A Novel Approach to Monitoring Cognitive Adverse Events for Interventional Studies Involving Advanced Dementia Patients: Insights From the Electroconvulsive Therapy for Agitation in Dementia Study.

OBJECTIVE: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). METHODS: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. RESULTS: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. CONCLUSIONS: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

The Effects of Baseline Impaired Global Cognitive Function on the Efficacy and Cognitive Effects of Electroconvulsive Therapy in Geriatric Patients: A Retrospective Cohort Study.

OBJECTIVES: This study explores the association between baseline impaired global cognitive function and changes in global cognitive function and depression among geriatric patients undergoing acute course electroconvulsive therapy (ECT). DESIGN: Retrospective cohort study. SETTING: Single freestanding psychiatric hospital. PARTICIPANTS: Patients aged 50 and older receiving ECT. INTERVENTIONS: 10 ECT treatments. MEASUREMENTS: Cognitive assessments with the Montreal Cognitive Assessment (MoCA). Depression assessment with the Quick Inventory of Depressive Symptomatology Self Report 16 item scale (QIDS). RESULTS: Baseline and follow-up data were available for 684 patients. On average, patients with baseline normal cognition (MoCA ≥26; N = 371) had a decrease in MoCA of -1.44±0.26 points over the course of treatment, while those with baseline impaired global cognitive function (MoCA <26; N = 313) had an increase in MoCA of 1.72±0.25 points. Baseline cognitive status was not associated with a differential response on the QIDS. CONCLUSIONS: Patients with baseline impaired global cognitive function did not demonstrate a worsening in cognition following ECT, and baseline global cognitive function was not associated with a differential change in depression with ECT. These results suggest that impaired global cognitive function should not be viewed as a contraindication to ECT in geriatric patients.

Identifying Delirium in Persons With Moderate or Severe Dementia: Review of Challenges and an Illustrative Approach.

Delirium and dementia are common causes of cognitive impairment among older adults, which often coexist. Delirium is associated with poor clinical outcomes, and is more frequent and more severe in patients with dementia. Identifying delirium in the presence of dementia, also described as delirium superimposed on dementia (DSD), is particularly challenging, as symptoms of delirium such as inattention, cognitive dysfunction, and altered level of consciousness, are also features of dementia. Because DSD is associated with poorer clinical outcomes than dementia alone, detecting delirium is important for reducing morbidity and mortality in this population. We review a number of delirium screening instruments that have shown promise for use in DSD, including the 4-DSD, combined Six Item Cognitive Impairment Test (6-CIT) and 4 'A's Test (4AT), Confusion Assessment Method (CAM), and the combined UB2 and 3D-CAM (UB-CAM). Each has advantages and disadvantages. We then describe the operationalization of a CAM-based approach in a current ECT in dementia project as an example of modifying an existing instrument for patients with moderate to severe dementia. Ultimately, any instrument modified will need to be validated against a standard clinical reference, in order to fully establish its sensitivity and specificity in the moderate to severe dementia population. Future work is greatly needed to advance the challenging area of accurate identification of delirium in moderate or severe dementia.

Simulated Electroconvulsive Therapy: A Novel Approach to a Control Group in Clinical Trials.

OBJECTIVES: Agitation is the most common behavioral symptom of Alzheimer disease (AD) affecting approximately 40% to 60% of the AD population, yet there are no Food and Drug Administration-approved therapies for the myriad of behavioral or psychological symptoms of dementia. There is growing evidence from naturalistic studies that electroconvulsive therapy (ECT) is a safe and effective treatment for agitation in AD patients who are refractory to pharmacotherapy and behavioral interventions. Despite the existing evidence, ECT remains underused because of stigma, lack of education, and concerns regarding adverse cognitive effects. Randomized controlled clinical trials of ECT are an opportunity to provide high-quality evidence of ECT as a safe and efficacious treatment for agitation in the AD population. We describe the methods for the Electroconvulsive Therapy in Alzheimer's Dementia study, which uses a novel, simulated ECT (S-ECT) control group to conduct a single-blind efficacy study of ECT for the treatment of agitation and aggression in individuals with moderate to severe AD. METHODS: We discuss the rationale, study design, methodology, ethical and practical challenges, and management strategies in using an S-ECT group as the comparator arm in this randomized controlled trial of ECT in AD-related treatment refractory agitation and aggression. CONCLUSIONS: Validation of the safety and efficacy of ECT in patients with advanced AD with refractory agitation and aggression is necessary. This can be accomplished through creative formulation of S-ECT groups that effectively maintain the blind while providing scientific integrity.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Dependent Personality in Depressed Older Adults: A Case Report and Systematic Review.

Personality pathology in older adults is largely understudied. Here, we present a case report of an older adult who presented to an inpatient geriatric psychiatry unit with dependent personality traits in the context of chronic major depressive disorder, followed by a systematic review of the literature to identify research regarding the diagnosis and prevalence of dependent personality in depressed older adults. We identified 11 studies relevant to this topic. Synthesis of these data revealed that dependent personality is generally more common in depressed older adults compared to other personality disorders. However, studies were limited by small sample sizes and the use of assessments not validated for use in older adults. Therefore, it is difficult to draw conclusions from the available data. Potential implications for patient outcomes and health care services utilization are discussed. Our review highlights the need for larger scale research and personality assessments which are sensitive to age-related factors in order to draw evidence-based conclusions.

Clinical Trials and Tribulations in the COVID-19 Era.

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

Lamotrigine Therapy and Biomarkers of Cerebral Energy Metabolism in Older Age Bipolar Depression.

OBJECTIVE: This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. METHODS: Individuals (n = 21, mean age: 62.0 ± 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 ± 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. RESULTS: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. CONCLUSION: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

Application of magnetic resonance spectroscopy in geriatric mood disorders.

The prevalence of mood disorders in the rapidly-growing older adult population merits attention due to the likelihood of increased medical comorbidities, risk of hospitalization or institutionalization, and strains placed on caregivers and healthcare providers. Magnetic resonance spectroscopy (MRS) quantifies biochemical compounds in vivo, and has been used specifically for analyses of neural metabolism and bioenergetics in older adults with mood disorders, usually via proton or phosphorous spectroscopy. While yet to be clinically implemented, data gathered from research subjects may help indicate potential biomarkers of disease state or trait or putative drug targets. Three prevailing hypotheses for these mood disorders are used as a framework for the present review, and the current biochemical findings within each are discussed with respect to particular metabolites and brain regions. This review covers studies of MRS in geriatric mood disorders and reveals persisting gaps in research knowledge, especially with regard to older age bipolar disorder. Further MRS work, using higher field strengths and larger sample sizes, is warranted in order to better understand the neurobiology of these prevalent late-life disorders.

Brain levels of high-energy phosphate metabolites and executive function in geriatric depression.

OBJECTIVES: Depression in late life has been associated with difficulties in cognitive processing, particularly in the domains of executive function, processing speed and memory, and increases the risk of developing dementia suggesting a neurodegenerative phenotype. Mitochondrial dysfunction is frequently an early event in neurodegenerative illnesses and may be operative in patients with late life depression. Phosphorus magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules produced by mitochondria. METHODS: Ten patients with late life depression and eight normal elderly controls were studied with Stroop color and interference tests, which are widely used measures of processing speed and executive function, respectively, followed by (31P) MRS 3-dimensional chemical-shift imaging measuring levels of adenosine triphosphate, phosphocreatine, inorganic phosphate, and pH over the whole brain. RESULTS: In all subjects, gray matter phosphocreatine was positively associated with Stroop interference. Levels of white matter adenosine triphosphate were associated with Stroop interference in subjects with late life depression but not normal elderly. There was also a complementary association between white matter inorganic phosphate and Stroop interference in late life depression patients. CONCLUSIONS: These findings suggest two independent sources of executive function dependence on bioenergetic state in the aging brain. The dependence of executive function performance in subjects with late life depression on ATP in white matter may be associated with mitochondrial impairment and is consistent with predictions of the vascular depression hypothesis. Further research with wider neuropsychological testing targeting bioenergetic markers could help clarify the scope of these effects. Copyright © 2016 John Wiley & Sons, Ltd.

