Brain amyloid load, subjective memory complaints, and cognitive trajectories in older individuals at risk for dementia.

BACKGROUND AND PURPOSE: This study evaluated associations of brain amyloid with 2-year objective and subjective cognitive measures in a trial-ready older general population at risk for dementia. METHODS: Forty-eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). RESULTS: Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB-PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2-year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. CONCLUSIONS: Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at-risk stage, although substantial decline likely requires >2 years to occur.

The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) score as a predictor for cognitive decline and potential surrogate outcome in the FINGER lifestyle randomized controlled trial.

BACKGROUND AND PURPOSE: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at-risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. METHODS: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU-ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU-ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU-ADRI, and the potential impact of baseline ANU-ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. RESULTS: A higher ANU-ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was -0.028 [-0.032 to -0.025]) and over the 2-year study (e.g., estimate for 2-year changes in ANU-ADRI and per-year changes in global cognition [95% confidence interval] was -0.068 [-0.026 to -0.108]). No significant beneficial intervention effect was reported for ANU-ADRI, and baseline ANU-ADRI did not significantly affect the response to the intervention on changes in cognition. CONCLUSIONS: The ANU-ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context.

Late-life personality traits, cognitive impairment, and mortality in a population-based cohort.

OBJECTIVES: We examined longitudinal associations between late-life personality traits and cognitive impairment, dementia, and mortality in the population-based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Study. METHODS: Anger expression and trait anger (State-Trait Anger Expression Inventory), anxiety (State-Trait Anxiety Inventory), and sense of coherence (Sense of Coherence Scale) were assessed at the 1998 CAIDE visit (1266 cognitively normal individuals, mean age 71.0 years). Totally, 582 participants had complete re-examination in 2005-2008 (105 mild cognitive impairment, MCI; and 29 dementia). National registers data until 2008 were also used for both participants and nonparticipants to ascertain incident dementia (96 cases) and mortality (227 died). Analyses were adjusted for age, sex, education, follow-up time, cardiovascular and lifestyle factors, and depressive symptoms. RESULTS: Higher anxiety was associated with higher risk of MCI/dementia (OR 1.68, 95% CI 1.07-2.63) and death (HR 1.46, 95% CI 1.08-1.98). High sense of coherence was associated with lower mortality (HR 0.65, 95% CI 0.45-0.93). These associations were attenuated after accounting for depressive symptoms (OR 1.57, 95% CI 0.96-2.58 for anxiety-MCI/dementia; HR 1.35, 95% CI 0.97-1.86 for anxiety-mortality; and HR 0.68, 95% CI 0.45-1.04 for sense of coherence-mortality). Trait anger was associated with higher dementia risk even after adjustments (HR 1.90, 95% CI 1.14-3.18). CONCLUSIONS: Anxiety was linked to worse cognitive outcome and mortality and sense of coherence to lower mortality. Depressive symptoms attenuated the associations. As a novel finding, trait anger was connected to dementia risk. These findings emphasize the importance of personality-related risk factors for dementia and mortality. J Am Geriatr Soc 68:-, 2020.

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus.

OBJECTIVES: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. METHODS: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. RESULTS: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58). CONCLUSIONS: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

The effect of TOMM40 poly-T repeat lengths on age of onset and cerebrospinal fluid biomarkers in Finnish Alzheimer's disease patients.

BACKGROUND: Poly-T repeat lengths of rs10524523 in TOMM40 together with APOE polymorphism have been reported to affect the risk of late-onset Alzheimer's disease (LOAD) and the age of onset (AOO). OBJECTIVE: To explore whether the AOO and cerebrospinal fluid biomarkers Aß42, total tau and phosphorylated tau are associated with different repeat lengths. METHODS: We conducted both the fragment and sequencing analysis of rs10524523 in 336 LOAD patients with a known APOE genotype. RESULTS: AOO and Aß42 levels associated significantly with certain poly-T repeat lengths of rs10524523 in LOAD patients encompassing APOE 34/44 genotype. CONCLUSION: We conclude that the poly-T repeat associations of rs10524523 in TOMM40 reflect the APOE ε4-dependent association in LOAD.

Comparing predictors of conversion to Alzheimer's disease using the disease state index.

BACKGROUND: The Disease State Index (DSI) is a method which interprets data originating from multiple different sources, assisting the clinician in the diagnosis and follow-up of dementia diseases. OBJECTIVE: We compared the differences in accuracy in differentiating stable mild cognitive impairment (S-MCI) and progressive MCI (P-MCI) obtained from different data combinations using the DSI. METHODS: We investigated 212 cases with S-MCI and 165 cases with P-MCI from the Alzheimer's Disease Neuroimaging Initiative cohort. Data from neuropsychological tests, cerebrospinal fluid, apolipoprotein E (APOE) genotype, magnetic resonance imaging (MRI) and positron emission tomography (PET) were included. RESULTS: The combination of all parameters gave the highest accuracy (accuracy 0.70, sensitivity 0.71, specificity 0.68). In the different categories, neuropsychological tests (0.65, 0.65, 0.65) and hippocampal volumetry (0.66, 0.66, 0.66) achieved the highest accuracy. CONCLUSION: In addition to neuropsychological testing, MRI is recommended to be included for differentiating S-MCI from P-MCI. APOE genotype, CSF and PET may provide some additional information.

Machine learning prediction of future amyloid beta positivity in amyloid-negative individuals.

BACKGROUND: The pathophysiology of Alzheimer's disease (AD) involves ß -amyloid (A ß ) accumulation. Early identification of individuals with abnormal ß -amyloid levels is crucial, but A ß quantification with positron emission tomography (PET) and cerebrospinal fluid (CSF) is invasive and expensive. METHODS: We propose a machine learning framework using standard non-invasive (MRI, demographics, APOE, neuropsychology) measures to predict future A ß -positivity in A ß -negative individuals. We separately study A ß -positivity defined by PET and CSF. RESULTS: Cross-validated AUC for 4-year A ß conversion prediction was 0.78 for the CSF-based and 0.68 for the PET-based A ß definitions. Although not trained for the clinical status-change prediction, the CSF-based model excelled in predicting future mild cognitive impairment (MCI)/dementia conversion in cognitively normal/MCI individuals (AUCs, respectively, 0.76 and 0.89 with a separate dataset). CONCLUSION: Standard measures have potential in detecting future A ß -positivity and assessing conversion risk, even in cognitively normal individuals. The CSF-based definition led to better predictions than the PET-based definition.

ß-Amyloid, Tau, Neurodegeneration Classification and Eligibility for Anti-amyloid Treatment in a Memory Clinic Population.

BACKGROUND AND OBJECTIVES: ATN (ß-amyloid [Aß], tau, neurodegeneration) system categorizes individuals based on their core Alzheimer disease (AD) biomarkers. An important potential future use for ATN is therapeutic decision-making in clinical practice once disease-modifying treatments (e.g., anti-amyloid), become widely available. In this cross-sectional study, we applied ATN and estimated potential eligibility for anti-amyloid treatment in a real-life memory clinic with biomarker assessments integrated into the routine diagnostic procedure and all specialized resources available for the implementation of novel treatments. METHODS: We included all consecutive patients at the Karolinska University Hospital Memory clinic in Solna, Stockholm, Sweden, who had their first diagnostic visit in April 2018-February 2021, informed consent for the clinic research database, and available clinical and biomarker (CSF and imaging) data. ATN classification was based on CSF Aß42 (or Aß42/40; A), CSF phosphorylated tau (T), and medial temporal lobe atrophy (N). For CSF markers, we applied laboratory cutoffs and data-driven cutoffs for comparison (determined with Gaussian mixture modeling). Eligibility for anti-amyloid treatment was assessed following the published recommendations for aducanumab (AD dementia or mild cognitive impairment [MCI] with no evidence of non-AD etiology, appropriate level of cognition, and AD-consistent CSF profile). RESULTS: The study population consisted of 410 patients (52% subjective cognitive impairment, 23% MCI, and 25% any dementia; age 59 ± 7 years, 56% women). Regardless of biomarker cutoffs, most patients were A-T-N- (54%-57%). A+ prevalence was 17%-30% (higher with data-driven cutoffs). Up to 13% of all patients (27% of those with MCI and 28% of those with dementia) were potentially eligible for anti-amyloid treatment when AD-consistent CSF was defined as any A+ profile. When A+T+ profile was required, treatment was targeted more to the dementia than MCI stage (eligibility up to 14% in MCI and 22% in dementia). The opposite applied to earlier-stage intervention (A+T-N-; eligibility up to 12% in MCI and 2% in dementia). DISCUSSION: In a memory clinic setting with all necessary infrastructure and national guidelines in place for dementia diagnostic examination (best-case scenario), most of the patients did not meet the eligibility criteria for anti-amyloid treatment. Continuing the development of disease-modifying treatments with different mechanisms of action is a priority.

Role of lipids in spheroidal high density lipoproteins.

