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.     

Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment

The aim of the study was to understand: (i), how far anticipatory postural adjustments (APA) participate in the sequences of a complex task; (ii), how, in the sagittal plane, horizontal and vertical progressions of the center of gravity (CG) are managed to achieve the prescribed goal. A posturo-kinetics sequence is identified during which forward CG progression is controlled in terms of a center of pressure (CP)-CG interaction. CP shifts and horizontal CG accelerations are correlated in timing and amplitude. There exists a control of whole body progression during the impulse, implying a braking of forwards movement. Vertical and horizontal CG accelerations are inter-dependent, and backward CP shift duration is related to its forward displacement. During the vertical jump initiation, whole body vertical propulsion and forward fall are linked. To increase impulse amplitude, initial whole body disequilibrium is lengthened and forward CG acceleration is greater. APA programming is probably elaborated on the basis of cognitive evaluation of the antero-posterior disturbance.     

Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75(NTR), which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422+ neurons increased in number, p75(NTR)+ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank NFT deposition.     

Associations between sleep duration and cognitive impairment in mild cognitive impairment

The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N = 50) or mild cognitive impairment (MCI; N = 121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population‐based cohort in the island of Crete, Greece (3140 older adults aged >60 years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3‐day 24‐hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24‐hr total sleep time (TST) compared to the MCI and NI groups. Long 24‐hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non‐memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.     

Increased tau protein differentiates mild cognitive impairment from geriatric depression and predicts conversion to dementia

Significantly increased cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated at threonine 181 tau (p-tau) levels were frequently found in patients with mild cognitive impairment (MCI) who have an increased risk of developing Alzheimer's disease (AD). Though MCI often overlaps with depressive symptoms making early diagnosis difficult, to date no CSF marker has been probed to support the differential diagnosis of geriatric major depressive disorder and MCI eventually converting to AD. CSF levels of t-tau and p-tau were determined by ELISA in 80 subjects with MCI (aging associated cognitive decline criteria), 54 patients with major depression and 24 cognitively healthy controls. Patients were reassessed after a follow-up period of at least 12 month. During follow-up, 29% of the MCI patients but only one patient with major depression converted to AD. Already at baseline converters to AD were characterized by significantly higher t-tau and p-tau levels compared to non-converters and the other diagnostic groups. Our findings demonstrate that both, CSF t-tau and p-tau levels facilitate the differential diagnosis of MCI and are of prognostic value.     

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.     

Cognitive estimation impairment in Alzheimer disease and mild cognitive impairment

Intact executive functioning is believed to be required for performance on tasks requiring cognitive estimations. This study used a revised version of a cognitive estimations test (CET) to investigate whether patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) were impaired on the CET compared with normal elderly controls (NECs). Neuropsychological tests were administered to determine the relationship between CET performance and other cognitive domains. AD patients displayed impaired CET performance when compared with NECs but MCI patients did not. Negative correlations between tests of working memory (WM) and semantic memory and the CET were found in NECs and AD patients, indicating that these cognitive domains were important for CET performance. Regression analysis suggests that AD patients were unable to maintain semantic information in WM to perform the task. The authors conclude that AD patients display deficits in working memory, semantic memory, and executive function, which are required for adequate CET performance.     

Structural correlates of mild cognitive impairment

The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.     

Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice

Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased CNS. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow–derived cells and by its direct actions on CNS cells. The overall objective of the study was to determine if G-CSF administration in a mouse model of Alzheimer's disease (AD) (Tg APP/PS1) would impact hippocampal-dependent learning by modifying the underlying disease pathology. A course of s.c. administration of G-CSF for a period of less than three weeks significantly improved cognitive performance, decreased β-amyloid deposition in hippocampus and entorhinal cortex and augmented total microglial activity. Additionally, G-CSF reduced systemic inflammation indicated by suppression of the production or activity of major pro-inflammatory cytokines in plasma. Improved cognition in AD mice was associated with increased synaptophysin immunostaining in hippocampal CA1 and CA3 regions and augmented neurogenesis, evidenced by increased numbers of calretinin-expressing cells in dentate gyrus. Given that G-CSF is already utilized clinically to safely stimulate hematopoietic stem cell production, these basic research findings will be readily translated into clinical trials to reverse or forestall the progression of dementia in AD. The primary objective of the present study was to determine whether a short course of G-CSF administration would have an impact on the pathological hallmark of AD, the age-dependent accumulation of Aβ deposits, in a transgenic mouse model of AD (APP+ PS1; Tg). A second objective was to determine whether such treatment would impact cognitive performance in a hippocampal-dependent memory paradigm. To explain the G-CSF triggered amyloid reduction and associated reversal of cognitive impairment, several mechanisms of action were explored. (1) G-CSF was hypothesized to increase activation of resident microglia and to increase mobilization of marrow-derived microglia. The effect of G-CSF on microglial activation was examined by quantitative measurements of total microglial burden. To determine if G-CSF increased trafficking of marrow-derived microglia into brain, bone marrow–derived green fluorescent protein-expressing (GFP+) microglia were visualized in the brains of chimeric AD mice. (2) To assess the role of immune-modulation in mediating G-CSF effects, a panel of cytokines was measured in both plasma and brain. (3) To test the hypothesis that reduction of Aβ deposits can affect synaptic area, quantitative measurement of synaptophysin immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers of calretinin-expressing cells were determined in dentate gyrus.     

