The effects of small vessel disease and amyloid burden on neuropsychiatric symptoms: a study among patients with subcortical vascular cognitive impairments

Neuropsychiatric symptoms (NPS) affect the quality of life of patients with dementia and increase the burden on caregivers. We aimed to evaluate how small vessel disease (SVD) such as lacunae or white matter hyperintensities (WMH), and amyloid burden affect NPS. We recruited 127 patients with subcortical vascular cognitive impairment who were assessed with brain magnetic resonance imaging, Pittsburgh compound-B (PiB) positron emission tomography and the neuropsychiatric inventory (NPI). To explore the association between lacunae, WMH, or PiB retention ratio and NPS, we performed multivariate regression analysis after controlling for possible confounders. Each additional lacuna, especially in the frontal region, was associated with higher odds of depression, apathy, aberrant motor behavior, nighttime behavior, appetite changes, and higher score of total NPI; larger WMH volume, especially in the frontal region, was associated with higher odds of apathy and higher score of total NPI. Furthermore, for the effects of lacunae or WMH on total NPI score we set Clinical Dementia Rating Sum of Boxes as the mediator. Greater PiB retention ratio was associated with higher odds of delusions and irritability. The SVD and amyloid pathologies did not show interactive effects on NPS. Our findings suggested that SVD and amyloid burden independently affected specific NPS.     

Cognition, glucose metabolism and amyloid burden in Alzheimer's disease

The authors investigated relationships between glucose metabolism, amyloid load, and measures of cognitive and functional impairment in Alzheimer's disease (AD). Patients meeting criteria for probable AD underwent ¹¹C-labeled Pittsburgh Compound-B ([¹¹C]PIB) and 18F-fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) imaging and were assessed on a set of clinical measures. The Pittsburgh Compound-B (PIB) Distribution volume ratios and fluorodeoxyglucose (FDG) scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden, and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.     

The impact of cerebrovascular aging on vascular cognitive impairment and dementia

As human life expectancy rises, the aged population will increase. Aging is accompanied by changes in tissue structure, often resulting in functional decline. For example, aging within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular aging can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. In this review, we summarize recent findings on VCID, with a focus on vascular age-related pathologies and their contribution to the development of this condition.     

White matter hyperintensities predict amyloid increase in Alzheimer's disease

Impaired amyloid clearance probably contributes to increased amyloid deposition in sporadic Alzheimer's disease (AD). Diminished perivascular drainage due to cerebral small-vessel disease (CSVD) has been proposed as a cause of reduced amyloid clearance. White matter hyperintensities (WMHs) are considered to reflect CSVD and can be measured using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Amyloid deposition can be determined in vivo using Pittsburgh compound B ([(11)C]PiB) positron emission tomography (PET). We aimed to elucidate the association between WMH and the progression of amyloid deposition in patients with AD. Twenty-two patients with probable AD underwent FLAIR-MRI and [(11)C]PiB-PET examinations at baseline (BL) and after a mean follow-up (FU) interval of 28 months. The relationship between BL-WMH and the progression of cerebral amyloid between BL and FU was examined using a regions-of-interest (ROI) approach. The region-specific variability of this relationship was analyzed using a voxel-based method. The longitudinal analysis revealed a statistically significant association between the amount of BL-WMH and the progression of amyloid load between BL and FU (p = 0.006, adjusted R(2) = 0.375, standardized coefficient β = 0.384). The association was particularly observed in parieto-occipital regions and tended to be closer in regions adjacent to the brain surface. According to our knowledge, this is the first in vivo study in human being supporting the hypothesis that impaired amyloid clearance along perivascular drainage pathways may contribute to β-amyloid deposition in sporadic AD. The extent of WMH might be a relevant factor to be assessed in antiamyloid drug trials.     

Hippocampal and cortical atrophy in amyloid-negative mild cognitive impairments: comparison with amyloid-positive mild cognitive impairment

Although patients with amnestic mild cognitive impairment (aMCI) are at higher risk of developing Alzheimer's disease (AD), their pathologies could be heterogeneous. We aimed to evaluate structural changes in amyloid-negative and amyloid-positive aMCI patients. Forty-eight aMCI patients who underwent Pittsburgh compound B (PiB) positron emission tomography were recruited. They were classified as PiB (−) aMCI (N = 16) and PiB (+) (N = 32). Hippocampal shape and regional cortical thickness were compared with 41 subjects with normal cognition (NC). Relative to NC, PiB(−) aMCI exhibited hippocampal deformity in the right cornu ammonis 1, whereas PiB(+) aMCI exhibited hippocampal deformity in bilateral subiculum and cornu ammonis 1 subregions. Relative to NC, PiB(−) aMCI showed cortical thinning in the left medial prefrontal and right anterior temporal regions, whereas PiB(+) aMCI exhibited cortical thinning in bilateral medial temporal regions, temporoparietal junctions and precuneus, and prefrontal cortices. Our findings suggest that structural changes in PiB(−) aMCI might be due to several possible pathologic changes, whereas structural changes in PiB(+) aMCI reflect AD-like structural changes.     