We study the structure and dynamics of spherical high density lipoprotein (HDL) particles through coarse-grained multi-microsecond molecular dynamics simulations. We simulate both a lipid droplet without the apolipoprotein A-I (apoA-I) and the full HDL particle including two apoA-I molecules surrounding the lipid compartment. The present models are the first ones among computational studies where the size and lipid composition of HDL are realistic, corresponding to human serum HDL. We focus on the role of lipids in HDL structure and dynamics. Particular attention is paid to the assembly of lipids and the influence of lipid-protein interactions on HDL properties. We find that the properties of lipids depend significantly on their location in the particle (core, intermediate region, surface). Unlike the hydrophobic core, the intermediate and surface regions are characterized by prominent conformational lipid order. Yet, not only the conformations but also the dynamics of lipids are found to be distinctly different in the different regions of HDL, highlighting the importance of dynamics in considering the functionalization of HDL. The structure of the lipid droplet close to the HDL-water interface is altered by the presence of apoA-Is, with most prominent changes being observed for cholesterol and polar lipids. For cholesterol, slow trafficking between the surface layer and the regimes underneath is observed. The lipid-protein interactions are strongest for cholesterol, in particular its interaction with hydrophobic residues of apoA-I. Our results reveal that not only hydrophobicity but also conformational entropy of the molecules are the driving forces in the formation of HDL structure. The results provide the first detailed structural model for HDL and its dynamics with and without apoA-I, and indicate how the interplay and competition between entropy and detailed interactions may be used in nanoparticle and drug design through self-assembly.

Detecting Amyloid Positivity in Elderly With Increased Risk of Cognitive Decline.

The importance of early interventions in Alzheimer's disease (AD) emphasizes the need to accurately and efficiently identify at-risk individuals. Although many dementia prediction models have been developed, there are fewer studies focusing on detection of brain pathology. We developed a model for identification of amyloid-PET positivity using data on demographics, vascular factors, cognition, APOE genotype, and structural MRI, including regional brain volumes, cortical thickness and a visual medial temporal lobe atrophy (MTA) rating. We also analyzed the relative importance of different factors when added to the overall model. The model used baseline data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) exploratory PET sub-study. Participants were at risk for dementia, but without dementia or cognitive impairment. Their mean age was 71 years. Participants underwent a brain 3T MRI and PiB-PET imaging. PiB images were visually determined as positive or negative. Cognition was measured using a modified version of the Neuropsychological Test Battery. Body mass index (BMI) and hypertension were used as cardiovascular risk factors in the model. Demographic factors included age, gender and years of education. The model was built using the Disease State Index (DSI) machine learning algorithm. Of the 48 participants, 20 (42%) were rated as Aß positive. Compared with the Aß negative group, the Aß positive group had a higher proportion of APOE ε4 carriers (53 vs. 14%), lower executive functioning, lower brain volumes, and higher visual MTA rating. AUC [95% CI] for the complete model was 0.78 [0.65-0.91]. MRI was the most effective factor, especially brain volumes and visual MTA rating but not cortical thickness. APOE was nearly as effective as MRI in improving detection of amyloid positivity. The model with the best performance (AUC 0.82 [0.71-0.93]) was achieved by combining APOE and MRI. Our findings suggest that combining demographic data, vascular risk factors, cognitive performance, APOE genotype, and brain MRI measures can help identify Aß positivity. Detecting amyloid positivity could reduce invasive and costly assessments during the screening process in clinical trials.

Serum neurofilament light chain in FTLD: association with C9orf72, clinical phenotype, and prognosis.

OBJECTIVE: The aim of the present study was to compare the levels of serum neurofilament light chain (sNfL) in frontotemporal lobar degeneration (FTLD) patients of different clinical subtypes (bvFTD, PPA, and FTLD-MND) and with or without the C9orf72 repeat expansion, and to correlate sNfL levels to disease progression, assessed by the brain atrophy rate and survival time. METHODS: The sNfL levels were determined from 78 FTLD patients (C9orf72 repeat expansion carriers [n = 26] and non-carriers [n = 52]) with Single Molecule Array (SIMOA). The progression of brain atrophy was evaluated using repeated T1-weighted MRI scans and the survival time from medical records. RESULTS: In the total FTLD cohort, sNfL levels were significantly higher in C9orf72 repeat expansion carriers compared to non-carriers. Considering clinical phenotypes, sNfL levels were higher in the C9orf72 repeat expansion carriers than in the non-carriers in bvFTD and PPA groups. Furthermore, sNfL levels were the highest in the FTLD-MND group (median 105 pg/mL) and the lowest in the bvFTD group (median 27 pg/mL). Higher sNfL levels significantly correlated with frontal cortical atrophy rate and subcortical grey matter atrophy rate. The higher sNfL levels also associated with shorter survival time. INTERPRETATION: Our results indicate that the C9orf72 repeat expansion carriers show elevated sNFL levels compared to non-carriers and that the levels differ among different clinical phenotypes of FTLD. Higher sNfL levels correlated with a shorter survival time and cortical and subcortical atrophy rates. Thus, sNfL could prove as a potential prognostic biomarker in FTLD.

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia.

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Metabolic Profiles Help Discriminate Mild Cognitive Impairment from Dementia Stage in Alzheimer's Disease.

Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-ß levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit.

cCOG: A web-based cognitive test tool for detecting neurodegenerative disorders.

INTRODUCTION: Web-based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia. METHODS: Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment. RESULTS: cCOG produced accuracies (receiver operating characteristic-area under the curve [ROC-AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69-0.77 MCI/0.91-0.92 dementia). DISCUSSION: cCOG provides a promising tool for detecting MCI and dementia with potential for a cost-effective approach including home-based cognitive assessments.

Understanding the effect of cognitive/brain reserve and depression on regional atrophy in early Alzheimer's disease.

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning.

The Association Between Distinct Frontal Brain Volumes and Behavioral Symptoms in Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia.

Our aim was to investigate the association between behavioral symptoms of agitation, disinhibition, irritability, elation, and aberrant motor behavior to frontal brain volumes in a cohort with various neurodegenerative diseases. A total of 121 patients with mild cognitive impairment (MCI, n = 58), Alzheimer's disease (AD, n = 45) and behavioral variant frontotemporal dementia (bvFTD, n = 18) were evaluated with a Neuropsychiatric Inventory (NPI). A T1-weighted MRI scan was acquired for each participant and quantified with a multi-atlas segmentation method. The volumetric MRI measures of the frontal lobes were associated with neuropsychiatric symptom scores with a linear model. In the regression model, we included CDR score and TMT B time as covariates to account for cognitive and executive functions. The brain volumes were corrected for age, gender and head size. The total behavioral symptom score of the five symptoms of interest was negatively associated with the volume of the subcallosal area (ß = -0.32, p = 0.002). High disinhibition scores were associated with reduced volume in the gyrus rectus (ß = -0.30, p = 0.002), medial frontal cortex (ß = -0.30, p = 0.002), superior frontal gyrus (ß = -0.28, p = 0.003), inferior frontal gyrus (ß = -0.28, p = 0.005) and subcallosal area (ß = -0.28, p = 0.005). Elation scores were associated with reduced volumes of the medial orbital gyrus (ß = -0.30, p = 0.002) and inferior frontal gyrus (ß = -0.28, p = 0.004). Aberrant motor behavior was associated with atrophy of frontal pole (ß = -0.29, p = 0.005) and the subcallosal area (ß = -0.39, p < 0.001). No significant associations with frontal brain volumes were found for agitation and irritability. We conclude that the subcallosal area may be common neuroanatomical area for behavioral symptoms in neurodegenerative diseases, and it appears to be independent of disease etiology.

Prediction models for dementia and neuropathology in the oldest old: the Vantaa 85+ cohort study.

BACKGROUND: We developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort. METHODS: We included participants without dementia at baseline and at least 2 years of follow-up (N = 245) for dementia prediction or with autopsy data (N = 163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included ß-amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, α-synuclein pathology, hippocampal sclerosis, and TDP-43. RESULTS: Prediction model performance was evaluated using AUC for 10 × 10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64-0.68 for Alzheimer's disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: ε4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; ε2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ε3ε3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology. CONCLUSIONS: Differences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies.

Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients.

Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer's disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear.

Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer's disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. OBJECTIVE: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. METHODS: 335 shunted iNPH-patients (median 74 years) were followed until death (n = 185) or 6/2015 (n = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). CONCLUSION: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD.

Modeling of the triglyceride-rich core in lipoprotein particles.

Triglycerides are a major component of many important biological entities such as lipoproteins and lipid droplets. This work focuses on two common triglycerides, tripalmitin and triolein, which have been simulated through atomistic molecular dynamics at temperatures of 310 and 350 K for 300-700 ns. In these systems, both structural and dynamical properties have been characterized, paying particular attention to understanding the packing of triglyceride molecules and their molecular conformations. Additionally, we study the liquid-to-crystalline phase transition of tripalmitin through a temperature quench from the high-temperature isotropic liquid phase to 310 K, corresponding to a polymorphic, crystalline-like phase. The transition is characterized in detail through density, average molecular shape, and, in particular, the relevant order parameter describing the transition.