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 Alzheimer's 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.

The trajectory of cognitive decline in the pre-dementia phase in memory clinic visitors: findings from the 4C-MCI study.

BACKGROUND: We investigated the course of decline in multiple cognitive domains in non-demented subjects from a memory clinic setting, and compared pattern, onset and magnitude of decline between subjects who progressed to Alzheimer's disease (AD) dementia at follow-up and subjects who did not progress. METHOD: In this retrospective cohort study 819 consecutive non-demented patients who visited the memory clinics in Maastricht or Amsterdam between 1987 and 2010 were followed until they became demented or for a maximum of 10 years (range 0.5-10 years). Differences in trajectories of episodic memory, executive functioning, verbal fluency, and information processing speed/attention between converters to AD dementia and subjects remaining non-demented were compared by means of random effects modelling. RESULTS: The cognitive performance of converters and non-converters could already be differentiated seven (episodic memory) to three (verbal fluency and executive functioning) years prior to dementia diagnosis. Converters declined in these three domains, while non-converters remained stable on episodic memory and executive functioning and showed modest decline in verbal fluency. There was no evidence of decline in information processing speed/attention in either group. CONCLUSIONS: Differences in cognitive performance between converters to AD dementia and subjects remaining non-demented could be established 7 years prior to diagnosis for episodic memory, with verbal fluency and executive functioning following several years later. Therefore, in addition to early episodic memory decline, decline in executive functions may also flag incident AD dementia. By contrast, change in information processing speed/attention seems less informative.

Cognitive correlates of visual hallucinations in non-demented Parkinson's disease patients.

BACKGROUND: Visual hallucinations (VH) in Parkinson's disease (PD) are associated with PD dementia and have been related to cognitive impairments in non-demented PD patients. Reports on the specific cognitive domains affected are conflicting. The aim of the present study was to investigate the presence of specific cognitive impairments in non-demented PD patients with VH, compared to those without VH. METHODS: We compared the clinical characteristics and neuropsychological test scores of 31 non-demented PD patients with VH with those of 31 PD patients without VH that were carefully matched for sex, age, disease duration and educational level. Several non-motor symptoms, including depression, anxiety and sleep disturbances, were also taken into account, as these may influence cognitive performance. RESULTS: The PD with VH group performed significantly worse on the Trail Making Test part A (p = 0.01) and the Rey Auditory Verbal Learning Test, immediate recall (p = 0.01). In addition, PD patients with VH were more anxious, more depressed and reported more sleep disturbances. Verbal learning scores were not associated with levels of anxiety, depression or sleep disruption, whereas worse Trail Making Test A performance was associated with concomitant sleep disturbances. CONCLUSIONS: In non-demented PD patients, the presence of VH is associated with a cognitive profile characterized by impairments in verbal learning and probably attention. Since these cognitive functions are believed to be non-dopaminergic mediated functions, the present results support the hypothesis that multiple neurotransmitter systems, other than dopamine, contribute to the pathophysiology of VH in PD.

Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease.

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.

Differential association of [11C]PIB and [18F]FDDNP binding with cognitive impairment.

OBJECTIVE: To evaluate associations of [(11)C]Pittsburgh compound B (PIB) and [(18)F]FDDNP with impairment in specific cognitive domains over the broader spectrum comprising cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). METHODS: Twelve patients with AD, 13 patients with MCI, and 15 cognitively normal elderly subjects were included. Paired [(11)C]PIB and [(18)F]FDDNP PET scans were performed in all subjects. Binding potential (BP(ND)) was calculated using parametric images of BP(ND) for global, frontal, parietal, and temporal cortex; medial temporal lobe; and posterior cingulate. Cognitive functions were assessed using a battery of neuropsychological tests. Linear regression analyses were used to assess associations of [(11)C]PIB and [(18)F]FDDNP binding with cognitive measures. RESULTS: Adjusted for age, sex, and [(18)F]FDDNP binding, higher global [(11)C]PIB binding was associated with lower scores on the Mini-Mental State Examination, immediate and delayed recall of the Rey Auditory Verbal Learning Task (RAVLT), Visual Association Task, and Trail Making Test part B. Conversely, higher [(18)F]FDDNP binding was independently associated with lower scores on immediate recall of the RAVLT. After additional adjustment for diagnosis, higher [(11)C]PIB binding remained independently associated with delayed recall (standardized beta = -0.39, p = 0.01), whereas higher [(18)F]FDDNP binding remained independently associated with immediate recall (standardized beta = -0.32, p = 0.03). When regional binding was assessed using stepwise models, both increased frontal [(11)C]PIB and temporal [(18)F]FDDNP binding were associated with memory, whereas increased parietal [(11)C]PIB binding was associated with nonmemory functions. CONCLUSION: Increased [(18)F]FDDNP binding is specifically associated with impairment of episodic memory, whereas increased [(11)C]Pittsburgh compound B binding is associated with impairment in a broader range of cognitive functions.

Cognitive complaints in patients after whiplash injury: the impact of malingering.

OBJECTIVES: The validity of memory and concentration complaints that are often reported after a whiplash trauma is controversial. The prevalence of malingering or underperformance in post-whiplash patients, and its impact on their cognitive test results were studied. METHODS: The Amsterdam short term memory (ASTM) test, a recently developed malingering test, was used as well as a series of conventional memory and concentration tests. The study sample was a highly selected group of patients, who were examined either as part of a litigation procedure (n=36) or in the normal routine of an outpatient clinic (n=72). RESULTS: The prevalence of underperformance, as defined by a positive score on the malingering test, was 61% (95% CI: 45-77) in the context of litigation, and 29% (95% CI: 18-40) in the outpatient clinic (p=0.003). Furthermore, the scores on the memory and concentration test of malingering post-whiplash patients (n=43) and non-malingering post-whiplash patients (n=65) were compared with the scores of patients with closed head injury (n=20) and normal controls (n=46). The malingering post-whiplash patients scored as low as the patients with closed head injury on most tests. CONCLUSIONS: The prevalence of malingering or cognitive underperformance in late post-whiplash patients is substantial, particularly in litigation contexts. It is not warranted to explain the mild cognitive disorders of whiplash patients in terms of brain damage, as some authors have done. The cognitive complaints of non-malingering post-whiplash patients are more likely a result of chronic pain, chronic fatigue, or depression.

[The diagnostic value of tests for mental control]. / De diagnostische waarde van tests voor mentale controle.

Designated as Mental Control, the recitation of word lists and arithmetic progressions is often used for a cursory examination of attention and concentration in elderly patients. We studied the psychometric properties of the EMCT (Expanded Mental Control Test), which consists of 12 mental control tasks. The test was given to 174 residents of rest homes and semi-independent housing projects (aged 68 to 94) and 74 neurologic patients (aged 65 to 87) who had been referred for neuropsychological assessment. The reliability of the EMCT was satisfactory. Performance was related to education level but not to sex or age. In healthy subjects the EMCT score was associated with the backward digit span score. The correlations between the EMCT and subtests of the Amsterdam Dementia Screening (Ads6) in patients appeared to depend on the complexity of the target behavior. Performance on the EMCT may reflect the functioning of the Supervisory Attentional System postulated by Shallice.