10 research outputs found
The impact of macronutritional composition and ketosis on cognitive health : from normal aging to Alzheimer’s disease
Ketogenic diets (KD) are increasingly investigated for the prevention of cognitive decline
and Alzheimer’s disease (AD). Without explicitly investigating a KD, this thesis
disentangles two of its hallmarks: a reduced dietary carbohydrate/fat-ratio (CFr) and
the metabolic state ketosis. Whether health effects from KD are primarily driven by
ketosis or from other pathways related macronutritional changes, is not fully
understood. Beyond CFr, KD may optionally be modified regarding protein, fat-subtypes,
plant/animal-based food proportions, the timing of nutrient intake, and ketogenic
supplements.
Strategies to induce ketosis in the absence of a carbohydrate restricted diet (Study I)
and subsequent associations between induced ketosis and a biomarker essential for
brain function (Study II) was investigated in a randomized clinical trial planned and
performed within this doctoral project: In a 6-arm cross-over design, 15 healthy older
adults (age 65-73, following their usual diet) were exposed to intake of oils with various
composition of medium-chain triglycerides (MCT), with and without glucose. Blood
levels of ketones (β-hydroxybutyrate, BHB) and brain-derived neurotrophic factor
(BDNF) were thereafter monitored for 4 hours. Mature BDNF (mBDNF) and its precursor
proBDNF are essential for brain plasticity, and their concentrations in serum have been
associated with cognitive health. A methods comparison for measuring blood ketones
(Study III) supports the internal validity of Study I and II.
The impact of self-reported CFr—in the non-ketogenic range—on cognitive performance
(Study IV/V) was investigated by panel analyses on data (year 0, 1, and 2) from the
Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability
(FINGER). The sample (n=1259, age 60–77, 47% females) had no substantial cognitive
impairment but had risk factors for developing dementia, and cognition at mean level or
slightly lower than expected in screening test. Study V added stratified analyses based
on genetics (APOE) and insulin status.
Study I: A 16-hour non-carbohydrate window and intake of 20 g caprylic acid (C8)
contributed roughly equally to induce transient ketosis (0.45 mmol/L, AUC/time venous
BHB hour 0-4, when combining the strategies). Coconut oil (which has a ≈7% fraction
constituted by C8 and is dominated by lauric acid) did not share the ketogenic
properties of purified C8 (difference –0.22 mmol/L, p<0.001).
Study II: Contrary to our expectations, change in mBDNF was lower (z-score: β=–0.88,
p<0.001) after intake of C8 (higher ketosis) compared to sunflower oil (lower ketosis).
Since associations between BHB and mBDNF appeared unrelated (p=0.43) on the
individual level, alternative explanations to ketosis as a driver were discussed. In
contrast, proBDNF increased more ( β=0.25, p=0.007) after intake of C8 compared to
sunflower oil, and individual associations between BHB and proBDNF ( β=0.40, p=0.006)
supported ketosis as a mechanistic link.
Study III: A handheld ketone meter correlated well with the laboratory method (r=0.91)
and agreement was high when applied to venous whole blood (which was our primary
outcome). However, absolute values were systematically higher in capillary blood, which should be considered in comparisons between studies.
Study IV: A lower CFr (log, z-score) estimated a higher composite z-score on a
Neuropsychological Test Battery ( β=–0.022, p=0.011) in linear mixed regression.
Methodological advantages of analyzing intake of carbohydrates and fat as a ratio
compared to single variables were discussed. No significant associations were found for
protein, and the saturated/total fat ratio had non-linear associations with cognitive
performance.
Study V: APOE (-2/3/4), which is the most important AD risk gene, modified estimates
between diet parameters (CFr, protein, saturated/total fat ratio, fiber, composite score)
and cognitive performance in a sub-sample with insulin data, excluding diabetics
(n=676). By increasing values of a continuous APOE-gradient [–1 (-23), –0.5 (-24),
0 (-33), 1 (-34), 2 (-44)], a less favorable estimate (p<0.0001 for interaction) was
found for a Higher-carbohydrates-fiber-Lower-fat-protein composite score. Estimates
for -33 were relatively close to zero whereas -44 (with some ambiguity for females)
typically had an antagonistic estimate to -23. Relative hypo- and hyper-insulinemia
significantly magnified several estimates diet ->cognition in a dose dependent manner,
primarily among -34/44. The plant/animal-based proportion of macronutrients was
discussed as a potential unmeasured confounder.
Conclusions: Macronutritional changes may be an alternative explanation to ketosis for
what may drive potential cognitive effects from KD. Time-restricted carbohydrate intake
may be considered as an alternative, or a complement, to C8-enriched MCT-oils for
achieving mild ketosis. Signaling functions of ketones may be at work in transient
mild/moderate ketosis, but whether our BDNF results have any cognitive implications
requires further studies. To guide further research, our diet ->cognition analyses have
strengthened the case for: (1) a precision nutrition approach based on APOE-genotype
and insulin status; (2) not limiting interventions on carbohydrate restriction to the
ketogenic range of CFr; (3) considering both ends of the insulin spectrum as
representing distinct at-risk types susceptible to diet modifications. APOE-34/44
carriers may be optimal targets for studying potential benefits on brain health from
CFr-reduction, and higher protein intake. The concept of universal macronutrient targets may be questioned, and stratified analyses may be encouraged in further studies
Consensus guidelines for the use and interpretation of angiogenesis assays
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference
A polygenic resilience score moderates the genetic risk for schizophrenia.
Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder