Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising ...candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia.
MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.
MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.
ClinicalTrials.gov (NCT05109169).
Background
Because of the shift towards earlier diagnosis of dementia and/or Alzheimer's disease (AD), increasing numbers of individuals with subjective cognitive decline (SCD) and mild cognitive ...impairment (MCI) are seen in memory clinics. Yet, evidence indicates that there is room for improvement when it comes to tailoring of the diagnostic work‐up to the needs of individual patients. To optimize the quality of care, we explored patients' perspectives regarding the diagnostic work‐up at a specialized memory clinic.
Methods
This interview study was conducted at Karolinska University Hospital (Sweden). The comprehensive diagnostic work‐up for dementia at the memory clinic in Solna is conducted within 1 week. A sample of 15 patients (8 female; mean age = 61 years range 50–72; 11 SCD, 1 MCI and 3 AD dementia) was purposively selected for a series of three semistructured interviews, focussing on (1) needs and expectations (during the week of diagnostic testing), (2) experiences (within 2 weeks after test‐result disclosure) and (3) reflections and evaluation (3 months after disclosure). Transcribed audio‐recorded data were analyzed using thematic content analysis (using MaxQDA software).
Results
Three key themes were identified: (1) the expectations and motivations of individuals for visiting the memory clinic strongly impacted their experience; (2) the diagnostic work‐up impacted individuals psychosocially and (3) the diagnostic work‐up provided an opportunity to motivate individuals to adopt a healthier lifestyle.
Conclusion
Our findings underscore the importance of enquiring about the expectations and needs of individuals referred to a specialized memory clinic, allowing for expectation management and personalization of provided information/advice, and potentially informing the selection of patients in need of a comprehensive diagnostic work‐up. Structural guidance might be needed to support those with SCD and MCI to help them cope with uncertainty, potentially resolve their issues, and/or stimulate brain health.
Patient or Public Contribution
We gathered the perspectives of 15 individuals who had been referred to the memory clinic at three different time points through semistructured interviews, and these interviews were the primary data source.
•Cortisol & neuroinflammation interacted in their relation to neuroimaging correlates.•Greater angiogenesis marker levels associated with more severe white matter lesions.•Neuroinflammation ...interacted with beta-amyloid in relation to visual rating scales.•Some evidence was found for interaction between diurnal cortisol and beta-amyloid.
Neuroinflammation is a hallmark of the Alzheimer’s disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates.
134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales.
Higher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales.
This study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.
Abstract INTRODUCTION Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. ...METHODS We examined cross‐sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD‐related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3‐year follow‐up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. RESULTS Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD‐related biomarkers. DISCUSSION Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. Highlights Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve CR) in memory clinic patients. Cortisol awakening response modified the relation between CR and P‐tau 181 , a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted.
Background
This is the study plan of the Karolinska NeuroCOVID study, a study of neurocognitive impairment after severe COVID‐19, relating post‐intensive care unit (ICU) cognitive and neurological ...deficits to biofluid markers and MRI. The COVID‐19 pandemic has posed enormous health challenges to individuals and health‐care systems worldwide. An emerging feature of severe COVID‐19 is that of temporary and extended neurocognitive impairment, exhibiting a myriad of symptoms and signs. The causes of this symptomatology have not yet been fully elucidated.
Methods
In this study, we aim to investigate patients treated for severe COVID‐19 in the ICU, as to describe and relate serum‐, plasma‐ and cerebrospinal fluid‐borne molecular and cellular biomarkers of immune activity, coagulopathy, cerebral damage, neuronal inflammation, and degeneration, to the temporal development of structural and functional changes within the brain as evident by serial MRI and extensive cognitive assessments at 3–12 months after ICU discharge.
Results
To date, we have performed 51 3‐month follow‐up MRIs in the ICU survivors. Of these, two patients (~4%) have had incidental findings on brain MRI findings requiring activation of the Incidental Findings Management Plan. Furthermore, the neuropsychological and neurological examinations have so far revealed varying and mixed patterns. Several patients expressed cognitive and/or mental concerns and fatigue, complaints closely related to brain fog.
Conclusion
The study goal is to gain a better understanding of the pathological mechanisms and neurological consequences of this new disease, with a special emphasis on neurodegenerative and neuroinflammatory processes, in order to identify targets of intervention and rehabilitation.
Allostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health ...problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up.
Data from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education.
Higher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years.
This study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.
