Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age‐matched controls

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5–21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3–5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the ?308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located ～ 10.5 kb upstream of TNF. When these two alleles were combined with the TNF ?238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby. © 2001 Wiley‐Liss, Inc.     

Cytogenetic studies of familial and sporadic Alzheimer disease

We present cytogenetic findings in 7 familial and 5 sporadic Alzheimer disease (AD) patients and 34 unaffected relatives, spouses, and normal controls. Our study was prompted by reports of increased chromosome abnormalities in patients and family members at risk for AD. Coded peripheral blood chromosome preparations were evaluated for aneuploidy, aberration rates, and banding patterns. Statistical analyses of our results showed no increase in aneuploidy or aberrations in AD patients, their relatives, or normals. Chromosome loss or gain in aneuploid cells was not specific except in two individuals. These two older persons studied, one with AD and one unaffected, were observed to have increased sex chromosome aneuploidy. This finding was attributed to aging and was not considered to be an effect of AD.     

Neuroprotective effects of IGF-I against TNFalpha-induced neuronal damage in HIV-associated dementia

Human immunodeficiency virus type 1 (HIV-1) infection often results in disorders of the central nervous system, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNFalpha) released by activated and/or infected macrophages/microglia plays a role in the process of neuronal damage seen in AIDS patients. In light of earlier studies showing that the activation of the insulin-like growth factor I receptor (IGF-IR) exerts a strong neuroprotective effect, we investigated the ability of IGF-I to protect neuronal cells from HIV-infected macrophages. Our results demonstrate that the conditioned medium from HIV-1-infected macrophages, HIV/CM, causes loss of neuronal processes in differentiated PC12 and P19 neurons and that these neurodegenerative effects are associated with the presence of TNFalpha. Furthermore, we demonstrate that IGF-I rescues differentiated neurons from both HIV/CM and TNFalpha-induced damage and that IGF-I-mediated neuroprotection is strongly enhanced by overexpression of the wt IGF-IR cDNA and attenuated by the antisense IGF-IR cDNA. Finally, IGF-I-mediated antiapoptotic pathways are continuously functional in differentiated neurons exposed to HIV/CM and are likely supported by TNFalpha-mediated phosphorylation of I(kappa)B. All together these results suggest that the balance between TNFalpha and IGF-IR signaling pathways may control the extent of neuronal injury in this HIV-related experimental setting.     

Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration

Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of frontal regions are features characterizing both NHD and other kinds of neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD), and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide Polymorphisms (SNPs) in TREM2 coding region were screened by allelic discrimination in a population of probable AD patients as well as FTLD patients as compared with age-matched controls. In addition, mutation scanning of the coding region of TREM2 gene was carried out in 7 patients with early onset AD (EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either in patients or controls. Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms. These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes.     

阿尔茨海默病、阿尔茨海默病混合型及血管性痴呆患者心理及行为症状的比较

目的 比较阿尔茨海默病(Alzheimer Disease，AD)、AD混合型痴呆(Mixed dementia，MD)、血管性痴呆(Vascular dementia，VD)心理和行为症状(Psychological and behavioral symptoms of dementia，PBSD)的特征。方法 AD、MD及VD患者各30名参加本研究。采用Alzheimer病行为症状评定量表(The Begavioral Pathlolgy in Alzheiner Disease Rating Scale，BEHAVE—AD)、Cohen—Masfield激惹性问卷(The Cohen Mansfield Agitation Inventory，CMAI)评定痴呆患者BPSD。结果 AD患者激惹、焦虑与恐惧发生率较高，VD患者无目的游荡发生率、严重程度较低，MD患者BPSD症状无特异性。结论 AD、VD患者BPSD症状有特异性，MD患者BPSD表现无特异性。     

Infrared spectroscopy: A new diagnostic tool in Alzheimer disease

Biological markers play an evolving role in the diagnosis of Alzheimer disease (AD). We compare conventional measurements of cerebrospinal fluid (CSF) tau and β-amyloid_1–42 proteins to a novel approach – Fourier transformed infrared (FT-IR) spectroscopy – a simple technique derived from chemical and physical sciences that characterizes intramolecular bonds. For automatic diagnostic analysis, we developed an artificial neural network (ANN). We examined 71 patients with a clinical diagnosis of AD and 66 controls. β-Amyloid_1–42 was decreased (sensitivity 80% and specificity 78%); tau was elevated (sensitivity 76% and specificity 88%) in CSF of AD patients. The combined tau/β-amyloid_1–42 quotient was able to distinguish healthy from diseased subjects with 99% sensitivity and 86% specificity. The ANN could separate FT-IR spectroscopy data with 88.5% sensitivity and 80% specificity. FT-IR spectroscopy proved to be cost-effective and simple to perform. Diagnostic sensitivity and specificity is in the range of CSF tau and β-amyloid_1–42 protein analysis. Larger sample numbers for ANN training and validation could increase diagnostic accuracy and thus prove to be a useful screening tool.     

The use of proteomics in biomarker discovery in neurodegenerative diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.     

脑血管性痴呆的辨证治疗经验

大脑动脉粥样硬化引起的脑血管性痴呆,以神智痴呆、记忆力减退、表情淡漠、呆滞或欣快感、头晕肢麻、手足瞤动等为特点,属于祖国医学的“文痴”、“语言颠倒”、“癫狂”、“善忘”等病症。中老年以后,肝血衰少,肾精亏损,脑失所养,大病久病,热灼真阴,心肝肾阴阳失调,肝阳化风,挟火挟痰,冲犯脑髓,元神失聪。因此,本病是本虚标实之证。虚者,治以培补真阴,补髓填精;实者,则平肝泻火,涤痰醒神,调气化瘀。文中附病案两例,经两个多月治疗,智力提高、记忆增强、精神活动基本恢复正常、生活自理,好转出院。     

Exploring online identity construction for the caregivers of adults living with dementia and the value of interactions with health and social care professionals

Becoming an informal caregiver for an adult living with dementia has been shown to have a significant impact upon the conception of identity. This study aimed to identify how identity is constructed online amongst caregivers of individuals living with dementia and how healthcare interactions can influence identity development through the analysis of online web blogs. Sixteen online blogs (172 entries) were selected through purposive and snowball sampling, and discourse analysis was used to analyse online identity construction for informal caregivers of adults living with dementia. Six areas of online identity construction were identified: changing family role; powerful expert social campaigner; being an advocate; guardian of their relative's selfhood; sustaining creative and spiritual individuality and wider community member in online and real life. Further to this, the importance of health and social care service interactions in the development of caregiver identity revealed that professionals must ensure person-centred service contacts for caregivers. This is a challenging task in the pandemic climate where interactions between health and social care professionals and caregivers are limited due to isolation measures. It is evident that the blog format can provide a forum through which the identity of the caregiver of an adult living with dementia can evolve. The six areas of identity construction reveal the multifaceted nature of identity for the caregiver and the value of belonging to an online community both in relation to identity construction and support. This finding is especially applicable in the current pandemic when accessing a face-to-face community is challenging for caregivers who may be shielding or living in isolation. The findings of this research can aid health and social care professionals in understanding the development of caregiver identity and in providing appropriate support during service interactions, on accessing virtual and face to face community support.