Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-ß and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype. METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-ß1-42, total (t-)Tau, and phosphorylated (p-)Tau. RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

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

OBJECTIVE: Alzheimer's 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.

Loss of EEG Network Efficiency Is Related to Cognitive Impairment in Dementia With Lewy Bodies.

OBJECTIVE: The aim of this study was to test whether disturbed EEG resting-state functional connectivity and network organization are a potential neurophysiological substrate of cognitive impairment in dementia with Lewy bodies. METHODS: EEG recordings were obtained in dementia with Lewy bodies patients, Alzheimer's disease patients and controls, matched for age and sex (N = 66 for each group; 14 [21%] female; mean age: 70 years). We analyzed functional connectivity of band-filtered EEG time series using the phase lag index. Functional brain network topology was analyzed with the minimum spanning tree. Mini-Mental State Examination, Trail Making Test A, and Visual Association Test were used as cognitive measures. RESULTS: Dementia with Lewy bodies patients showed lower connectivity strength in the alpha frequency band, compared to both controls and Alzheimer's disease patients (P < 0.001). Functional network topology in dementia with Lewy bodies patients was less efficient and contained less hubs (P < 0.01). Network characteristics in Alzheimer's disease patients were in between (but did not differ from) those of the other two groups. In dementia with Lewy bodies patients, lower alpha band phase lag index correlated with Visual Association Test scores and Trail Making Test scores (ρ = 0.33 and ρ = 0.31, respectively), whereas leaf fraction (a measure of 'network efficiency') correlated with Visual Association Test scores (ρ = 0.29) and Mini-Mental State Examination scores (ρ = 0.27). CONCLUSION: Functional networks of dementia with Lewy bodies patients are characterized by decreased connectivity strength and a loss of network efficiency and hubs. Severity of these disturbances is related to cognitive impairment, suggesting that network disturbances mediate between neuropathology and the clinical syndrome in dementia with Lewy bodies.

Early onset APOE E4-negative Alzheimer's disease patients show faster cognitive decline on non-memory domains.

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 (ß ± 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 (ß ± 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 (ß ± SE:-0.36 ± 0.1), attention (ß ± SE:-0.42 ± 0.1), executive (ß ± SE:-0.41 ± 0.1) and visuo-spatial functioning (ß ± 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.

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.

The influence of co-morbidity and frailty on the clinical manifestation of patients with Alzheimer's disease.

Co-morbidity and frailty are common in Alzheimer's disease (AD) and may contribute to the heterogeneity in clinical manifestations of the disease. We cross-sectionally investigated whether co-morbidity and frailty were independently associated with the clinical manifestation of AD in the 4C-Dementia study; a multicenter, longitudinal study in newly diagnosed AD patients. Clinical manifestation was operationalized using a composite of cognitive performance (neuropsychological assessment), activities of daily living (Disability Assessment for Dementia; DAD) and neuropsychiatric symptoms (Neuropsychiatric Inventory). As predictors of prime interest, co-morbidity was determined using the Cumulative Illness Rating Scale (CIRS-G) and frailty by the Fried criteria. In total, 213 AD patients participated (mean age 75 ± 10 years; 58% females). In linear regression models adjusted for age, gender, education, and disease duration, CIRS-G (ß = -0.21, p < 0.01) and frailty (ß = -0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (ß = -0.12, p = 0.12) lost statistical significance when both were combined (frailty: ß = -0.31, p < 0.001). Models with the individual components of clinical AD manifestation as dependent variables show significant associations between cognitive performance and CIRS-G (ß = -0.22, p = 0.01), and between DAD and frailty (ß = -0.37, p < 0.001). Our findings indicate that physical health and clinical AD manifestation are associated. This association may be responsible for part of the heterogeneity in the presentation of AD. This emphasizes the importance of adequate assessment of co-morbid medical conditions and frailty in patients with AD.

Single-subject gray matter graph properties and their relationship with cognitive impairment in early- and late-onset Alzheimer's disease.

Abstract We investigated the relationships between gray matter graph properties and cognitive impairment in a sample of 215 patients with Alzheimer's disease (AD) and also whether age of disease onset modifies such relationships. We expected that more severe cognitive impairment in AD would be related to more random graph topologies. Single-subject gray matter graphs were constructed from T1-weighted magnetic resonance imaging scans. The following global and local graph properties were calculated: betweenness centrality, normalized clustering coefficient γ, and normalized path length λ. Local clustering, path length, and betweenness centrality measures were determined for 90 anatomically defined areas. Regression models with as interaction term age of onset (i.e., early onset when patients were ≤65 years old and late onset when they were >65 years old at the time of diagnosis)×graph property were used to assess the relationships between cognitive functioning in five domains (memory, language, visuospatial, attention, and executive). Worse cognitive impairment was associated with more random graphs, as indicated by low γ, λ, and betweenness centrality values. Three interaction effects for age of onset×global graph property were found: Low γ and λ values more strongly related to memory impairment in early-onset patients; low beta values were significantly related to impaired visuospatial functioning in late-onset patients. For the local graph properties, language impairment showed the strongest relationship with decreased clustering coefficient in the left superior temporal gyrus across the entire sample. Our study shows that single-subject gray matter graph properties are associated with individual differences in cognitive impairment.