ObjectiveThis study aims to investigate the relationship between diurnal cortisol patterns, cognition and Alzheimer’s disease (AD) biomarkers in memory clinic patients.MethodMemory clinic patients ...were recruited from Karolinska University Hospital in Sweden (n=155). Diurnal cortisol patterns were assessed using five measures: awakening levels, cortisol awakening response, bedtime levels, the ratio of awakening to bedtime levels (AM/PM ratio) and total daily output. Cognition was measured in five domains: memory, working memory, processing speed, perceptual reasoning and overall cognition. AD biomarkers Aβ42, total tau and phosphorylated tau were assessed from cerebrospinal fluid (CSF). Cognition was measured at follow-up (average 32 months) in a subsample of participants (n=57).ResultsIn assessing the associations between cortisol and cognition, higher awakening cortisol levels were associated with greater processing speed at baseline. No relationship was found between diurnal cortisol patterns and change in cognition over time or CSF AD biomarkers in the total sample. After stratification by CSF Aβ42 levels, higher awakening cortisol levels were associated with worse memory performance in amyloid-positive participants. In amyloid-negative participants, higher bedtime cortisol levels and a lower AM/PM ratio were associated with lower overall cognition, greater awakening cortisol levels were associated with better processing speed, and a higher AM/PM ratio was associated with better perceptual reasoning. Additionally, higher awakening cortisol levels were associated with lower CSF Aβ42 levels in amyloid-positive participants, while higher bedtime cortisol levels and a lower AM/PM ratio were associated with higher CSF total tau in amyloid-negative participants.ConclusionsOur findings suggest that diurnal cortisol patterns are associated with cognitive function and provide new insights into the association between diurnal cortisol patterns and AD-related CSF biomarkers. Further research is needed to examine the complex relationship between cortisol, cognition and brain pathology.
Background
Receiving a diagnosis of dementia before the age of 65 has a considerable impact on a person’s everyday life. The social impact most likely include work and family life, as the person may ...be the main or sole provider for the family. During the disease there are several critical points, some may differ from those identified in late‐onset dementia. Transitions are initiated by critical points or events, followed by a period of instability and distress, in which the person is vulnerable and at risk of making unhealthy decisions. This study aims to describe transitions and identify critical points in the initial phase of early‐onset dementia.
Method
Participants younger than 65 (mean age 60), with a MMSE score greater than 24, were recruited from a specialized memory clinic in Sweden. In‐dept interviews were conducted shortly after diagnosis, focusing on the period before receiving the diagnosis, on how the diagnosis has impacted their daily life, as well as their thoughts about the future. A preliminary analysis, using qualitative content analysis, was performed on nine interviews.
Results
In the preliminary results early (forced) retirement was identified as a main critical point, leading to both economic and psychosocial issues. The participants all knew about the later phases of dementia but had different thoughts how to approach this. Most of the participants actively searched for information about the disease and prognosis, as well as information about how to postpone decline, while others did not want any further information about the disease.
Conclusion
Several signs of transitions and critical points were identified, some of them being specific to people younger than 65. The results from this study can help professional caregivers to facilitate transitions and enhance the wellbeing and quality of life in young people living with dementia and their family.
Abstract
Background
Receiving a diagnosis of dementia before the age of 65 has a considerable impact on a person’s everyday life. The social impact most likely include work and family life, as the ...person may be the main or sole provider for the family. During the disease there are several critical points, some may differ from those identified in late‐onset dementia. Transitions are initiated by critical points or events, followed by a period of instability and distress, in which the person is vulnerable and at risk of making unhealthy decisions. This study aims to describe transitions and identify critical points in the initial phase of early‐onset dementia.
Method
Participants younger than 65 (mean age 60), with a MMSE score greater than 24, were recruited from a specialized memory clinic in Sweden. In‐dept interviews were conducted shortly after diagnosis, focusing on the period before receiving the diagnosis, on how the diagnosis has impacted their daily life, as well as their thoughts about the future. A preliminary analysis, using qualitative content analysis, was performed on nine interviews.
Results
In the preliminary results early (forced) retirement was identified as a main critical point, leading to both economic and psychosocial issues. The participants all knew about the later phases of dementia but had different thoughts how to approach this. Most of the participants actively searched for information about the disease and prognosis, as well as information about how to postpone decline, while others did not want any further information about the disease.
Conclusion
Several signs of transitions and critical points were identified, some of them being specific to people younger than 65. The results from this study can help professional caregivers to facilitate transitions and enhance the wellbeing and quality of life in young people living with dementia and their family.
Receiving a diagnosis of dementia before the age of 65 has a huge impact on everyday life. Previously, the disease trajectory has mainly been described from the perspective of older persons. However, ...young persons with dementia are confronted with specific challenges, influencing the type of life-changing events, or ‘critical points’ that they may experience. The aim of this study was therefore to describe experiences of persons recently being diagnosed with young-onset dementia. In total, 14 participants with dementia due to Alzheimer’s disease (10 woman/4 men) with an average age of 59 were included in the study. Interviews were conducted within 2 months after receiving the diagnosis and analyzed using qualitative content analysis with an inductive approach, resulting in three categories: (1) A life changing moment, (2) An ongoing process, and (3) Remaining in control. The findings show that receiving such a diagnosis was experienced by participants as a life changing moment, followed by them seeking to come to terms with the diagnosis and reflecting on its meaning, in which various strategies were adopted to remain in control. The current study highlights three critical points considering the diagnosis of young-onset dementia that warrant special attention and provides insight into factors related to delay in healthy transitioning after receiving the diagnosis, as well as factors that may facilitate successful transitions.
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