Brain white matter damage in aging and cognitive ability in youth and older age

Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = ?0.14, p < 0.01) and processing speed (β = ?0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = ?0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging.     

Association of homocysteine with hippocampal volume independent of cerebral amyloid and vascular burden

This study aimed to clarify whether homocysteine has independent association, not mediated by cerebral beta amyloid protein deposition and vascular burden, with whole brain or hippocampal volume in elderly individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease. Nineteen mild cognitive impairment and 24 Alzheimer's disease patients were recruited from the Dementia Clinic of the Seoul National University Hospital. Fourteen cognitively normal elderly subjects were also selected from a pool of elderly volunteers. Multiple linear regression analyses showed that plasma total homocysteine level was significantly associated with hippocampal volume even after controlling the degree of global cerebral beta amyloid deposition and vascular burden as well as other potential confounders including age, gender, education, and apolipoprotein E ε4 genotype. On the contrary, plasma total homocysteine level did not show any significant association with whole brain volume. Our finding of the independent negative association between homocysteine and hippocampal volume suggests that homocysteine has a direct adverse effect, not mediated by cerebral beta amyloid deposition and vascular burden, on the hippocampus.     

Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease

Accumulation of amyloid beta peptide (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD); the underlying mechanism, however, is not well understood. In this study, we show that expression of plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), increases with age in the brain of wild type and Aβ precursor protein-presenilin 1 (APP/PS1) transgenic mice as well as in AD patients. Most importantly, we show that knocking out the PAI-1 gene dramatically reduces Aβ burden in the brain of APP/PS1 mice but has no effect on the levels of full-length APP, alpha or beta C-terminal fragments. Furthermore, we show that knocking out the PAI-1 gene leads to increases in the activities of tPA and plasmin, and the plasmin activity inversely correlates with the amounts of SDS insoluble Aβ40 and Aβ42. Together, these data suggest that increased PAI-1 expression/activity contributes importantly to Aβ accumulation during aging and in AD probably by inhibiting plasminogen activation and thus Aβ degradation.     

PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with ¹¹C-PIB, and ¹⁸F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps < 0.01). The PIB retention in MCI converters was comparable to AD patients (p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ_1-42, total Tau and episodic memory, respectively.     

A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.     

糖尿病对脑白质病变伴轻度认知功能障碍患者认知功能的影响

目的 探讨糖尿病与脑白质病变(WML)伴轻度认知功能障碍(MCI)患者认知功能减退的关系。方法 2012年1—12月在大坪医院神经内科住院病人中选择257例WML伴MCI患者进行前瞻性研究,随访时间为1年。收集患者血管危险因素(VRFs)及颅脑MRI检查结果,同时行神经心理学测试了解认知功能状态;根据1年内简易精神状态检查量表(MMSE)减少值分为认知功能下降组(≥3分)及无认知功能下降组(≤2分),并比较两组各种危险因素的差异。结果 257例中有246例(95.7%)患者完成了1年的观察随访过程,11例删失者中8例死亡、3例退出观察。246例中,认知功能下降组154例(62.6%),无认知功能下降组92例(37.4%);其中36例在观察期间发生卒中,余210例患者纳入线性回归分析。除受教育水平及血脂异常外,年龄、性别、高血压、糖尿病、短暂性脑缺血发作等各危险因素两组比较差异均有统计学意义 (P值均＜0.05)。糖尿病、基线WML程度及随访期间WML程度的加重与1年内MMSE减少值呈显著的线性关系,且对认知功能减退的影响由大至小依次为基线WML程度(β_j′=0.570)、随访期间WML加重程度(β_j′=0.244)、糖尿病(β_j′=0.171)。结论 糖尿病可使WML伴MCI患者认知功能进一步减退。重度WML伴MCI的糖尿病患者应作为痴呆的高危人群进行早期干预。     

Neuropep-1 ameliorates learning and memory deficits in an Alzheimer's disease mouse model,increases brain-derived neurotrophic factor expression in the brain,and causes reduction of amyloid beta plaques

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library. Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aβ_1–42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.     

PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition

The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimer's disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (Aβ) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on Aβ-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by Aβ₄₂ oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients.     

Detection of amyloid beta protein in the urine of Alzheimer's disease patients and healthy individuals

To seek for a new valid biomarker using non-invasive specimens for the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI), we carried out the detection of amyloid beta (Abeta) protein in urine. Ten-millilitre urine samples were first sedimented with trichloroacetic acid, and the pellets were resuspended for further analysis by Western blotting with anti-Abeta antibody. The detection sensitivity of the method was 40pg/ml. Rates of subjects positive for monomeric Abeta according to their clinical dementia rating (CDR) were 11.1% for CDR 0, 62.5% for CDR 0.5, 83.3% for CDR 1, 54.5% for CDR 2 and 0% for CDR 3. A single Abeta band relative to the CDR score reflects an alteration in the production, solubility and clearance of Abeta in the brain. Thus, the method could be used as both a diagnostic and monitoring tool in assessing AD and MCI patients during disease-modifying therapies.     

绞股蓝对海马注射Aβ1-40大鼠脑内细胞周期蛋白表达和钙稳态变化的影响

目的：探讨绞股蓝对海马注射Aβ₁-40大鼠脑内细胞周期蛋白异常表达和钙稳态变化的影响。方法： 动物随机分为绞股蓝组、模型组、对照组。运用淀粉样β蛋白双侧海马注射,模拟阿尔茨海默病脑内Aβ对神经系统的损害。Y型迷宫测试大鼠学习记忆能力,免疫组织化学染色和积分吸光度分析检测细胞周期蛋白A、B₁(cyclin A、cyclin B₁)，Fura-2/AM-荧光法测定海马细胞内Ca2＋含量；并对绞股蓝组大鼠给予绞股蓝皂苷灌胃，观察其对AD大鼠上述各项指标变化的影响。结果： Aβ₁-40海马注射大鼠学习记忆能力明显低于对照组(P＜0.05)，脑内细胞周期蛋白A、B₁蛋白水平明显高于对照组，海马神经元内Ca2＋含量显著高于对照组；而给予绞股蓝在一定程度上能改善大鼠学习记忆能力，降低cyclin A、cyclin B₁蛋白和Ca2＋含量的水平(P＜0.05)。结论：绞股蓝对Aβ引起的动物学习记忆能力减退、海马神经元内异常表达细胞周期蛋白和钙稳态失衡有一定的逆转作用。     

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta. We have measured Abeta40 and Abeta42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n=18). We observed a clear correlation between CSF and plasma levels for both Abeta40 and Abeta42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of Abeta42 in AD CSF, whereas there were no significant differences in plasma Abeta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma Abeta may be disrupted with the initiation of amyloid deposition in the brain.     

脑电近似熵、失匹配负波在检测帕金森病患者认知功能障碍中的评估作用

目的:对比帕金森病(PD)患者与对照组的脑电近似熵(ApEn)、失匹配负波(MMN)检查结果,分析两种方法在帕金森病患者认知功能障碍中的评估作用.方法:病例组15例、对照组36例受试对象均接受常规16信道脑电图检查,选用脑电非线性指数近似熵对安静闭眼、闭眼心算、安静睁眼三种状态下的原始脑电数据进行分析;并收集简易智力状态检查量表(MMSE)得分、MMN的潜伏期和波幅相关数据,运用统计学方法对两组结果进行分析.结果:①病例组与对照组MMN在Cz、Fz点的潜伏期差异虽然没有统计学意义,但从数值上可见病例组的潜伏期有延长趋势;两组在Cz、Fz点的波幅比较差异无统计学意义;②病例组与对照组脑电ApEn对比,只在闭眼心算时,两组于中央感觉运动区(C3)、顶叶(P3)、枕叶(O2)点的脑电ApEn差异有统计学意义,病例组较对照组测值降低.结论:脑电ApEn和MMN潜伏期都可作为认知功能的评价措施.并且闭眼心算状态的脑电ApEn评价效果的敏感性较MMN潜伏期强.三种状态下,闭眼心算的脑电ApEn评价效果最好.     

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aβ deposition; (3) enhanced astrocyte-mediated Aβ degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.     

Effects of sustained cognitive activity on white matter microstructure and cognitive outcomes in healthy middle-aged adults: A systematic review

Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes.