMD in dementia, for example, of the type seen in AD, can easily be detected, measured and graded quantitatively, with AOR being a significant indicator of the severity of changes. This could serve as a tool for differentiating white matter pathologies in dementia and may be the basis for recognition of the mildest white matter changes with new imaging methods, and enable potential clinical intervention.     

Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer's disease and dementia

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia. Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A sub-set of the population (n = 723) with serum measurements of CRP and IL6 was included in 1) a nested case-control study of incident dementia cases, and 2) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and gender-matched controls, OR 2.24 (95% CI 1.27-3.95), p-value 0.006. In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age- and gender-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias.     

Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease

Introduction - Inflammatory processes are suspected in the pathomechanism of Alzheimer's dementia (AD) but the serum and cerebrospinal fluid (CSF) levels of inflammatory cytokines are not yet determined in the different forms of the disorder. Subjects and methods - Interleukin-6 (IL-6) levels were examined in the sera and CSF of patients with mild-moderate and severe stage of late onset sporadic type of AD and in the sera of demented Down syndrome (DS) probands with similar stages of AD and compared with data of age-matched healthy controls. Results - Normal serum IL-6 levels were found in the mild-moderate stage, but significantly increased levels were found in the severe stage of both dementia groups. The CSF concentrations remained within the normal range in all groups. Positive correlations between the serum IL-6 levels and age and the severity of the disease were present. Conclusion - These findings suggest a disease stage dependent general activation of the immune system both in sporadic AD and in DS with AD.     

Magnetoencephalographic analysis of cortical activity in Alzheimer's disease: a pilot study.

OBJECTIVES: In the present study, MEG was used to analyze spectral power and reference-free coherence in patients with probable Alzheimer's disease (AD).METHODS: Sixty-one channel MEG was recorded in 5 AD patients and 5 age-matched controls at rest with eyes open and eyes closed, as well as during the performance of two different mental tasks. Artefact-free epochs were selected for the analysis of power and coherence values in each of 5 4-Hz wide frequency bands ranging from 2 to 22 Hz.RESULTS: In AD patients, the absolute low frequency magnetic power was significantly and rather diffusely increased relative to controls with a fronto-central maximum. High frequency power values were significantly decreased over the occipital and temporal areas. Reactivity to eye-opening and mental tasks was reduced in the patient group. Relative to controls, a general decrease of MEG coherence values, including all frequencies analyzed, was found in AD patients.CONCLUSIONS: These observations confirm the pattern of changes in spectral power and reactivity known from EEG studies and suggest that coherence decreases in AD patients are widespread and include frequencies outside the alpha band.     

Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.     

Association of estrogen receptor alpha gene with Alzheimer's disease: a case-control study

Recent experimental data have offered the biological background to study the estrogen receptor (ER) alpha gene as a candidate gene for AD. Genetic association studies proposed ERalpha PvuII and XbaI gene polymorphisms as susceptibility factors for AD, although subsequent studies did not replicate this finding. To verify this association in a Caucasian Italian sample, we conducted a case-control study in a dataset of 172 clinic-based probable AD cases and 172 age- and sex-matched controls. Possible interaction between ERalpha polymorphisms and sex, age at onset of AD or apolipoprotein E (APOE) was examined. The xx-genotype of the XbaI polymorphism was associated with the risk of developing AD in the total sample (OR 1.9, 95% CI [1.2-3.1]). The risk increased in women (OR 2.3, 95% CI [1.3-4.2]), and in subjects with late-onset AD (OR 2.1, 95% CI [1.2-3.5]). PvuII polymorphism did not contribute to the risk of AD. There was no evidence for a statistical interaction between the APOE and either the PvuII and XbaI polymorphisms. This result shows that ERalpha XbaI polymorphism is an additional risk factor for women with late-onset AD.     

Discriminant power of combined cerebrospinal fluid τ protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease

Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of τ protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that τ protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF τ protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.     

Neuroleptic-induced extrapyramidal symptoms and serum calcium levels. Results of a pilot study

In a prospective study, the association between neuroleptic-induced extrapyramidal symptoms (EPS) and serum calcium levels with special regard to ionized calcium was investigated. The sample included 24 newly admitted psychotic patients who received neuroleptic treatment. The 11 patients in whom EPS developed had significant lower ionized calcium levels and a significant lower ionized calcium/total calcium ratio in the predrug period than the 13 patients without EPS. The difference in predrug total calcium between the same two groups did not reach significance. There was no decrease of calcium levels at the time of onset of EPS. pH values showed a significant negative correlation to ionized calcium levels. Protein levels were within the normal limits during neuroleptic treatment.     

Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients

OBJECTIVES: Neprilysin (NEP) is an amyloid beta-peptide (Abeta) degrading enzyme expressed in the brain, and accumulation of Abeta is the neuropathological hallmark in Alzheimer's disease (AD). In this study we investigated whether polymorphisms in the NEP gene have an effect on the risk for AD. METHODS: The frequencies of seven single nucleotide polymorphisms (SNPs) and apolipoprotein E (APOE) were assessed in 390 AD patients and 468 cognitively healthy controls. Genotypes of the study groups were compared using binary logistic regression analysis. Haplotype frequencies of the SNPs were estimated from genotype data. RESULTS: Two SNPs, rs989692 and rs3736187, had significantly different allelic and genotypic frequencies (uncorrected p = 0.01) between the AD and the control subjects and haplotype analysis showed significant association between AD and NEP polymorphisms. CONCLUSION: Taken together, these findings suggest that polymorphisms in the NEP gene increase risk for AD and support a potential role for NEP in AD.     

