Relationship between neuronal loss and 'inflammatory plaques' in early onset Alzheimer's disease

We have previously described a novel 'inflammatory plaque' in the cortex of early onset Alzheimer's disease (EOAD) cases with presenilin 1 mutations (PS1). These plaques are associated with a significant inflammatory infiltrate consisting of reactive microglia and astrocytes. We speculated that these inflammatory plaques might be responsible for the more severe disease process seen in EOAD. In the present study using the superior frontal cortex, 63 EOAD cases with mutations in PS1, presenilin 2 (PS2) and amyloid precursor protein (APP) were categorized as either having inflammatory plaques (13 cases, two APP and 11 PS1) or not. To determine the impact on cell loss, seven EOAD cases with inflammatory plaques (EOIP) and seven EOAD cases without (EONIP) were selected and neuronal cell counts performed. These were compared with neuronal counts taken from the same cortical region of seven control and six sporadic AD cases. Cases with EOAD had significantly less neurones per field compared with sporadic AD and control cases (EOAD = 19.5 +/- 0.8 neurones/field, spAD = 23.7 +/- 1.2 neurones/field, controls = 30.37 +/- 1.2 neurones/field). However, no significant difference in the number of neurones per field was seen in EOAD cases with or without inflammatory plaque pathology (EOIP = 19.2 +/- 1.4, EONIP = 19.7 +/- 0.8). These data demonstrate that EOAD cases exhibit greater neuronal cell loss in the superior frontal cortex than sporadic AD and that this effect is independent of the presence or absence of inflammatory plaque pathology.     

Association between presenilin 1 intronic polymorphism and late onset Alzheimer's disease in the North Chinese population

The association between presenilin 1 intronic polymorphism (rs165932) and late onset Alzheimer's disease (LOAD) has been a matter of controversy. Within China, varied results have been reported. Therefore, we collected a large sample from the North Chinese population to test the association of the PS1 polymorphism with LOAD. AD patients (467 total, mean age=75.3+/-7.3, age at onset=70.2+/-5.1) and age-matched normal elderly controls (480 total) were recruited. Genotypes of PS1 and apolipoprotein E (APOE) were determined by PCR and RFLP. The results showed that there were significant differences in the distributions of both alleles (chi(2)=45.305, P<10(-5)) and genotypes (chi(2)=53.055, P<10(-5)) of PS1 gene between the AD and control groups. The APOE epsilon4 allele was more prevalent in patients than in controls (chi(2)=46.389, P<10(-5)). It was significantly different when PS1 alleles and genotypes were compared between AD and controls with APOE epsilon4 negative. However, no significance was found when PS1 alleles or genotypes were compared between AD and controls with APOE epsilon4 positive. Furthermore, with PS1 2/2 genotype as a reference, the odds ratios (ORs) of LOAD with PS1 1/2, 1/1+1/2 and 1/1 genotypes gradually increased allele 1 copy number, suggesting that allele 1 is a crucial risk for LOAD. In summary, we found an association between presenilin 1 intronic polymorphism and LOAD, but no influence of APOE epsilon4 on the distribution of the PS1 intronic polymorphism. In addition, the larger sample size raises the possibility that ethnic and regional differences in China may explain the differences in reported results.     

Quantitative EEG mapping and PET in Alzheimer's disease

Quantitative analysis of topographical EEG was studied in comparison with measurement of regional glucose metabolism by PET in 42 patients with clinical diagnosis of probable dementia of Alzheimer type (AD) and in 15 age-matched normal controls. Measures analyzed included global and regional data from areas typically affected and not affected by AD pathology. While disturbance of metabolism followed a typical regional pattern, relative alpha, theta and delta power were more globally altered without selectivity for specific regions. Separation between AD and age matched controls by relative theta power was correct in 86% and was close to that by temporo-parietal glucose metabolism (correct classification 87%). Relative theta power as well as temporo-parietal glucose metabolism were significantly correlated (τ_B = 0.54 and −0.53, respectively) to severity of AD assessed by the global deterioration scale. These results indicate that EEG measures may be used with an accuracy close to metabolic values from PET for the assessment of severity of AD.     

Progress in neuroimaging of Alzheimer's disease

The main purposes of neuroimaging in Alzheimer’s disease (AD) have progressed from diagnosis of advanced AD to diagnosis of very early AD at a prodromal stage of mild cognitive impairment (MCI), prediction of conversion from MCI to AD and differential diagnosis from other diseases causing dementia. Structural MRI studies and functional studies using FDG‐PET and brain perfusion SPECT are widely used in diagnosis of AD. Outstanding progress in the diagnostic accuracy of these neuroimaging modalities has been obtained using statistical analysis on a voxel‐by‐voxel basis after spatial normalization of individual scans to a standardized brain‐volume template instead of visual inspection or a conventional region of interest technique. In a very early stage of AD, this statistical approach revealed gray matter loss in medial temporal areas prominently in the entorhinal cortex and hypometabolism or hypoperfusion in the posterior cingulate cortex and precunei. These two findings might be related in view of anatomical knowledge that the regions are linked through the circuit of Papez. This statistical approach also offers a predictive value of conversion from MCI to AD and accurate evaluation of therapeutic effects on brain metabolism or perfusion. This development in functional and structural imaging might be an important surrogate marker for trials of disease‐modifying agents.     

Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer's disease.

BACKGROUND: Since the measurement of human cerebral glucose metabolism (GluM) by positron emission tomography (PET) and that of human cerebral electrical activity by EEG reflect synaptic activity, both methods should be related in their cerebral spatial distribution. Healthy subjects do indeed demonstrate similar metabolic and neuroelectric spatial patterns. OBJECTIVE: The aim of the study was to show that this similarity of GluM and EEG spatial patterns holds true in a population with a high variability of glucose metabolism. METHODS: We investigated healthy control subjects and patients with varying degrees of cognitive dysfunction and varying GluM patterns by applying [18F]FDG PET and EEG. RESULTS: We demonstrated that the localization of intracerebral generators of EEG correlates with spatial indices of GluM. CONCLUSION: These results indicates that EEG provides similar spatial information about brain function as GluM-PET. Since EEG is a non-invasive technique, which is more widely available and can be repeated more often than PET, this may have important implications both for neuropsychiatric research and for clinical diagnosis. However, further studies are required to determine whether equivalent EEG dipole generators can yield a diagnostic specificity and sensitivity similar to that of GluM-PET.     

Presence of parieto-temporal symptomatology distinguishes early and late onset Alzheimer's disease

Thirty-one patients with early onset Alzheimer's disease (EAD) and 44 with late onset Alzheimer's disease (LAD) were examined with regard to symptoms reflecting disturbances in various brain regions, ie frontal, parietal and subcortical symptoms. Clinical vascular factors were recorded. The albumin ratio (CSF albumin/serum albumin) was used as a measure of the blood-brain barrier (BBB) function. Parietal symptoms were more common in EAD than in LAD, both among mildly demented patients (60% in EAD, 10% in LAD; p<0.01) and among moderately demented patients (93% in EAD, 58% in LAD; p<0.01). Among moderately and severely demented patients, predominance parietal symptoms was more common in EAD (93%) than in LAD (26%) (p<0.01). Patients with predominant parietal symptoms had significantly lower age at onset, absence of concomitant diseases, and normal BBB function, and we suggest that they constitute the classical AD group. A symptom profile without parietal predominance was found to be associated with higher age at onset, presence of clinical vascular factors and impaired BBB function, suggesting that age-related and/or vascular factors may influence the symptomatology in this group.     

早发型阿尔茨海默病发病的可调控危险因素分析

目的分析早发型阿尔茨海默病(EOAD)患者发病的可调控危险因素,为EOAD的一级预防提供依据。方法选择福建省立医院神经内科自2015年1月至2020年4月收治的40例EOAD患者作为EOAD组,选择门诊同期体检、年龄、性别和受教育程度与EOAD组患者相匹配的健康对照者120例作为对照组。回顾性比较EOAD组与对照组人口学特征和临床资料,多因素Logistic回归分析确定EOAD发病的独立危险因素。结果与对照组比较,EOAD组患者伴有高血压、非外伤性牙齿松动和(或)脱落、颅脑外伤史、听力障碍、慢性应激和(或)焦虑及睡眠障碍者所占比例增高,差异均有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,高血压(OR=4.559,95%CI:1.523~13.643,P=0.007)、非外伤性牙齿松动和(或)脱落(OR=5.345,95%CI:1.989~14.346,P=0.001)、听力障碍(OR=9.336,95%CI:2.033~27.850,P=0.000)、慢性应激和(或)焦虑(OR=7.375,95%CI:2.612~20.822,P=0.000)以及睡眠障碍(OR=4.875,95%CI:1.520~15.625,P=0.002)是EOAD发病的独立危险因素。结论有高血压、非外伤性牙齿松动和(或)脱落、听力障碍、慢性应激和(或)焦虑及睡眠障碍者易发生EOAD,重视上述危险因素的筛查和干预可作为EOAD的一级预防策略。     

Patterns of neuropsychological impairment in mild dementia: a comparison between Alzheimer's disease and multi-infarct dementia

The objective was to investigate the clinical and psychometric differences between patients with dementia of Alzheimer type (DAT) and patients with multi-infarct dementia (MID), matched for age, sex, education, and severity. Sixteen patients with DAT, 16 patients with MID, and 30 healthy individuals, were drawn from a longitudinal study on aging and dementia. Subjects with medical or previous mental disorders were excluded. DAT and controls with focal brain abnormalities on magnetic resonance imaging (MRI) were excluded. Diagnosis of dementia was carried out according to DSM-III-R criteria. Dementia severity was staged using the Clinical Dementia Rating (CDR) scale, and only patients with a score of 0.5-1 on CDR were studied. The main outcome measures were quantitative clinical scales of the assessment of global mental status, depression and anxiety, as well as a wide battery of neuropsychological tests for the evaluation of executive/conceptual functions and memory, as well as attention verbal ability, and visuospatial skill functions. The performance of demented patients compared to normal controls was affected on all measurements except for depression and anxiety. DAT patients showed compared to MID patients a greater extent of impairment on tasks assessing verbal comprehension and memory while MID patients were more significantly impaired on measures of frontal lobe functioning. Clinically matched DAT and MID patients show a differential pattern of neuropsychological impairment when studied in an early stage of dementia and with a mild degree of severity. Such patterns might be of value for the development of clinical diagnostic criteria.     

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

Background:  Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned.
Methods:  We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls.
Results:  Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices.
Discussion:  We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD.