Teddy Koene

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 Alzheimers 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 Alzheimers disease. These findings imply the relevance of regarding dementia as a functional network disorder.

Early Onset Alzheimer's Disease is Associated with a Distinct Neuropsychological Profile

Alzheimers disease (AD) in younger patients is associated with a higher prevalence of atypical symptoms. We examined neuropsychological performance according to age-at-onset. We assessed cognition in 172 patients with AD (81 early and 91 late onset) in five cognitive domains (memory, language, visuo-spatial functioning, executive functioning, attention). Dementia severity was assessed using the Mini-Mental State Examination (MMSE) and global cognitive decline using Cambridge Cognitive Examination (CAMCOG). Analyses of variance were performed with age-at-onset as between-subjects factor, and gender and education as covariates. Analysis was repeated after stratification for dementia severity (based on median MMSE). In early onset AD, age (mean ± SD) was 60 ± 4 years; 44 (54%) were female. In late onset AD, age was 72 ± 5 years; 47 (52%) were female. Dementia severity and global cognitive decline did not differ between groups (early onset: MMSE: 20 ± 5, CAMCOG: 69 ± 15, late onset: MMSE: 21 ± 5, CAMCOG: 70 ± 15; p > 0.05). Early onset patients performed worse than late onset patients on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01). Late onset patients performed worse on memory, although not significantly (p = 0.11). Stratification for dementia severity showed that in mildly demented early onset patients, memory function was remarkably preserved compared to late onset patients (p < 0.01). In moderate AD, differences in memory function disappeared, but early onset patients performed worse on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01) than late onset patients. Adjustment for APOE left results unchanged. In conclusion, early onset AD presents with a different cognitive profile and the disease course seems different. Relative sparing of memory function in early stages stresses the need to adequately test other cognitive domains.

Preclinical AD predicts decline in memory and executive functions in subjective complaints

Objective: We assessed whether preclinical Alzheimer disease (AD) based on CSF biomarkers at baseline predicts decline in cognitive functioning as measured by repeated neuropsychological tests for 4 cognitive domains in patients with subjective complaints. Methods: We included 132 patients with subjective complaints from our memory clinic–based Amsterdam Dementia Cohort, who underwent lumbar puncture and had repeated (range 2–7) neuropsychological evaluations. Follow-up was 2 ± 1 years. CSF biomarkers amyloid-β (Aβ42), total tau (Tau), and hyperphosphorylated tau-181 were used to define National Institute on Aging–Alzheimers Association (NIA-AA) preclinical AD stages. Predictive value of preclinical AD stages as defined by CSF biomarkers, individual biomarkers, and Aβ42/tau ratio was assessed using linear mixed models. Outcome measures were compound z scores for memory, attention, executive functioning, language, and global cognition. Analyses were adjusted for age, sex, and education. Results: Patients were 61 ± 8 years old; 56 (42%) were women. Average baseline Mini-Mental State Examination score was 28.3 ± 1.5. Patients who fulfilled criteria for preclinical AD (stage 1: n = 11 + stage 2: n = 10) showed decline over time in memory (β ± SE −0.41 ± 0.14, p < 0.01), executive functions (−0.21 ± 0.08, p < 0.01), and global cognition (−0.29 ± 0.10, p < 0.01). There were no differences in cognitive decline between NIA-AA preclinical AD stages 1 and 2. In patients with normal CSF biomarkers, we observed memory improvement (0.19 ± 0.07, p < 0.01) and stable performance in all other domains. Conclusions: CSF evidence of preclinical AD in patients with subjective complaints predicted cognitive decline over time, encompassing more than memory alone. Executive functioning and global cognitive functioning also deteriorated. On the other hand, 2-year prognosis for patients without evidence of AD pathophysiology was good.

Cognitive Impairment in Alzheimer’s Disease Is Modified by APOE Genotype

Aim: We examined whether impairment in specific cognitive domains in Alzheimer’s disease (AD) differed according to APOE genotype and age at onset. Methods: Cognitive functions of 229 consecutive AD patients were assessed using Visual Association Test (VAT), Memory Impairment Screen+ (MIS+), VAT object naming, fluency test and Trail Making Test (TMT). Dementia severity was assessed using MMSE. ANOVAs were performed with APOE genotype and age at onset as independent variables and sex, education and MMSE as covariates. Results: 28% of patients were APOE Ε4-negative, 58% heterozygous and 14% homozygous. A significant association between APOE genotype and VAT and MIS+ was found when correcting for sex and education. An interaction effect between APOE genotype and age at onset on VAT and VAT object naming was found, with young carriers performing worse than young noncarriers. By contrast, when additionally correcting for MMSE, a significant association between APOE genotype and VAT object naming, TMT-A and TMT-B was found, with noncarriers performing worse than carriers. Conclusion: Memory was more impaired among APOE Ε4 carriers than among noncarriers. By contrast, naming, executive functions and mental speed were more impaired among APOE Ε4 noncarriers. This suggests that the APOE genotype modifies the clinical phenotype in terms of cognitive impairment in AD.