Apraxia in mild cognitive impairment and Alzheimer's disease: validity and reliability of the Van Heugten test for apraxia.

AIM: To assess the reliability and validity of the Van Heugten test for apraxia (VHA), developed for and used in stroke patients, in a memory clinic population. Furthermore, we assess the presence and severity of apraxia in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and investigate which AD patients are likely to develop apraxia. METHODS: We included 90 controls (age: 60 ± 9 years, MMSE: 28 ± 2), 90 MCI patients (age: 65 ± 7 years, MMSE: 26 ± 2) and 158 AD patients (age: 66 ± 8 years, MMSE: 20 ± 5). Apraxia was evaluated by the VHA assessing ideational and ideomotor praxis. We retested 20 patients to assess reliability. RESULTS: Intrarater reliability was 0.88 and interrater reliability was 0.73. AD patients performed worse on the VHA (median: 88; range: 51-90) than controls (median: 90; range: 88-90) and MCI patients (median: 89; range: 84-90) (both p < 0.001). Apraxia was prevalent in 35% of AD patients, in 10% of MCI and it was not observed in controls (0%; p < 0.001). In AD, dementia severity was the main risk for apraxia; 15% of mildly versus 52% of moderately demented patients had apraxia (OR = 6.7, 95% CI 2.9-15.6). The second risk factor was APOE genotype. APOE ε4 noncarriers (47%) were at increased risk compared to carriers (30%) (OR = 2.1, 95% CI 1-4.7). CONCLUSION: Apraxia can be reliably measured with the VHA and is present in a proportion of patients with MCI and AD. The presence of apraxia in AD is related to dementia severity and APOE ε4.

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

BACKGROUND: In Alzheimer's 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. METHODS: In 329 patients with AD, we assessed five cognitive domains: memory, language, visuospatial functioning, executive functioning, and attention. Magnetic resonance imaging (MRI) was rated visually for the presence of MTA and PA. Two-way analyses of variance were performed with MTA and PA as independent variables, and cognitive domains as dependent variables. Gender, age, and education were covariates. As PA is often encountered in younger patients, analyses were repeated after stratification for age of onset (early onset, ≤65 years). RESULTS: The mean age of the participants was 67 years, 175 (53%) were female, and the mean Mini-Mental State Examination (score±standard deviation) was 20±5 points. Based on dichotomized magnetic resonance imaging ratings, 84 patients (26%) had MTA and PA, 98 (30%) had MTA, 57 (17%) had PA, and 90 (27%) had neither. MTA was associated with worse performance on memory, language, and attention (all, P<.05), and PA was associated with worse performance on visuospatial and executive functioning (both, P<.05). Stratification for age showed in patients with late-onset AD (n=173) associations between MTA and impairment on memory, language, visuospatial functioning, and attention (all, P<.05); in early-onset AD (n=156), patients with PA tended to perform worse on visuospatial functioning. CONCLUSIONS: Regional atrophy is related to impairment in specific cognitive domains in AD. The prevalence of PA in a large set of patients with AD and its association with cognitive functioning provides support for the usefulness of this visual rating scale in the diagnostic evaluation of AD.

The Dutch Parelsnoer Institute--Neurodegenerative diseases; methods, design and baseline results.

BACKGROUND: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. METHODS: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). DISCUSSION: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.

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-ß (Aß42), total tau (Tau), and hyperphosphorylated tau-181 were used to define National Institute on Aging-Alzheimer's Association (NIA-AA) preclinical AD stages. Predictive value of preclinical AD stages as defined by CSF biomarkers, individual biomarkers, and Aß42/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 (ß ± 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.

Early onset Alzheimer's disease is associated with a distinct neuropsychological profile.

Alzheimer's 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.

EEG abnormalities are associated with different cognitive profiles in Alzheimer's disease.

OBJECTIVE: Our purpose was to investigate associations between different cognitive profiles and their underlying functional brain changes as measured by electroencephalogram (EEG) in Alzheimer's disease (AD). METHODS: EEG was obtained and neuropsychological performance assessed in 254 patients with AD. The EEGs were visually assessed for the presence of focal and/or diffuse abnormalities. Multivariate analysis of variance for repeated measures was performed with presence of focal and/or diffuse abnormalities as between-subjects factor and neuropsychological tests as within-subject factor. Age, sex and education were entered as covariates. RESULTS: Twenty-eight percent of the patients had a normal EEG, 32% had focal abnormalities, 14% diffuse abnormalities and 26% had both focal and diffuse abnormalities. Patients with a normal EEG presented with a cognitive profile in which memory was mostly impaired. Patients with focal and diffuse EEG abnormalities presented with a nonmemory profile. CONCLUSION: These results illustrate that specific types of EEG abnormalities are associated with different cognitive profiles in AD, providing biological support in terms of brain functioning for variability in cognitive impairment.