Heike Kölsch

Prediction of Dementia by Subjective Memory Impairment Effects of Severity and Temporal Association With Cognitive Impairment

CONTEXT Subjective memory impairment (SMI) is receiving increasing attention as a pre-mild cognitive impairment (MCI) condition in the course of the clinical manifestation of Alzheimer disease (AD). OBJECTIVES To determine the risk for conversion to any dementia, dementia in AD, or vascular dementia by SMI, graded by the level of SMI-related worry and by the temporal association of SMI and subsequent MCI. DESIGN Longitudinal cohort study with follow-up examinations at 1(1/2) and 3 years after baseline. SETTING Primary care medical record registry sample. PARTICIPANTS A total of 2415 subjects without cognitive impairment 75 years or older in the German Study on Aging, Cognition and Dementia in Primary Care Patients. MAIN OUTCOME MEASURES Conversion to any dementia, dementia in AD, or vascular dementia at follow-up 1 or follow-up 2 predicted by SMI with or without worry at baseline and at follow-up 2 predicted by different courses of SMI at baseline and MCI at follow-up 1. RESULTS In the first analysis, SMI with worry at baseline was associated with greatest risk for conversion to any dementia (hazard ratio [HR], 3.53; 95% confidence interval [CI], 2.07-6.03) or dementia in AD (6.54; 2.82-15.20) at follow-up 1 or follow-up 2. The sensitivity was 69.0% and the specificity was 74.3% conversion to dementia in AD. In the second analysis, SMI at baseline and MCI at follow-up 1 were associated with greatest risk for conversion to any dementia (odds ratio [OR], 8.92; 95% CI, 3.69-21.60) or dementia in AD (19.33; 5.29-70.81) at follow-up 2. Furthermore, SMI at baseline and amnestic MCI at follow-up 1 increased the risk for conversion to any dementia (OR, 29.24; 95% CI, 8.75-97.78) or dementia in AD (60.28; 12.23-297.10), with a sensitivity of 66.7% and a specificity of 98.3% for conversion to dementia in AD. CONCLUSION The prediction of dementia in AD by SMI with subsequent amnestic MCI supports the model of a consecutive 3-stage clinical manifestation of AD from SMI via MCI to dementia.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins α and β (sAPPα and sAPPβ) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination⩾20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloidβ peptides, Tau and phospho-Tau. sAPPα and sAPPβ were measured with multiplexing method based on electrochemiluminescence. sAPPα and sAPPβ CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPPα and sAPPβ CSF concentrations in patients with NDD characteristic for Alzheimers disease (AD) compared to those with NDD negative results. sAPPα and sAPPβ highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPPα: cutoff, 117.4 ng ml−1, sensitivity, 68%, specificity, 85%, P<0.001; sAPPβ: cutoff, 181.8 ng ml−1, sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPPα and sAPPβ might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease

Cholesterol and 24S-hydroxycholesterol are involved in the pathogenesis of Alzheimers disease (AD). Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24S-hydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C → T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A → G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C → T polymorphism was associated with an increased 24S-hydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain.

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment

Objective: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. Method: [18F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. Results: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. Conclusion: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Noradrenergic modulation of emotion-induced forgetting and remembering.

We used a free-recall paradigm to establish a behavioral index of the retrograde and anterograde interference of emotion with episodic memory encoding. In two experiments involving 78 subjects, we show that negatively valenced items elicit retrograde amnesia, whereas positively valenced items elicit retrograde hypermnesia. These data indicate item valence is critical in determining retrograde amnesia and retrograde hypermnesia. In contrast, we show that item arousal induces an anterograde amnesic effect, consistent with the idea that a valence-evoked arousal mechanism compromises anterograde episodic encoding. Randomized double-blind administration of the β-adrenoceptor antagonist propranolol compared with the selective norepinephrine (NE) reuptake-inhibitor reboxetine, and placebo, demonstrated that the magnitude of this emotional amnesia and hypermnesia can be upregulated and downregulated as a function of emotional arousal and central NE signaling. We conclude that a differential processing of emotional arousal and valence influences how the brain remembers and forgets.

The neurotoxic effect of 24-hydroxycholesterol on SH-SY5Y human neuroblastoma cells

Neurodegenerative disorders are characterized by a massive loss of nerve cells. The neuronal cell death is accompanied by an increased cholesterol release and conversion of cholesterol into the polar metabolite, 24-hydroxycholesterol (24-OH-Chol), appears to be an important mechanism in the central nervous system for eliminating cholesterol from the brain. We tested the influence of 24-OH-Chol on SH-SY5Y human neuroblastoma cells by recording cell morphology, Trypan blue exclusion, LDH-release into the culture medium, intracellular calcium and reactive oxygen species (ROS). The exposure of SH-SY5Y human neuroblastoma cells to 50 microM 24-OH-Chol led to a 90% loss in cell viability within 30 h, the LDH-release into the medium increased rapidly after 24 h, and after 24 to 30 h we found an elevation in intracellular calcium. These results show that, in a physiological concentration range, 24-OH-Chol damages neuronal cells, thus we speculate that this oxysterol may be involved in the etiology of neurodegenerative disease.

KIBRA gene variants are associated with episodic memory in healthy elderly.

The first hypothesis free genome wide association study on cognition recently revealed the thus far unknown association of a single nucleotide polymorphism (SNP) of the KIBRA gene with episodic memory in healthy young and middle aged volunteers. Here, we report the first independent replication of this finding in an in-depth characterized sample of healthy elderly subjects. The effectsizes of the respective KIBRA SNP on memory even exceed those of the initial report. In parallel to the first study, the effect is restricted to hippocampus-related episodic memory without effects on frontal lobe function. The impact of KIBRA on memory is most likely of high relevance in elderly subjects as it is in young.

Neurotoxicity of 24-hydroxycholesterol, an important cholesterol elimination product of the brain, may be prevented by vitamin E and estradiol-17β

Summary. 24-Hydroxycholesterol, the main cholesterol elimination product of the brain is increased in serum of Alzheimer patients. This oxysterol behaves neurotoxic towards the human neuroblastoma cell line, SH-SY5Y. Here we demonstrate, that 24-hydroxycholesterol-induced neurotoxicity in differentiated SH-SY5Y cells was due to apoptosis, as indicated by DNA-fragmentation, caspase-3 activation and a decrease of the mitochondrial membrane potential. Free radicals were generated, resulting in the death of 75% of the cells within 48 h; neurotoxicity in differentiated SH-SY5Y cells was partially prevented by physiological concentrations of vitamin E (50–100 μM) in that 75% of the cells survived. Physiological concentrations of estradiol-17β (1–100 nM) elicited a protective effect in differentiated cells, which was not significant; however, in undifferentiated cells a significant protection was noted by this steroid hormone. Vitamin C and melatonin did not prevent 24-hydroxycholesterol-induced neurotoxicity. These in vitro data support the in vivo observed beneficial effects reported as circumstantial evidence of vitamin E and estradiol-17β treatment in the prevention and therapy of neurodegenerative disease.

Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke.

Background: Glutathione S-transferase omega-1 (GSTO1) protects from oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia (VaD), and stroke. Polymorphisms in GSTO1 might influence the function of the protein and thus the risk of AD, VaD, and stroke. Methods: The GSTO1 gene was screened for variations. The effect of the detected polymorphisms on the risk of AD, VaD, and stroke was evaluated. CSF levels of cholesterol and plasma homocysteine levels were compared according to the GSTO1 genotype. Results: Two missense polymorphisms in exon 4 of GSTO1 (Ala140Asp and Glu155ΔGlu) were detected and tested for their association with AD, VaD, and stroke. The Asp/Asp and Ala/Asp genotypes increased the risk of stroke (p = 0.003, OR = 2.1), and the Asp/Asp genotype increased the risk of VaD (p = 0.02, OR = 2.2). GSTO1 polymorphisms did not influence the risk of AD, but the Asp allele influenced the age at onset (p = 0.05). In nondemented probands CSF levels of cholesterol were increased in carriers of the Asp/Asp genotype (p = 0.004); however, in patients with manifest dementia the authors found decreased CSF levels of cholesterol in carriers of the Asp/Asp genotype (p = 0.028). Serum homocysteine levels in stroke patients were higher in carriers of at least one Asp allele (p = 0.011). Conclusion: The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.