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Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer's disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤ 65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5 ± 1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65 ± 8 years, 98(49%) were female and MMSE was 22 ± 4. LMM showed that early onset patients declined faster on executive functioning (β ± SE:-0.09 ± 0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β ± SE:-0.1 ± 0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β ± SE:-0.36 ± 0.1), attention (β ± SE:-0.42 ± 0.1), executive (β ± SE:-0.41 ± 0.1) and visuo-spatial functioning (β ± SE:-0.43 ± 0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Objective: To identify the existence of discrete cognitive subtypes among memory clinic patients without dementia and test their prognostic values., Methods: In a retrospective cohort study of 635 patients without dementia visiting the Alzheimer centers in Maastricht or Amsterdam, latent profile analysis identified cognitive subtypes based on immediate and delayed memory recall, delayed recognition, information-processing speed, attention, verbal fluency, and executive functions. Time to dementia was tested in weighted Cox proportional hazard models adjusted for confounders., Results: Five latent classes represented participants with high-normal cognition (15%), low-normal cognition (37%), primary memory impairment in recall (MI) (36%), memory impairment in recall and recognition (MI+) (5%), and primary nonmemory impairment (NMI) (6%). Compared with low-normal cognition, participants with NMI had the highest risk of dementia (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.46-10.18) followed by MI (HR = 3.05, 95% CI = 2.09-4.46) and MI+ (HR = 3.26, 95% CI = 1.72-6.17), while participants with high-normal cognition had the lowest risk (HR = 0.24, 95% CI = 0.07-0.80). Subtypes further showed differential relationships with dementia types, with MI and MI+ most often converting to Alzheimer-type dementia and NMI to other forms of dementia., Conclusions: Cognitive subtypes can be empirically identified in otherwise heterogeneous samples of memory clinic patients and largely confirm current strategies to distinguish between amnestic and nonamnestic impairment. Studying more homogeneous cognitive subtypes may improve understanding of disease mechanisms and outcomes.

Background: [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population., Methods: One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results., Results: [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients., Conclusions: In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

We used a recently developed test of spatial memory--the Four Mountains Test--to investigate the core cognitive processes underpinning topographical disorientation in patients with amnestic mild cognitive impairment (a-MCI) and mild Alzheimer's disease (AD). Performance of these clinical groups was compared with age-matched controls, patients with frontotemporal lobar degeneration (FTLD), and patients with subjective memory impairments. We investigated the perception (concurrent match-to-sample) and short-term retention (2-s delayed match-to-sample) of the configuration of topographical features in computer-generated landscapes shown from different viewpoints. Thirty-one patients were tested (7 AD, 6 a-MCI, 7 temporal variant FTLD, 5 frontal variant FTLD, 6 subjective memory impairment) and 25 age- and gender-matched controls. Brain MRI was available for 27 patients; medial temporal lobe atrophy was assessed using a visual rating scale. Patients with a-MCI or mild AD were impaired on topographical short-term memory, but not perception. No other group differences were found on the topographical subtests. Notably, patients with temporal variants of FTLD performed normally, regardless of the laterality of damage. Subtests for the perception and retention of nonspatial aspects of the landscapes (weather conditions, seasonal and daily variations in lighting and color) were poor at differentiating the patient groups. These results indicate a core deficit in representing topographical layout, even for very short durations, within the context of more general long-term memory impairments found in AD, and suggest that this function is particularly sensitive to the earliest stages of the disease., (© 2009 Wiley-Liss, Inc.)

Background: Informant questionnaires may be useful in diagnosing early dementia. Conflicting results were found when these questionnaires were used to differentiate patients with mild cognitive impairment (MCI) from healthy elderly subjects. We evaluated the ability of the most commonly used informant questionnaire, the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), to discriminate between Alzheimer's disease (AD), MCI and subjective memory complaints (SMC)., Methods: Informants of 180 AD patients, 59 MCI patients and 89 SMC subjects who visited the Alzheimer Center of the VU University Medical Center between 2004 and 2007 completed the short Dutch version of the IQCODE. Logistic regression and receiver operating characteristic curves were used to evaluate the diagnostic ability of the IQCODE., Results: The IQCODE was able to differentiate AD from MCI and SMC, but was not able to differentiate SMC from MCI., Conclusions: The IQCODE may be helpful in diagnosing AD but is of limited use in differentiating MCI from SMC., (Copyright © 2010 S. Karger AG, Basel.)

Background: Although EEG is not considered as standard in memory clinics, evidence indicates that epileptiform discharges are of value in diagnosing cognitive complaints as epilepsy., Objective: To determine prevalence and significance of epileptiform discharges in a memory clinic., Methods: 1,674 consecutive patients underwent routine EEGs [mean age 66 years, diagnoses: Alzheimer disease (AD; n = 510), other dementia (n = 193), mild cognitive impairment (MCI; n = 225), subjective complaints (n = 368), and other disorders (n = 378)]. Database statistics, charts and EEG reports were reviewed., Results: Epileptiform discharges were present in 42 (3%) patients, of which 60% lacked clinical seizures. All discharges were focal and predominantly temporally localized. Epileptiform activity was not associated with a dementia diagnosis (2% in AD and 1% in other dementia vs. 2% in MCI, 2% in subjective complaints and 5% in other disorders, p = 0.07) or with lower Mini-Mental State Examination scores (p = 0.69). Two (diagnoses: AD, vascular dementia) of 20 patients with epileptiform activity without clinical seizures developed first seizures after 2 years., Conclusion: In a memory clinic cohort, epileptiform discharges are rare, nonspecific and indicate a moderate risk of first-ever seizures in demented patients. These findings should be taken into account when routinely evaluating memory clinic patients with EEG.

Purpose: To determine the frequency of neurological signs in a memory clinic population and to explore their associations with white matter hyperintensity (WMH)., Methods: We included patients with Alzheimer disease (AD; n = 210), vascular dementia (VaD; n = 34), mild cognitive impairment (MCI; n = 86) and subjective complaints (n = 153). The presence of extrapyramidal and unilateral signs was assessed from medical charts. On MRI, WMH volumes were extracted automatically., Results: Extrapyramidal signs were found in 10% and unilateral signs in 12% of the patients. Age- and sex-adjusted extrapyramidal signs occurred more often in VaD compared to patients with subjective complaints. Unilateral signs were more prevalent in all groups compared to patients with subjective complaints. Two-way analysis of variance (ANOVA) with WMH as the dependent variable showed a main effect of diagnosis (p < 0.001), but not of extrapyramidal signs (p = 0.62). In contrast, 2-way ANOVA showed main effects of diagnosis (p < 0.001) and unilateral signs (p = 0.001). Furthermore, there was an interaction between these factors (p = 0.04); if unilateral signs were present, patients with subjective complaints and VaD showed more WMH, whereas there was no relation in AD and MCI., Conclusion: Extrapyramidal and unilateral signs are common in memory clinic patients, but are only modestly related to WMH., (Copyright (c) 2010 S. Karger AG, Basel.)

Background/aims: The goal of the present study was to evaluate the diagnostic accuracy of the core diagnostic criteria for frontotemporal dementia (FTD) [Neary D, et al: Neurology 1998;51:1546-1554] within a memory clinic population., Methods: The 5 core diagnostic criteria for FTD were operationalised in an informant-based written questionnaire. For a diagnosis of FTD the total clinical picture was weighted with findings on additional investigations and possible exclusion criteria, with follow-up of at least 1 year., Results: The operationalised core criteria for FTD had a sensitivity of 79% (95% CI = 57-92) and a specificity of 90% (95% CI = 85-94)., Conclusion: The core diagnostic criteria for FTD applied in a caregiver questionnaire have good diagnostic accuracy among subjects without advanced dementia attending a memory clinic. This stresses the importance of the informant-based history in the differential diagnosis of dementia., (Copyright (c) 2008 S. Karger AG, Basel.)

Aim: To describe the distribution of apolipoprotein E (APOE) genotypes in a cohort of memory clinic patients., Methods: We included 749 memory clinic patients. Diagnoses were made in a multidisciplinary consensus meeting and the APOE genotype was determined. The community-based cohort of the Longitudinal Aging Study Amsterdam was used as control population (n = 2,233)., Results: In the memory clinic sample, there were 173 patients with subjective complaints, 125 patients with mild cognitive impairment (MCI), 251 patients with Alzheimer disease (AD), 107 patients with another type of dementia, and 93 patients with another neurologic or psychiatric diagnosis. The APOE allele distribution differed among groups. There was no difference in the prevalence of the epsilon2 allele, but there were differences in distribution of the epsilon3 and epsilon4 alleles. Compared with the control population (15%), the prevalence of APOE epsilon4 was increased among patients with subjective complaints (22%), MCI (36%), AD (42%) and other types of dementia (25%)., Conclusion: We observed an increased prevalence of APOE epsilon4 in patients with MCI and subjective complaints. This finding is of great clinical importance as nondemented patients positive for APOE epsilon4 could be identified as being at genetic risk of AD, and for that reason monitored more closely., ((c) 2008 S. Karger AG, Basel)

Objectives: To compute the synchronization likelihood of multichannel electroencephalogram (EEG) data in Alzheimer (AD) patients, subjects with mild cognitive impairment (MCI) and subjects with subjective memory complaints (SC)., Material and Methods: EEGs (200 Hz sample frequency; 21 channels; average reference) were recorded in 10 AD patients (two males; age 76.2; SD 9.36; range 59-86), 17 subjects with MCI (eight males; age 77.41; SD 6.25; range 62-88) and 20 subjects with SCI (11 males; age 68.9; SD 12.96; range: 51-89). The synchronization likelihood, a novel type of coherence measure, was computed, comparing each channel with all other channels, for the 2-6, 6-10, 10-14, 14-18, 18-22 and 22-50 Hz band., Results: The synchronization likelihood was significantly decreased in the 14-18 and 18-22 Hz band in AD patients compared with both MCI subjects and healthy controls. Lower beta band synchronization correlated with lower Mini-Mental state examination (MMSE) scores., Conclusion: Loss of beta band synchronization occurs early in mildly affected AD patients and correlates with cognitive impairment.