Lecture 6 PAD - MCI Treatment PDF

LECTURE 6 – MILD COGNITIVE IMPAIRMEN T (MCI) TREATMENT Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Date Lectur Details Theme e 1 Introduction to Ageing and Dementia 2...

LECTURE 6 – MILD COGNITIVE IMPAIRMEN T (MCI) TREATMENT Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Date Lectur Details Theme e 1 Introduction to Ageing and Dementia 2 Biological Ageing “HEALTHY 3 Cognitive Ageing AGEING AND THE BRAIN” 4 Neurophysiological and Psychosocial Ageing “Talking about Healthy Ageing” discussion 5 MCI – Diagnosis / Research “AGE-RELATED 6 MCI – Treatment DISEASES AND PATHOLOGY” 7 Dementia – Diagnosis / Research 8 Dementia – Treatment “Talking about Dementia” discussion 9 Living with Dementia “THE INTRA- 10 Dementia friendly INDIVIDUAL PERSEPCTIVE” 11 Revision – Feedback and OVERVIEW OF TODAY’S LECTURE PART ONE Current treatment options for MCI. PART TWO Emerging research into improving cognition in MCI.  PA RT O N E : TRE AT M E N T OPTIONS F O R M C I A N BE DON E FOR M CI WHAT CLINICALLY C PATIENTS ? MCI - TREATMENT Currently there are NO drugs or treatments that have been approved by the FDA (Food and Drugs Administration) agency. This is unlike AD in which prescribe cholinesterase inhibitors for memory loss. However, these have big side effects and have not shown any reduction in progression of MCI. The main avenue of treatment is in trying to manage any other cause for the MCI i.e. depression, high blood pressure, sleep disturbances etc..  Recommendations are: (i) Physical Activity (ii) Cognitive Interventions (iii)Dietary and Nutritional Interventions Chen et al (2021) did a systematic review of the current SRR OF diagnosis and treatment of MCI. CLINICAL Guidelines were categorized into 4 main sections: (i) PRACTICE FOR interventions for risk reduction, (ii) pharmacological , MCI (iii) non-pharmalogical interventions (iv) counselling. TREATMENT Green = strong recommendation, Yellow = moderate recommendation, Red = weak recommendation PHYSICAL ACTIVITY AND MCI A number of studies have shown benefits in physical activity (particularly aerobic exercise) and subsequent improvement in cognition especially executive function and memory in MCI, independent functioning and psychological well- being (for review see Nuzum et al., 2019). Parvin and Bolouki, 2022 review that exercise supports cognition in the brain. Mechanisms involved: - Brain Circulation - Myokines (secreted by skeletal muscles). - Brain derived neurotropic factor (BDNF). - Adrenaline (neurotransmitter) - Insulin-like Growth Factor-1 (IGF-1). - Improving Insulin Sensitivity So overall we see a reduction in the auto-immune response (inflammation), increases in neurotropics that support good https://www.frontier neuronal functioning and sin.org/articles/10 increases in neurogenesis i.e..3389/fnhum.2021.77 creation of new neurons. 1553 AE = aerobic exercise; BMI = body mass index; CVRF = cardiovascular risk factor; DASH = Dietary Approaches to Stop Hypertension; ITT = intention to treat; MoCA = Montreal Cognitive Assessment. LIFESTYLE AND NEUROCOGNITION IN OLDER ADULTS WITH COGNITIVE IMPAIRMENTS A RANDOMIZED TRIAL [BLUMNETHAL ET AL (2019)]  AE AND DASH RESULTED IN TheGREATEST largest improvements were observed for participants randomized to IMPROVEME the combined AE and DASH diet NT to those receiving HE. group (d = 0.40, p = 0.012) compared Greater aerobic fitness (b = 2.3, p = 0.049), reduced CVD risk (b = 2.6, p = 0.042), and reduced sodium intake (b = 0.18, p = 0.024) were associated with improvements in executive function. There were no significant improvements in the memory or language/verbal fluency domains. Blumenthal et al (2019) Lifestyle and neurocognition in older adults with cognitive impairments: A randomized trial. Neurology, 92 (3) e212-e223. NUTRITION AND MCI Nutrition can play a key role in providing neuroprotective mechanisms in the brain and ensuring the right micronutrients are provided to optimise brain function. NUTRITIONAL INTERVENTIONS AND MCI Good nutrition in older age has been found to be associated with “Successful Ageing”. Certain nutritional vitamins and minerals are often poorly absorbed or lacking in individual diets which can affect neuronal activity: 1) 1-carbon metabolism, 2) DNA damage and repair, 3) mitochondrial function and glucose metabolism, 4) lipid and phospholipid metabolism and myelination, 5) neurotransmitter synthesis and synaptogenesis, and 6) amyloidosis and Tau protein phosphorylation. B vitamins (and folic acid) are consistently reported as beneficial to brain health. 3 main diets have been linked to improvements in Cognitive function: (i) DASH diet, (ii) Ketogenic (KD) diet, and (iii) Mediterranean (MedDi) diet.  DASH DIET AND MCI The Dietary Approaches to Stop Hypertension (DASH) is designed to reduced high blood pressure and reduce fatty meats, full fat diary and sugar/salt intake. The focus on improving cardiovascular health and increasing blood flow and nutrients to the brain. COMPARISONS OF DIETS  MEDITERRA NEAN DIET AND MCI It is thought that the benefits from this diet are: high intake of monounsaturated fats (MUFAs) and polyphenols from olive oil, the high consumption of polyunsaturated fats (PUFAs) from fish, and the antioxidant properties of vegetables & fruits. NB: many studies performed on These results in reduced individuals in Mediterranean, countries and therefore other lifestyle factors may oxidative stress and contribute to findings? neuro-inflammation, Proposed protective mechanisms of Vinciguerra et al (2020). Influence of Mediterranean diet on brain health and cognitive aswell asand the Mediterranean improved Ketogenic Diets functions. Abbreviations: LDL, Low-Density on Cognitive Status and Decline: A Lipoprotein; ROS, Reactive Oxygen Species cardiovascular Narrative function. Review. Nutrients. 12(4):1019.  KETOGENIC DIET AND MCI Decrease in Amyloid Precursor Protein (APP) results in a decrease in Aβ deposits. Improves insulin secretion and insulin sensitivity resulting in decrease in thickening/hardening of the arteries (atherosclerosis). A lot of supporting evidence for ketogentic diet although caution needed with Proposed protective mechanism of ketogenic diet comorbidity and elderly on brain health and cognitive functions. malnutrition. Abbreviations: ATP, Adenosine Triphosphate; AGEs, Advanced Glycosylated End-products; APP, Amyloid Precursor Protein; PPAR-γ, Peroxisome Vinciguerra et al (2020). Influence of Proliferator-Activated Receptor gamma; ROS, the Mediterranean and Ketogenic Diets Reactive Oxygen Species. on Cognitive Status and Decline: A Narrative Review. Nutrients. 12(4):1019.  THE MIND DIET This takes the benefits to the brain of both the DASH and Mediterranean diets and combines them as a specific diet for those wanting to minimise cognitive decline. The MIND trial followed 923 individuals aged Participants' diets were 58 to 98 for an average of 4.5 years (in a scored by how closely they range of two to 10 years). Diet was assessed matched up with using a 154-item guided questionnaire, and recommendations for the cognitive function was measured yearly using Mediterranean, DASH, or 19 cognitive tests. MIND eating patterns. The MIND DIET shows the best overall improvement for reducing cognitive decline and being neuroprotective even in those with higher AD risk factors. [https://www.todaysgeriatricmedicine.com/archive/0 COGNITIVE TRAINING AND MCI Cognitive interventions have also been outlined as potentially beneficial to MCI patients. COGNITIVE INTERVENTIONS AND MCI In general there is a lot of literature on cognitive interventions on MCI. Many reveal a significant improvement on cognition after adherence. We can categorize cognitive interventions into several types: (1) cognitive stimulation, (2) cognitive training, (3) cognitive rehabilitation, and (4) multicomponent involving physical exercise or another intervention type (meditation/nutrition) alongside cognition.  COGNITIVE STIMULATION – ENGAGEMENT IN A RANGE OF ACTIVITIES/DISCUSSION (GROUP) COGNITIVE TRAINING – IMPROVE OR MAINTAIN GLOBAL COGNITIVE FUNCTION. COGNITIVE REHABILITATION – AIMED AT RESTORING A LOST IMPAIRED COGNITIVE FUNCTION  REVIEW OF COGNITIVE INTERVENTIONS IN MCI (WANG ET AL., 2020) Wang et al (2020) did a meta analysis of 25 RCT studies: (i) CS, (ii) CT, (iii) CR (iv) MT (v) PE and (vi) MI interventions. They found that NPT were beneficial and ranked them in order of effect size from best to worst: CS, PE, MI, MT, CT and CR. The used the MMSE (before versus after) as the output measure of success of the intervention. MCI – Treatments: TEST YOUR KNOWLEDGE https://vevox.app/#/m/122977973 Session ID: 122-977-973  Interactive Task In groups of 3 students each one will take a intervention strategy for MCI, and argue it’s value in preventing delaying further cognitive decline: Physical Cognitive Nutrition Activity Intervent al ions intervent ions BRAIN BREAK  PART T W O: POTENTIALS APPR OACH RESEARCH IN MCI Can Brain Stimulation Delay Cognitive Decline? Prof Melanie Burke Professor in Cognitive Ageing and Neuroimaging School of Psychology University of Leeds  Acknowledgements: PhD Student: Amy Miller MSc and UG students: Valashi Balaji, Abbie Croucher, Samantha Booth, Tessa Vuister, Sophie Harrison, Alisha Juma RESEARCH ARTICLE (Open Access) Does repetitive transcranial magnetic stimulation improve cognitive function in age-related neurodegenerative diseases? A systematic review and meta-analysis. Amy Miller, Richard J. Allen, Alisha A. Juma, Rumana Chowdhury, Melanie Burke  Overview Introduction to cognitive decline and neuroplasticity. – Current research questions Methods: – Introduction to TMS and fNIRS – Experimental Design Preliminary results: – Cognitive results – fNIRS results Conclusions and future directions.  Linking AD Pathology to Cognition Amyloid (plaques) and neurofibrillary (tangles) pathology results in neuronal and synaptic dysfunction. Selective neurodegeneration. Cognitive Impairment: attention, working memory, learning etc.. https:// www.nia.nih.gov/  Brain Adaptation Theory in Cognitive Decline (STAC model) Reuter-Lorenz and Park (2014) review advocates that the core to successful aging is brain adaptation. Plasticity in the cortex is needed to adjust to neural challenges (atrophy/neurodegeneration). This is known as the Scaffolding Theory of Ageing and Cognition (STAC). A failure of neuroplasticity has been related to a number of neurodegenerative diseases including Alzheimer's (Rowan et al, 2003). Plastici ty Measures If adequate of cognitive neuroplasticity is function Workin not happening in g Memory Plastic AD then ity what can Attentio be done ? n Inhibiti on Learnin g Reuter-Lorenz and  Does stimulation influence cognitive performance ? SRR and Meta analysis (Miller et al, 2023, Int J Geriatric Psychiatry). Good, but only reports global cognitive effect. What about more specific cognitive effects and how is this impacting neural activity ? NB: Outcome cognitive measures = MoCA or MMSE  Current Research Focus … Regions of DLPFC Interest: The Attention DLPFC for it’s role (RH), in a plethora of Working executive functions. memory (RH), This area is part of Inhibition the dorsal and stream pathway learning used in most cognitive tasks. Research Questions: 1) Can we artificially induce plasticity in the DLPFC? 2) How does this stimulation influence specific cognitive domains? 3) What changes in the brain do we see post-  Methods: Brain Stimulation Transcranial Magnetic Stimulation (TMS) - A magnetic coil is placed next to the scalp which transmits electrical pulses directly through the scalp and skull into the underlying neuronal tissue. - Intermittent Theta Burst Stimulation (iTBS): Excitation is achieved when 3 pulses (triplet) are delivered at 50Hz for 2s, followed by a 8s wait for 600 pulses in total. Huang et al (2005)  Methods: Brain Imaging  In functional Near Infra-Red Spectroscopy (fNIRS), optodes transmit infra-red light into the brain (passes through skin, bone), but RED blood absorbs the red light.  The more oxygen in the blood, the redder it is and hence the more infra-red light gets absorbed and is NOT reflected. We can record how much IR light is reflected back using detector and transmitter optodes. Detector Transmitter Optode Optode  Method – fNIRS and  47 Participants: 19–73TBS years old (M = 47, SD = 20), 20M/33F. N Age (years) Young 17 21.87 (2.36) Age Middle 15 54.27 (5.23) Older 15 66.33 (4.58)  Record fNIRS (across DLPFC @ 10Hz, Oxymon, Artinis) throughout. iTBS applied to F3 (LH) and F4 (RH).  iTBS stimulated at 50Hz maximum stimulator output for all participants. Localization using 10-20 EEG cap configuration on fNIRS cap.  