Randomized pilot study of nimesulide treatment in Alzheimer's disease

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID) may be useful in the treatment of AD. Clinical and laboratory experience with nimesulide, an NSAID with preferential cyclooxygenase-2 inhibition, suggests that it may be a good candidate for AD therapy. METHODS: This pilot study investigated the clinical feasibility of nimesulide treatment in AD. Forty persons with probable AD, most of whom were taking cholinesterase inhibitors, were enrolled in a randomized, controlled, parallel-group trial designed to assess tolerability and short-term cognitive/behavioral effects of nimesulide. In the initial 12-week double-blind phase, participants were treated with nimesulide 100 mg by mouth twice daily or matching placebo; during the second 12-week phase all participants received active drug. Participants who tolerated the drug well and perceived benefit were invited to continue open-label nimesulide treatment. RESULTS: Short-term therapy with nimesulide, compared with placebo, had no significant effect on total assessment scores of measures of cognition, clinical status, activities of daily living, affect, and behavior. Long-term therapy was well tolerated for periods exceeding 2 years. CONCLUSION: These findings support the feasibility of nimesulide therapy in AD; assessment of efficacy will require a larger, long-term treatment study.     

Neurologic signs in Alzheimer's disease. Results of a prospective clinical and neuropathologic study.

Neurologic signs and their neuropathologic correlates were examined in a sample of 56 patients with autopsy-proved Alzheimer's disease (13 men, 43 women; mean age at death, 83.1 years; range, 67 to 96 years) from a prospective longitudinal study. Full-range regular rigidity with cog-wheeling was found in 20 patients and was significantly associated with lower neuron counts in the substantia nigra and with the presence of Lewy bodies in the brain stem and neocortex. Twelve patients with myoclonus had a younger age at onset, a lower age at death (mean, 78.6 years), and lower neuron counts in the serotoninergic dorsal raphe nucleus and in the noradrenergic locus coeruleus than did the patients without myoclonus. Generalized motor seizures were reported in six patients, and they had significantly lower counts of pyramidal cells in cortical layers III through IV of the parietal cortex (area 7) and slightly decreased pyramidal cell numbers in the parahippocampal gyrus (area 28). The 19 patients with a positive grasp reflex had an earlier onset of illness and a significantly inferior performance on the Mini-Mental State examination and Cambridge Cognitive Examination tests. They, and 25 patients with a positive snout reflex, had significantly lower counts of large pyramidal cells in layers III through V of the frontal cortex (area 32). These results indicate that different neurologic symptoms in Alzheimer's disease can be related to disproportionate neuronal degeneration in functionally different brain areas.     

A pilot study of low-dose L-deprenyl in Alzheimer's disease

The use of low-dose L-deprenyl, a selective MAO-B inhibitor, in Alzheimer's disease patients has been associated previously with improvements in agitation and episodic learning and memory. Behavioral, cognitive, and regional electroencephalogram (EEG) measures were obtained in a 4-week open pilot study of 14 patients with probable Alzheimer's disease by NINCDS criteria who were administered 10 mg L-deprenyl per day. L-Deprenyl administration was associated with significant improvements on the agitation and depression factors of the Brief Psychiatric Rating Scale, the Cornell Scale for Depression in Dementia, and spouses' blind ratings. Recall improved on the Buschke Selective Reminding Task, but intrusions also tended to increase; verbal fluency decreased. Absolute EEG delta measures were selectively suppressed in the right frontal region. The pattern of changes suggests that L-deprenyl may be associated with improvement in behavioral and cognitive performance, in part through a mild behavioral disinhibiting effect.     

Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer's disease.

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. In previous studies, we have demonstrated intrathecal production of the proinflammatory cytokine tumor necrosis factor (TNF)alpha in patients with Alzheimer's disease (AD). The aim of the present study was to investigate the downstream products of TNF-alpha expression including interleukin (IL)1beta and its naturally occurring antagonist IL-1 receptor agonist (ra) in patients with AD. The cytokine levels were related to neuronal damage, as measured by intrathecal tau and beta-amyloid concentration and certain clinical features of the disease. Fifty-two patients with AD and 25 healthy controls were analyzed with respect to cerebrospinal fluid (CSF) levels of IL-1beta and IL-1ra. CSF IL-1beta was neither detectable in CSF of AD nor in control CSF. In contrast, a significantly lower (p < 0.01) number of patients (24 of 49) than of controls (20 of 24) showed detectable levels of IL-1ra in the CSF. The intrathecal levels of IL-1ra were significantly lower in patients with AD than in the controls. Our study demonstrates a decreased production of the anti-inflammatory compound IL-1ra, suggesting a propensity towards inflammation in patients with AD.