轻度认知功能障碍患者的语义记忆损害与神经调控

文题释义：轻度认知障碍：是介于正常衰老与痴呆的过渡状态,是相对于年龄与教育程度的记忆或其他认知功能减退,记忆力、语言功能、注意力、执行能力等不同认知领域的减退,以记忆力减退为最常见的临床表现。国际轻度认知功能障碍工作组在2003年制定了轻度认知障碍的诊断标准：①有认知主诉,本人或知情者提供的认知功能障碍线索;②有认知功能损害的客观证据,选用蒙特利尔认知评估量表进行评分,高中及以上文化程度者≤26分,初中及以下文化程度者≤25分,且主要表现为记忆项异常者;③日常生活能力正常或仅有复杂日常能力轻度减退;④简易认知状态量表≥24分,不符合精神疾病的诊断和统计手册第四版诊断为痴呆的标准。语义记忆：包括对词语的意义、概念与事实的记忆。语义记忆涉及概念和实际知识是储存。广义上语义记忆包括对世界的所有认识。严格意义上的语义记忆,则是根据命名、分类任务判定。语义记忆障碍的患者表现为对熟悉的物品命名障碍。轻度的可能表现为语义分类词生成的减少,而严重的语义记忆障碍则表现为告知物品用途也不能进行命名,或给予名称也不能说出物品的用途,严重者可能表现为常识的缺失。 背景：阿尔茨海默病是一种进行性神经系统退化疾病,以认知下降为主要特点。认知力下降会导致老年人逐渐失去自我照料的能力,影响日常生活和活动。轻度认知障碍作为阿尔茨海默病的前驱状态,尽早对轻度认知障碍进行诊断和治疗,对预防阿尔茨海默病发展有重大的意义。 目的：针对轻度认知障碍语义记忆障碍评估与治疗的发展及未来前景做一综述。 方法：应用计算机在PubMed、Web of Science和中国知网、万方等数据库检索轻度认知障碍语义记忆评估、治疗的相关研究,检索关键词为“mild cognitive impairment,semantic memory impairment,semantic memory deficit,语义记忆,轻度认知功能障碍,轻度认知损害”,检索时间为2009年1月至2019年11月。结果与结论：语义记忆障碍为轻度认知障碍的主要临床症状之一,有一定的特异性。目前有不同类型的记忆量表可作为轻度认知障碍语义记忆障碍的神经心理学测量,颞叶、额叶和前运动区可能参与语义记忆环路。针对性的语义记忆神经生理学及辅助检查,靶向进行语义记忆康复训练,可利于早期识别轻度认知障碍的发生与转化。 ORCID: 0000-0002-2121-1523(关汉添) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Reduced interhemispheric inhibition in mild cognitive impairment

In mild cognitive impairment (MCI), the corpus callosum is known to be affected structurally. We evaluated callosal function by interhemispheric inhibition (IHI) using transcranial magnetic stimulation (TMS) in MCI patients. We investigated 12 amnestic MCI patients and 16 healthy age-matched control subjects. The IHI was studied with a paired-pulse TMS technique. The conditioning TMS was given over the right primary motor cortex (M1) and the test TMS over the left M1. Motor evoked potentials were recorded from the relaxed first dorsal interosseous muscle. We also studied other motor cortical circuit functions; short-latency afferent inhibition (SAI), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Both the amount of IHI and SAI were significantly reduced in MCI patients as compared with control subjects, whereas SICI or ICF did not differ between them. The degree of IHI significantly correlated with neither the mini-mental state examination score nor the degree of SAI. Our results suggest that transcallosal connection between bilateral M1 is primarily involved in MCI, regardless of SAI dysfunction.     

Vascular predictors of cognitive decline in patients with mild cognitive impairment

Our aim in this study was to assess the relationship between the state of cerebral vessels and the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We included 117 MCI patients. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). After a 12-month follow-up period, neuropsychological examinations demonstrated a progression to dementia in 21 patients. Pathological values of BHI and IMT significantly increased the risk of conversion (BHI: odds ratio, 5.80; 95% confidence interval, 1.83-18.37, p < 0.05; IMT: odds ratio, 3.08; 95% confidence interval, 1.02-9.33; p < 0.05, multinomial logistic regression analysis). Comparison between patients with all normal values and those with the simultaneous alteration of the 2 vascular indexes showed an increase in the risk of conversion from 9% to 33% (ordinal regression analysis). Our findings show that alterations of cerebral vessel functional and anatomic status increase the risk of conversion from MCI to dementia.     

Cholinergic system function and cognition in mild cognitive impairment

Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N-[(11)C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function.     

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.     

CSF cortisol in Alzheimer's disease and mild cognitive impairment

Hypercortisolaemia occurs in Alzheimer's disease (AD) and may be involved in the AD related neurodegenerative process. In order to determine whether brain structures are exposed to high cortisol concentrations early in AD, we measured cerebrospinal fluid (CSF) cortisol in 66 subjects with AD, 33 subjects with mild cognitive impairment (MCI) and 34 control subjects. CSF cortisol concentrations were higher in AD subjects compared to controls (p<0.001) and to MCI subjects (p=0.002). There was no significant increase of cortisol in MCI subjects compared with controls suggesting that the increase of CSF cortisol is not an early event in the course of AD.     

Association of the interleukin 1 beta gene and brain spontaneous activity in amnestic mild cognitive impairment

Purpose

The inflammatory response has been associated with the pathogenesis of Alzheimer’s disease (AD). The purpose of this study is to determine whether the rs1143627 polymorphism of the interleukin-1 beta (IL-1β) gene moderates functional magnetic resonance imaging (fMRI)-measured brain regional activity in amnestic mild cognitive impairment (aMCI).

Methods

Eighty older participants (47 with aMCI and 33 healthy controls) were recruited for this study. All of the participants were genotyped for variant rs1143627 in the IL1B gene and were scanned using resting-state fMRI. Brain activity was assessed by amplitude of low-frequency fluctuation (ALFF).

Results

aMCI patients had abnormal ALFF in many brain regions, including decreases in the inferior frontal gyrus, the superior temporal lobe and the middle temporal lobe, and increases in the occipital cortex (calcarine), parietal cortex (Pcu) and cerebellar cortex. The regions associated with an interaction of group X genotypes of rs1143627 C/T were the parietal cortex (left Pcu), frontal cortex (left superior, middle, and medial gyrus, right anterior cingulum), occipital cortex (left middle lobe, left cuneus) and the bilateral posterior lobes of the cerebellum. Regarding the behavioral significance, there were significant correlations between ALFF in different regions of the brain and with the cognitive scores of each genotype group.

Conclusions

The present study provided evidence that aMCI patients had abnormal ALFF in many brain regions. Specifically, the rs1143627 C/T polymorphism of the IL1B gene may modulate regional spontaneous brain activity in aMCI patients.

     

Dietary ketosis enhances memory in mild cognitive impairment

We randomly assigned 23 older adults with mild cognitive impairment to either a high carbohydrate or very low carbohydrate diet. Following the 6-week intervention period, we observed improved verbal memory performance for the low carbohydrate subjects (p = 0.01) as well as reductions in weight (p < 0.0001), waist circumference (p < 0.0001), fasting glucose (p = 0.009), and fasting insulin (p = 0.005). Level of depressive symptoms was not affected. Change in calorie intake, insulin level, and weight were not correlated with memory performance for the entire sample, although a trend toward a moderate relationship between insulin and memory was observed within the low carbohydrate group. Ketone levels were positively correlated with memory performance (p = 0.04). These findings indicate that very low carbohydrate consumption, even in the short term, can improve memory function in older adults with increased risk for Alzheimer's disease. While this effect may be attributable in part to correction of hyperinsulinemia, other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism also may have contributed to improved neurocognitive function. Further investigation of this intervention is warranted to evaluate its preventive potential and mechanisms of action in the context of early neurodegeneration.