Safety and utility of acute electroconvulsive therapy for agitation and aggression in dementia.

OBJECTIVE: Agitation and aggression are among the most frequent and disruptive behavioral complications of dementia that contribute to increased cost of care, hospitalization, caregiver burden, and risk of premature institutionalization. This current study examined the safety and efficacy of electroconvulsive therapy (ECT) as a treatment for behavioral disturbances in dementia. We hypothesized that ECT would result in reduced agitated and aggressive behaviors between baseline and discharge. METHODS: Twenty-three participants admitted to McLean Hospital (Belmont, MA, USA) and Pine Rest Christian Mental Health Services (Grand Rapids, MI, USA), with a diagnosis of dementia who were referred for ECT to treat agitation and/or aggression, were enrolled in the study. We administered the Cohen-Mansfield Agitation Inventory-Short Form, Neuropsychiatric Inventory-Nursing Home Version, Cornell Scale for Depression in Dementia, and the Clinical Global Impression Scale at baseline, during, and after the ECT course. RESULTS: Regression analyses revealed a significant decrease from baseline to discharge on the Cohen-Mansfield Agitation Inventory (F(4,8) = 13.3; p = 0.006) and Neuropsychiatric Inventory (F(4,31) = 14.6; p < 0.001). There was no statistically significant change in scores on the Cornell Scale for Depression in Dementia. The Clinical Global Impression scores on average changed from a rating of "markedly agitated/aggressive" at baseline to "borderline agitated/aggressive" at discharge. Treatment with ECT was well tolerated by most participants; discontinuation of ECT occurred for two participants because of recurrence of agitation and for three participants because of adverse events. CONCLUSIONS: Electroconvulsive therapy may be a safe treatment option to reduce symptoms of agitation and aggression in patients with dementia whose behaviors are refractory to medication management.

Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms.

OBJECTIVE: Behavioral disturbances occur frequently in demented individuals and greatly increase the burden of their care. The efficacy of pharmacotherapeutic treatment options is modest. This study was conducted to explore the efficacy and safety of dronabinol as an adjunctive treatment for agitation and aggressive behavior in severely demented patients. METHODS: Using a retrospective systematic chart review, we studied 40 inpatients from the McLean Hospital Geriatric Neuropsychiatry Inpatient Unit diagnosed with dementia and treated with dronabinol for behavioral or appetite disturbances. A group of geriatric psychiatrists consulted medical records to rate the patients' behaviors prior to initiation of dronabinol treatment and following up to seven days of treatment, using the Pittsburgh Agitation Scale, Clinical Global Impression, and Global Assessment of Functioning. Data on percentage of food consumed at each meal, sleep duration, and adverse events were also collected from medical records. RESULTS: The addition of dronabinol to patients' treatment regimens was associated with significant decreases in all domains of the Pittsburgh Agitation Scale. There were also significant improvements in Clinical Global Impression scores, sleep duration and percentage of meals consumed during the treatment periods. Twenty-six adverse events were recorded during dronabinol treatment, none of which led to medication discontinuation. CONCLUSION: This report represents the largest studied cohort of dementia patients treated with dronabinol to date and confirms earlier reports that dronabinol can serve as an adjunctive treatment for neuropsychiatric symptoms in dementia. Further research, including prospective controlled trials, is needed to clarify dronabinol's role in treating noncognitive behavioral symptoms of demented individuals.

Tissue-specific differences in brain phosphodiesters in late-life major depression.