White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline

Background and Purpose— In patients with subjective cognitive decline, we assessed whether small vessel disease was associated with clinical progression and cognitive decline. Methods— We included 334 patients with subjective cognitive decline. Follow-up was 3±2 years. Results— Fifty-three (16%) patients progressed clinically to mild cognitive impairment or dementia. White matter hyperintensities were associated with clinical progression and with annual decline on memory, attention, executive functioning, and global cognition. Microbleeds and lacunes were not associated with clinical progression or cognitive decline. Conclusions— In patients with subjective cognitive decline, patients with white matter hyperintensities are at increased risk of clinical progression and cognitive decline.

The identification of cognitive subtypes in Alzheimer's disease dementia using latent class analysis

Objective Alzheimers disease (AD) is a heterogeneous disorder with complex underlying neuropathology that is still not completely understood. For better understanding of this heterogeneity, we aimed to identify cognitive subtypes using latent class analysis (LCA) in a large sample of patients with AD dementia. In addition, we explored the relationship between the identified cognitive subtypes, and their demographical and neurobiological characteristics. Methods We performed LCA based on neuropsychological test results of 938 consecutive probable patients with AD dementia using Mini-Mental State Examination as the covariate. Subsequently, we performed multinomial logistic regression analysis with cluster membership as dependent variable and dichotomised demographics, APOE genotype, cerebrospinal fluid biomarkers and MRI characteristics as independent variables. Results LCA revealed eight clusters characterised by distinct cognitive profile and disease severity. Memory-impaired clusters—mild-memory (MILD-MEM) and moderate-memory (MOD-MEM)—included 43% of patients. Memory-spared clusters mild-visuospatial-language (MILD-VILA), mild-executive (MILD-EXE) and moderate-visuospatial (MOD-VISP) —included 29% of patients. Memory-indifferent clusters mild-diffuse (MILD-DIFF), moderate-language (MOD-LAN) and severe-diffuse (SEV-DIFF) —included 28% of patients. Cognitive clusters were associated with distinct demographical and neurobiological characteristics. In particular, the memory-spared MOD-VISP cluster was associated with younger age, APOE e4 negative genotype and prominent atrophy of the posterior cortex. Conclusions Using LCA, we identified eight distinct cognitive subtypes in a large sample of patients with AD dementia. Cognitive clusters were associated with distinct demographical and neurobiological characteristics.

Widespread Disruption of Functional Brain Organization in Early-Onset Alzheimer's Disease

Early-onset Alzheimer’s disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 “young” (<65 years old) and 31 “old” (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed.

Regional atrophy is associated with impairment in distinct cognitive domains in Alzheimer's disease.

In Alzheimers disease (AD), some patients present with cognitive impairment other than episodic memory disturbances. We evaluated whether occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) could account for differences in cognitive domains affected.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease

We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimers disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD).

Episodic memory and the medial temporal lobe: not all it seems. Evidence from the temporal variants of frontotemporal dementia

Background Disproportionate medial temporal lobe atrophy (MTA) is an early finding in Alzheimers disease (AD). Episodic memory impairment in AD is associated with the degree of MTA. Episodic memory impairment and MTA are also found in semantic dementia (SD) and in right temporal lobe atrophy (RTLA), the temporal variants of frontotemporal dementia, but their relationship is unclear. Objective To compare episodic memory impairment among patients with these temporal variants of frontotemporal dementia with that of patients with AD with the same degree of MTA. Methods Episodic memory was tested with the visual association test, and semantic memory (SM) with animal fluency and the visual association naming test. MTA was measured using a visual rating scale. Each patient with SD or RTLA was matched for MTA with two patients with AD. Comparisons of episodic memory and SM were made for patients with SD versus matched patients with AD; patients with RTLA versus matched patients with AD and for SD, RTLA and all patients with AD. Results 27 patients with SD and 11 with RTLA were matched with 54 and 22 patients with AD, respectively. Episodic memory was less impaired in patients with SD than in those with AD (8 versus 2; p<0.001) and in patients with RTLA than in those with AD (10 versus 4.5; p=0.009). Semantic memory was more affected in patients with SD than in those with AD, and the Mini Mental State Examination score was higher in patients with RTLA than in those with AD. Comparison of the three diagnostic groups showed that episodic memory was most impaired in AD, whereas SM was most impaired in SD. Conclusion Since episodic memory impairment is more severe in AD than in SD and RTLA, despite a comparable degree of MTA, atrophy of the medial temporal lobe alone cannot account for episodic memory dysfunction.