Biology subjects

Kivipelto, M.

Publications and source records attributed to Kivipelto, M..

4 recordsLinked to original sources

bioRxiv2024

Mouse PAW: reverse-translating the FINGER multimodal lifestyle intervention enhances synaptic plasticity and cognition in adult wild type female mice

BackgroundTargeting multiple risk factors through preventive interventions can halt the onset or progression of dementia. The clinical efficacy of this approach was shown in the multimodal FINGER trial, yet knowledge of the underlying biological mechanisms is limited. In the current study, we applied for the first time a multimodal lifestyle intervention in mice to study effects on cognition and associated molecular pathways. MethodsWe have established a novel experimental model, the lifestyle intervention PAW (Prevention of Alzheimers by a Multimodal Lifestyle Protocol - Working-mechanisms for Memory Gains) in mice. In this model, we combined different modalities of intervention aiming to achieve synergistic effects. The animals were given access to running wheels (voluntary exercise), Fortasyn Connect (a medical food that slows disease progression in early Alzheimers disease), and they were subjected to cognitive training in an IntelliCage environment (PAW group). To separately investigate the effects of pharmacological vascular management as a preventive measure, another group of mice was given Atorvastatin and Enalapril (cholesterol and blood pressure lowering pharmaceuticals, respectively) dosed in the diet (Pharma group). Control mice were housed in normal conditions. We included 12 wild type C57BL/6J female mice 6.5 months of age per group. The full intervention lasted for 8 weeks. Blood pressure was measured at baseline and the end of the intervention. All mice underwent a battery of behavioural testing after the eight weeks of intervention. Hippocampi were dissected for proteomics analysis. ResultsDuring the intervention, the PAW group actively participated in the intervention by learning the different cognitive training programs and by using the running wheels. At the end of the intervention, the PAW group showed a lowering of blood pressure to a similar extent as in the Pharma group (systolic 158 mmHg to 139 mmHg, p = 0.003, and 163 mmHg to 136 mmHg, p = 0.042, respectively). Furthermore, the PAW group displayed a better short-term spatial working memory compared to the control group as assessed by the spontaneous alternation in the Y maze test (66.5% and 56.7%, respectively, p = 0.036). Proteomic analysis of the hippocampi and downstream bioinformatic analysis revealed that several pathways were upregulated in the PAW mice including synaptogenesis (Z = 4.27, p = 1.26E-18) and glutamate binding, activation of AMPA receptors and synaptic plasticity (Z = 3.74, p = 3.16E-19). ConclusionsOur findings suggest that the PAW model effectively mimics the clinical effects of multimodal lifestyle dementia prevention, and further demonstrates the activation of hippocampal-specific molecular drivers of memory gains.

neuroscience↗

bioRxiv2022

Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities

Alzheimers disease is a multifactorial disorder with a heterogeneous patient population. Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to the disease progression. Indeed, therapies targeting these disorders have been shown efficient in dementia prevention. However, their mechanistic contribution to Alzheimers pathology and neurodegeneration has not been fully clarified. In the current study, we used CSF samples from a memory clinic cohort of 90 patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, to investigate 13 molecular markers representing key mechanisms underlying Alzheimers pathogenesis. Levels were compared between clinical groups of subjective cognitive decline, mild cognitive impairment, and Alzheimers disease. Associations between markers and groups of markers were analyzed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were further analyzed by immunofluorescence staining in hippocampus from control and AD individuals without hypertension, hypercholesterolemia nor diabetes. CSF angiotensinogen, thioredoxin-1, and interleukin-15 were the biomarkers with the most prominent associations with Alzheimers pathology, synaptic and axonal damage. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer cases. When we grouped biomarkers by biological function, we found that inflammatory and survival components were associated with Alzheimers pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data-driven analysis, two patient clusters were identified; Older participants with increased CSF markers of oxidative stress, vascular pathology and neuroinflammation were assigned to cluster 1, that was also smaller and characterized by increased synaptic and axonal damage, compared to individuals in cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post-mortem hippocampal tissue, showed that, compared to controls, angiotensinogen staining was higher in Alzheimers disease and was also found to co-localize with phosphorylated-tau. In a population free of common comorbidities, we could still find associations between Alzheimers disease biomarkers and markers of pathways associated with increased risk for Alzheimers disease (i.e., neuroinflammation, vascular function, oxidative stress and cholesterol homeostasis), suggesting that these pathways are contributing to Alzheimers disease mechanisms even in absence of clinically diagnosed comorbidities. The identification of distinct biomarker-driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of Alzheimers disease and the importance of developing tailored prevention and treatment strategies.

neuroscience↗

bioRxiv2021

Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging

Cholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimers Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.

animal behavior and cognition↗

bioRxiv2018

Effects of daily L-dopa administration on learning and brain structure in older adults undergoing four weeks of cognitive training: a randomised, parallel-group, double-blind, placebo-controlled trial.

BackgroundCognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signaling in plasticity. We investigated whether transient enhancement of dopaminergic neurotransmission via administration of L-dopa improves effects of cognitive training on performance. MethodsParticipants for this randomised, parallel-group, double-blind, placebo-controlled trial were recruited via newspaper advertisements. Inclusion criteria were: age of 65-75 years, Mini-Mental State Examination score >25, absence of serious medical conditions. Eligible subjects were randomly allocated to either receive 100/25mg L-dopa/benserazide or placebo prior to each of twenty cognitive training sessions administered during a four-week period. Participants and staff were masked to group assignment. Primary outcomes were latent variables of spatial and verbal fluid intelligence. This trial was preregistered at the European Clinical Trial Registry, EudraCT#2016-000891-54. FindingsBetween January 1st and October 10th 2017, we screened 235 people from the population in Stockholm, Sweden and randomly assigned 63 eligible subjects to receive L-dopa (n=32) or placebo (n=31) during cognitive training. Compared to the placebo group, subjects receiving L-dopa improved less in spatial intelligence (-0{middle dot}267 SDs; 95% CI [-0{middle dot}498, -0{middle dot}036]; p=0{middle dot}024). Change in verbal intelligence did not significantly differ between the groups (-0{middle dot}081 SDs, 95% CI [-0{middle dot}242, 0{middle dot}080]; p=0{middle dot}323). Adverse events occurred for 10 subjects (31%) in the active and for 7 participants (23%) in the control groups. InterpretationThe results speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system and provide no support for learning-enhancing properties of L-dopa supplements. The findings warrant closer investigation about the cognitive effects of early dopamine-replacement therapy in neurological disorders. FundingEuropean Research Council (ERC Grant agreement #617280-REBOOT), Wallenberg Clinical Scholars, and Stiftelse Stockholms Sjukhem. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWhilst pharmacological treatments have so far been largely unsuccessful in making an impact on age-related cognitive decline, recent findings have suggested small improvements of cognitive performance in older people by combining cognitive training with a healthy diet and aerobic exercises. Both exercise and dietary factors may exhibit plasticity-enhancing properties, and therefore increase effectiveness of cognitive training. In related basic research, dopaminergic signaling has been implicated in brain plasticity. An extensive PubMed search was conducted during the preparatory stage of the study (September 2014-July 2016) to investigate the role of dopamine signaling in neural plasticity and learning, as well as the effects of its deterioration on these characteristics in aging and neurodegenerative disorders. As a result, we found a substantial number of studies reporting acute improvements in cognitive performance and learning by administration of exogenous dopamine precursor L-dopa. A similar search was conducted specifically for this drug to evaluate its pharmacological and safety profile. We found a large body of basic research on both animal models and humans that supported the role of dopamine signaling in learning and plasticity. In addition, two smaller studies reported promising effects of repeated L-dopa administration on learning in the healthy younger population. In all studies, standard small-dose (100mg) L-dopa interventions were safe and well-tolerated. Added value of this studyOur study is the first of its kind to evaluate effects of repeated pro-dopaminergic medication on learning during cognitive training and cognitive performance in healthy older adults. Our results do not support the hypothesis of plasticity- and learning-promoting effects of enhanced dopaminergic neurotransmission by administration of exogenous dopamine precursor L-dopa in the healthy older population. The findings indicate that L-dopa treatment may in fact be detrimental to learning and cognitive performance and lead to structural brain changes within the dopaminergic circuit. Implications of all the available evidenceThe results put constraints on the hypothesis of a key role of the deteriorated dopaminergic system in age-related decline of learning abilities, and speak against early pharmacological interventions in older healthy adults to improve cognitive functions by targeting the dopaminergic system. Our findings also raise concerns about usefulness of novel L-dopa-containing supplements that claim to have neuroprotective and learning-enhancing properties, and present an urgent need to carefully investigate the cognitive outcomes of early pro-dopaminergic interventions in clinical populations often receiving substantially larger doses of L-dopa.

clinical trials↗