1. Language Functions in the Aging Brain: A Pathophysiological Exploration Dalia Cahana-Amitay VA Boston Healthcare System & Boston University School of Medicine LSA 2013 Language & Aging Workshop

2. Gap: Neurobiological Mechanisms 1

3.  Cardiovascular and metabolic changes in the brain are factors underlying some of the language changes observed with age  Evidence from studies examining effects of  Hypertension  Diabetes  The metabolic syndrome What Do we Know? 2

4. 3 Effects of Hypertension (HTN) and Diabetes Mellitus (DM) on Lexical Retrieval (Albert et al., 2009, JAGS) * * + + * - p<.05 + - p<.10 Percentage Difference in Naming Accuracy from Participants with HTN and DM

5. Effects of HTN and DM on Sentence Processing in Aging (Cahana-Amitay et al., 2013, JGPS) 4

6. 5 Effect of Metabolic Syndrome on Lexical Retrieval AND Sentence Processing * - p<.05 * * Percent difference in Accuracy on Naming and Sentence Comprehension Tasks in those with Metabolic Syndrome

7.  Decline in vascular health and occurrence of metabolic diseases, can result from chronic multisystem physiologic dysregulation (McEwen & Stellar, 1993; McEwen, 1998; Glei et al., 2005; Piazza et al., 2010).  Physiologic dysregulation: the long-term effects of over/under-activation of physiological systems, in response to environmental stressors, often interpreted as “aging effects” 6 Vascular and Metabolic Health: Pathophysiologic Consequences

8. Biological Systems Affected 7 Systems  The hypothalamic- pituitary-adrenal (HPA) axis,  The sympathetic nervous system (SNS),  The immune system,  Cardiovascular and metabolic processes Biomarkers  Cardiovascular  Metabolic  Inflammatory  Example: glucocorticoids, such as cortisol, related to HPA system

9.  Studied mostly in relation to memory  Chronically elevated levels of cortisol among older adults are associated with impaired memory (e.g., Lupien et al., 2005; Lupien et al., 2007; MacLullich et al., 2005)  Chronicity accelerates neural changes that “age” the brain 8 Cognitive effects of Physiologic Dysregulation

10.  Not all biomarkers of physiologic dysregulation carry equal weight in predicting functional changes among older adults (Karlamangla et al., 2002)  Cumulative effect among older adults associated with:  Physical decline  Cognitive impairment  Mood changes  Increased risk of mortality (Goldman et al., 2006; Juster, McEwen, & Lupien, 2010; Seeman et al., 2010) 9 Cumulative Effects

11.  BUT some  Impairments in recall of confrontation naming (Seeman et al., 2010)  Reduced category fluency (Greendale et al., 2000; MacLullich et al., 2005; Beluche et al., 2010) 10 Effects on Language? Unexplored

12. Age-related language decrements are associated with vascular and metabolic changes in brain regions which are also a prime target of stress-induced pathophysiological processes 11 Why Look at Language and Physiologic Dysregulation?

13. The Neural Correlates of Cortisol Regulation in Response to Stress Dedovic, Duchesne, Andrews, Engert, & Pruessner, 2009, NeuroImage) 12

14.  (1) Does stress-induced physiologic dysregulation (measured by a summary index of biomarkers and self-ratings of stress) adversely affect lexical retrieval and sentence processing abilities (measured in terms of poorer accuracy)?  (2) If so, are these effects independent of age effects? 13 Research Questions

15. Cardiovascular/ Respiratory AnthropometryMetabolicInflammation Systolic Blood Pressure Diastolic Blood Pressure Heart Rate FVC FEV 1 Body mass index (BMI) Waist circumference Waist/Hip Ratio Fasting Glucose Insulin HbA1c Triglycerides Low Density Lipoprotein high Density Lipoprotein Homocysteine Albumin Creatinine High-Sensitivity C- Reactive Protein White blood cell count 14 Biomarkers for Physiologic Dysregulation Index

16. MeasureDescription Perceived Stress Scale (PSS) (Rohleder et al., 2004) Related with basal HPA axis activity. The PSS is a 10-item questionnaire probing participants’ feelings and thoughts experienced during the last month. The participants are asked to rate how often they have felt or thought in a certain way. Participants with higher PSS scores have been found to have lower Mini-Mental scores (Wolf et al,. 2005). Perceived Stress Reactivity Scale (PSRS) (Kirschbaum & Hellhammer, 1994) Related to Sympathetic Nervous System (salivary alpha-amylase (sAA)). A 23-item questionnaire consisting of 1 overall scale and 5 subscales, designed to assess participants’ subjective perception of stress in dealing with different situations they may have encountered in the past. The test has been shown to have high consistency and has been associated with self-efficacy, neuroticism, chronic stress and perceived stress. Chronic Stress Screening Scale (CSSS) (Rohleder et al., 2009) Related to Sympathetic Nervous System (salivary alpha-amylase (sAA)). The CSSS is a 12- item scale derived from the Trier Inventory for the Assessment of Chronic Stress a large chronic stress inventory. 15 Perceived Stress Measures

17.  Those with greater degree of physiologic dysregulation and perceived stress will evidence worse language performance  These effects will be independent of age 16 Predictions

18. Stress-Induced Pathophysiology of Language in the Aging Brain 17 Existing evidenceAim 1 Aim 2