Steffen Wolfsgruber

AD dementia risk in late MCI, in early MCI, and in subjective memory impairment

To compare the risk of developing Alzheimers disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with normal test performance.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease

Objective: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). Methods: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimers Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale–Revised. CSF was obtained from all patients. Results: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aβ1-42/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD− patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. Conclusions: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

Cognitive Trajectory After Transcatheter Aortic Valve Implantation

Background—Transcatheter aortic valve implantation (TAVI) is known to be associated with silent cerebral injury, which could contribute to cognitive impairment. Considering its increasing use, thorough longitudinal investigation of cognitive trajectory after TAVI is pivotal. Methods and Results—Repeatable battery for the assessment of neuropsychological status was performed before (E1), 3 days (E2), 3 months (E3), 1 (E4) year, and 2 years (E5) after TAVI. Baseline characteristics, procedural data, imaging parameters of brain injury (diffusion-weighted MRI), and the use of conceivable neuroprotective approaches were investigated for their effect on cognitive function. Cognitive performance was investigated in 111 patients (mean log EuroSCORE, 30±13%). Global cognitive function (repeatable battery for the assessment of neuropsychological status total score) increased transiently at E2 (P=0.02) and was comparable with baseline levels at E3, E4, and E5. Six patients (5.4%) demonstrated early cognitive decline. Persistence and late onset were seen infrequently (n=3, 2.7% and n=4, 3.6%, respectively). Hence, early cognitive decline was ruled out in 105 patients (94.6%), and a majority of patients (91%) demonstrated sustained cognitive performance throughout all investigated time points. Interestingly, only patient age (P=0.012), but not prior cerebrovascular events, cognitive status, direct TAVI, cerebral embolism in diffusion-weighted MRI, or the use of a cerebral embolic protection device was found to be independently associated with cognitive decline, linking higher age to cognitive impairment along the first 2 years after TAVI. Conclusions—Long-term cognitive performance was preserved in the great majority (91%) of patients throughout the first 2 years after TAVI, despite the high intrinsic risk for cognitive deterioration. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00883285.

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimers disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

Assessing cognitive changes in the elderly: Reliable Change Indices for the Mini‐Mental State Examination

Stein J, Luppa M, Maier W, Wagner M, Wolfsgruber S, Scherer M, Köhler M, Eisele M, Weyerer S, Werle J, Bickel H, Mösch E, Wiese B, Prokein J, Pentzek M, Fuchs A, Leicht H, König H‐H, Riedel‐Heller SG for the AgeCoDe Study Group. Assessing cognitive changes in the elderly: Reliable Change Indices for the Mini‐Mental State Examination.

Cognitive performance before and after the onset of subjective cognitive decline in old age

Our objectives were (1) to test the association between the report of subjective cognitive decline (SCD) and prospective objective cognitive performance in high age individuals and (2) to study the course of longitudinal cognitive performance before and after the first report of SCD.

Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI

Objective: To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). Methods: We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. Results: Abnormal CSF β-amyloid 1–42 (Aβ42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aβ42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concerns, respectively. In addition, both SCD measures predicted risk of having a biomarker signature indicative of prodromal AD defined as presence of low CSF Aβ42 together with either high CSF tau or CSF phosphorylated tau 181 levels. Conclusions: In MCI, specific aspects of SCD severity and quality are related to CSF biomarkers indicative of AD. This extends findings in pre-MCI samples and calls for an improved operational assessment of SCD in MCI. This might be useful for sample enrichment strategies for increased likelihood of AD pathology.

Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimers disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.

The CERAD Neuropsychological Assessment Battery Total Score Detects and Predicts Alzheimer Disease Dementia with High Diagnostic Accuracy

OBJECTIVES To establish the diagnostic accuracy of the Total Score of the Consortium to Establish a Registry for Alzheimers Disease neuropsychological assessment battery (CERAD-NP) both for cross-sectional discrimination of Alzheimer disease (AD) dementia and short-term prediction of incident AD dementia. DESIGN Longitudinal cohort study with two assessments at a 1.5-year interval. SETTING Primary care sample randomly recruited via medical record registries. PARTICIPANTS As part of the German Study on Ageing, Cognition, and Dementia (AgeCoDe), a sample of elderly individuals (N = 1,606; mean age: 84 years) was assessed. MEASUREMENTS Subjects were assessed with the CERAD-NP and followed up for 18 months (97.6% follow-up rate). Logistic regression and receiver-operating-characteristic (ROC) curve analysis were used to compare the diagnostic accuracy of the CERAD-NP Total Score (CTS) with that of single CERAD-NP scores and the Mini-Mental-State-Examination (MMSE) score. RESULTS ROC curve analysis resulted in excellent (area under the curve [AUC]: 0.97) cross-sectional discrimination between non-AD and AD dementia subjects. Prediction of incident AD dementia with the CTS was also very good (AUC: 0.89), and was significantly better than prediction based on the MMSE. CONCLUSIONS The cross-sectional results confirm that the CTS is a highly accurate diagnostic tool for detecting AD dementia in elderly primary care patients. In addition, we provide evidence that the CTS is also accurate for the prediction of incident AD dementia. These findings further support the validity of the CTS as an index of overall cognitive functioning for detection and prediction of AD dementia.

Genome-wide significant risk factors for Alzheimer’s disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment

Few data are available concerning the role of risk markers for Alzheimer’s disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054–1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029–2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimers Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.