Triplets of pulses at 50Hz delivered at 5Hz for 2 seconds followed by a 8 second rest = 600 pulses during the 190s stimulation.  Method – Session Design Control iTBS vertex  All subjects performed all conditions with a week between each session.  Touch screen and eye movements were recorded throughout as a measure of cognitive performance (RT and accuracy).  Baseline versus vertex (SHAM/Control) to adjust for  Q1) Can we artificially induce plasticity in the We did a pilotDLPFC? study of 43 young adults and recorded brain activity in the DLPFC during Right iTBS brain stimulation. Hemisphere Left Hemisphere iTBS RH iTBS – LH iTBS iTBS  iTBS on the Right Hemisphere causes reduced BOLD responses in both the ipsi, mid and contralateral hemisphere.  iTBS on the Left Hemisphere results in increased BOLD signal in the midline  Q2) What effect does iTBS have on cognitive ability ? Significantly faster reaction times in Working Memory after Left and Right iTBS in MIDDLE and OLDER participants. Before iTBS After iTBS 1600 1400 1200 RT (milliseconds) 1000 800 600 400 Significantly more 200 accurate in Working 0 L iTBS Young R iTBS Memory with RH iTBS L iTBS R iTBS Middle-age L iTBS Older R iTBS in MIDDLE and OLDER participants. Age group  Q3) What changes in the brain do we see to task in response to the stimulation when performing tasks?  So younger and older adults show this improvement with faster responses AFTER right hemisphere iTBS.  NB: Decreases in midline also shown DURING iTBS more prominently during RH iTBS.  Interestingly changes in oxygenation levels are completely different in these groups. Young = excitation, older = inhibition.  Conclusions What can we say about Brain Stimulation and Cognitive Performance: Artificial brain stimulation  Q1: Can we canartificially improve induce plasticity in the DLPFC? cognitive performance  Yes, we can withinRH induce alterations brain activity and networks in the brain. iTBS.  LH iTBS causes midline and contralateral excitation during iTBS could provide a more stimulation targeted method of  RH iTBS midline addressing cognitiveinhibition during stimulation. and contralateral decline without drug-  Q2: How does this stimulation influence cognitive related side effects. performance ?  Working memory RT improved with RH iTBS only in middle and older participants.  Q3: What changes in the brain do we see to cognitive tasks in response to the stimulation when performing tasks ?  We found significant decreases in HbO post RH iTBS in ipsi and  Future Directions Further analysis on subsequent data:  Within subject analyses: responders versus non-responders.  BOLD is limited, what about connectivity and time-course changes in the signals.  More comparisons across age groups as there are clear differences. Especially middle age !! Further brain area & protocols:  Looking at effects of RH iTBS in Mild Cognitive Impairment/AD for improving cognitive outcomes.  Considerations for long-term improvement  Thank – you for listening. Any questions Dr Melanie Burke: ? [email protected] Acknowledgements and contributions to this project include: Elliott Groves, Jack Dagless, Michael Wyeth, Rebecca Udall, Stephanie Mavrou, Sumayyah Patel, and Zoe Tomlinson  READING LIST FOR TODAYS LECTURE: Chen Y-X, et al (2021) Diagnosis and Treatment for Mild Cognitive Impairment: A Systematic Review of Clinical Practice Guidelines and Consensus Statements. Front. Neurol. 12:719849. Nuzum H, et al. (2020) Potential Benefits of Physical Activity in MCI and Dementia. Behav Neurol. 12;2020 :7807856. Blumenthal et al (2019) Lifestyle and neurocognition in older adults with cognitive impairments: A randomized trial. Neurology, 92 (3) e212-e223. Wang et al. (2020) Effects of non-pharmacological therapies for people with mild cognitive impairment. A Bayesian network meta-analysis. Int J Geriatr Psychiatry. 35(6):591-600. Further reading: Vinciguerra et al (2020). Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review. Nutrients. 12(4):1019. Morris et al. (2014) MIND diet more predictive than DASH or Mediterranean diet scores. Alzheimers Dement. 10(4):P166. Wang et al (2020) Effects of non-pharmacological therapies for people with mild cognitive impairment. A Bayesian network meta-analysis. Int J Geriatr