OBJECTIVE: Late-life depression has been hypothesized to have a neurodegenerative component that leads to impaired executive function and increases in subcortical white matter hyperintensities. Phosphorus magnetic resonance spectroscopy (MRS) can quantify several important phosphorus metabolites in the brain, particularly the anabolic precursors and catabolic metabolites of the constituents of cell membranes, which could be altered by neurodegenerative activity. METHODS: Ten patients with late-life major depression who were medication free at time of study and 11 aged normal comparison subjects were studied using (31)P MRS three-dimensional chemical shift imaging at 4 Tesla. Phosphatidylcholine and phosphatidylethanolamine comprise 90% of cell membranes in brain but cannot be quantified precisely with (31)P MRS. We measured phosphocholine and phosphoethanolamine, which are anabolic precursors, as well as glycerophosphocholine and glycerophosphoethanolamine, which are catabolic metabolites of phosphatidylcholine and phosphatidylethanolamine. RESULTS: In accordance with our hypotheses, glycerophosphoethanolamine was elevated in white matter of depressed subjects, suggesting enhanced breakdown of cell membranes in these subjects. Glycerophosphocholine did not show any significant difference between comparison and depressed subjects but both showed an enhancement in white matter compared with gray matter. Contrary to our hypotheses, neither phosphocholine nor phosphoethanolamine showed evidence for reduction in late-life depression. CONCLUSION: These findings support the hypothesis that neurodegenerative processes occur in white matter in patients with late-life depression more than in the normal elderly population.

Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial.

PURPOSE: Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (ßHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy. METHODS: Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary ßHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months. RESULTS: Capillary ßHB indicated women achieved nutritional ketosis (Phase I mean: 0.8 mM (n = 15); Phase II mean: 0.7 mM (n = 9)). Body weight decreased 10% after three months, primarily from body fat. Fasting plasma glucose, plasma insulin, and insulin resistance also decreased significantly after three months (p < 0.01), an effect that persisted at six months. CONCLUSIONS: Women diagnosed with MBC undergoing chemotherapy can safely achieve and maintain nutritional ketosis, while improving body composition and insulin resistance, out to six months.

Safety and efficacy of electroconvulsive therapy for the treatment of agitation and aggression in patients with dementia.

OBJECTIVES: Noncognitive behavioral disturbances including agitation and aggression frequently accompany the cognitive symptoms of dementia accounting for much of dementia's morbidity, yet treatment options are currently limited. The authors examine the safety and efficacy of Electroconvulsive Therapy (ECT) for agitation and aggression in dementia patients. DESIGN: Retrospective systematic chart review. SETTING: McLean Hospital's geriatric neuropsychiatry unit. PARTICIPANTS: Sixteen patients with a diagnosis of dementia treated with ECT for agitation/aggression during 2004-2007. MEASUREMENTS: Clinical charts were rated on the Pittsburgh Agitation Scale as the primary outcome, the Clinical Global Impression scale and the Global Assessment of Functioning pre- and post-ECT. RESULTS: 16 patients of mean age 66.6 ± 8.3 years were studied. Their average overall and pre-ECT lengths of stay were 59.7 ± 39.7 days and 23 ± 15.7 days, respectively. Patients received a mean of 9 ECT treatments, mostly bilateral. Patients showed significant reductions in their total Pittsburgh Agitation Scale scores from baseline after ECT (from 11.0 ± 5.0 to 3.9 ± 4.3 [F = 30.33, df = 1, 15, p < 0.001]). Clinical Global Impression scale decreased significantly (from 6.0 ± 0.6 pre-ECT to 2.1 ± 1.6 post-ECT [F = 112.97, df = 1, 15, p < 0.001]). Global Assessment of Functioning change was not significant (from 23.0 ± 4.9 to 26.9 ± 6.9 [F = 5.73, df = 1, 13, p = 0.32]). Only one patient, in whom ECT was discontinued following 11 bilateral treatments, showed no improvement. Eight patients showed transient postictal confusion, which typically resolved within 48 hours. Two patients showed more severe postictal confusion that required modification of treatment. CONCLUSIONS: These results suggest that ECT is an effective and safe treatment for agitation and aggression in dementia. Further prospective studies are warranted.

Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression.

INTRODUCTION: Despite the prevalence, associated comorbidities, and functional consequences of bipolar depression (BPD), underlying disease mechanisms remain unclear. Published studies of individuals with bipolar disorder implicate abnormalities in cellular energy metabolism. This study tests the hypotheses that the forward rate constant (k(for)) of creatine kinase (CK) is altered in older adults with BPD and that CoEnzyme Q10 (CoQ10), known to have properties that enhance mitochondrial function, increases k(for) in elderly individuals with BPD treated with CoQ10 compared with untreated age- and sex-matched controls. METHODS: Ten older adults (ages 55 and above) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition [DSM IV]) bipolar disorder, current episode depressed and 8 older controls underwent two 4 Tesla (31)Phosphorus magnetic resonance spectroscopy ((31)PMRS) scans 8 weeks apart using a magnetization transfer (MT) acquisition scheme to calculate k(for). The BPD group was treated with open-label CoEnzyme Q10 400 mg/d titrated up by 400 mg/d every 2 weeks to a maximum of 1200 mg/d. The Montgomery Asberg Depression Rating Scale (MADRS) was used to measure depression symptom severity. Baseline k(for) and changes in k(for) were compared between individuals with BPD and controls, not receiving CoQ. Clinical ratings were compared across time and associated with k(for) changes using repeated measures linear regression. RESULTS: The k(for) of CK was nonsignificantly lower for BPD than healthy controls at baseline (BPD mean (standard deviation [SD]) = 0.19 (0.02), control mean (SD) = 0.20 (0.02), Wilcoxon rank sum exact P = .40). The k(for) for both CoQ10-treated BPD and controls increased after 8 weeks (mean increase (SD) = 0.03 (0.04), Wilcoxon signed rank exact P = .01), with no significant difference in 8-week changes between groups (BPD mean change (SD) = 0.03 (0.03), control mean change (SD) = 0.03 (0.05), Wilcoxon rank sum exact P = .91). In an exploratory analysis, depression severity decreased with CoQ10 treatment in the group with BPD (F (3,7) = 4.87, P = .04) with significant reductions in the MADRS at weeks 2 (t (9) = -2.40, P = .04) and 4 (t (9) = -3.80, P = .004). CONCLUSIONS: This study employing the novel MRS technique of MT did not demonstrate significance between group differences in the k(for) of CK but did observe a trend that would require confirmation in a larger study. An exploratory analysis suggested a reduction in depression symptom severity during treatment with high-dose CoEnzyme Q10 for older adults with BPD. Further studies exploring alterations of high-energy phosphate metabolites in geriatric BPD and efficacy studies of CoQ10 in a randomized controlled trial are both warranted.

Predictors of Patients' Responses to Spiritual Psychotherapy for Inpatient, Residential, and Intensive Treatment (SPIRIT).

OBJECTIVE: Spiritual Psychotherapy for Inpatient, Residential, and Intensive Treatment (SPIRIT) is a flexible clinical protocol for delivering spiritually integrated group psychotherapy within acute psychiatric settings. The authors evaluated SPIRIT's feasibility by examining patients' perceptions of its benefits and clinical and spiritual predictors of observed effects associated with this intervention. METHODS: Over a 1-year period, 22 clinicians stationed on 10 clinical units provided SPIRIT to 1,443 self-referred patients with a broad range of demographic, clinical, and spiritual and religious characteristics. RESULTS: Overall, patients' perceptions of benefit from SPIRIT were not associated with demographic factors. Clinical factors similarly did not predict treatment responses, suggesting that SPIRIT is equally suitable for patients with mood, anxiety, traumatic, substance use, psychotic, feeding or eating, or personality disorders and for patients with high levels of acuity. Patients with high levels of religious belief responded better to treatment, but patients with low levels of spiritual and religious identity also reported significant benefits. Patients responded better to SPIRIT when it was delivered by clinicians who reported not being affiliated with a religion than did patients receiving the SPIRIT intervention through clinicians who reported a religious affiliation. CONCLUSIONS: Results indicate that SPIRIT is feasible in providing spiritually integrated treatment to diverse patients across multiple levels of acute psychiatric care.

Age-related changes in brain energetics and phospholipid metabolism.

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.