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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.

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.

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 pharmacological options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to pre-clinical 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.

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.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.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.Results indicate that SPIRIT is feasible in providing spiritually integrated treatment to diverse patients across multiple levels of acute psychiatric care.

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging (70%). Neuropsychiatric symptoms (NPS) in AD are a major cause of burden to patients, caregivers, and society and are near-universal at some point in the AD course (97%). One of the most troubling NPS is agitation (Agit-AD), typified by a variety of problem behaviors including combativeness, yelling, pacing, lack of cooperation with care, insomnia, and restlessness. Neurobiological mechanisms that contribute to Agit-AD include brain atrophy, degradation of neurotransmission, neuroinflammation, disrupted circadian rhythms, comorbidities, and frailty. There is a great need for better interventions that target Agit-AD, which is a major source of disease progression, patient disability, financial burden, and caregiver stress. Dronabinol is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis) and is FDA approved for anorexia and nausea. Cannabinoids may improve Agit-AD by providing protection against neuroinflammation and excitotoxicity, regulating neurotransmitters, improving comorbidities, stabilizing circadian rhythms, and increasing cerebral blood flow. This pilot trial could open the door to "re-purposing" dronabinol as a novel and safe treatment for Agit-AD with significant public health impact. Methods THC-AD is a three-week placebo-controlled, double-blind, randomized clinical trial of dronabinol (10 mg QD) in 80 patients with severe Agit-AD. Capsules of dronabinol contain 2.5 mg per dose (5 mg daily) during Week 1, then increase to 5 mg per dose (10 mg daily) for Weeks 2 and 3. The half-life of dronabinol is ∼4 hours, so study medication is administered BID at 08:00 and 14:00 to maximize daytime coverage for agitation and to minimize sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation as determined by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), and being 60-95 years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes are a change in the Pittsburgh Agitation Scale and NPI-C Agitation/Aggression subscales. Secondary outcomes are measures of agitation, cognition, sleep, and global functioning as determined by the following assessments: the NPI-C, Cohen Mansfield Agitation Inventory, Clinical Global Impression of Change, Activities of Daily Living, Mini-Mental State Examination (MMSE), Severe Impairment Battery (8 item), and subjective and observer-rated drug effects. Safety outcomes include monitoring for adverse events (AEs), weekly health assessments, EKG changes, incident delirium (Confusion Assessment Method), and changes in laboratory values. DNA specimens are collected to explore cannabinoid receptor polymorphisms that may affect response to dronabinol. Serum samples are collected to examine the association of peripheral markers of inflammation with agitation and response to dronabinol. Concomitant medications are limited to currently used antipsychotics, antidepressants, and benzodiazepines, as well as anticonvulsant therapy when not used for seizure disorder. PRN rescue medications include total daily doses up to 0.75 mg of lorazepam and 100 mg of trazodone. Results We have enrolled 37 out of 80 participants (Table 1: mean age 78.2 years, 78.4% female, 83.8% Caucasian, mean education 13.2 years, 48.6% family history). Study participants are significantly cognitively impaired (Table 2: mean baseline MMSE of 7.1), agitated (mean NPI-C Agitation 14.8, mean NPI-C Aggression 6.4) and in reasonable overall health (Figure 1: General Medical Health Rating, 10.8% “excellent,” 48.6% "good" and 40.5% "fair”). Recorded AEs have been tolerable (Figure 2). Due to the COVID-19 pandemic, we expanded our inpatient trial to include outpatient enrollments and implemented hybrid visits with telemedicine to limit in-person interactions. To bolster our recruitment, we are collaborating with additional clinical sites, increasing dementia bed capacity, and deploying recruitment strategies for outpatients, including referrals from providers and other research trials, social media ads, and virtual community outreach. Updated results will be presented at AAGP (estimated 6-10 additional participants). Conclusions Agitation is one of the most common behavioral manifestations of AD and is associated with greater caregiver burden and shorter time to institutionalization. Current treatments for Agit-AD have a plethora of safety limitations, and there is a particularly acute need for interventions for severe Agit-AD in advanced dementia. One important question for treatment development is whether Agit-AD represents a specific target for intervention or a nonspecific syndrome shared with many other diseases. This clinical trial may enable us to understand if targeting the cannabinoid system will be a safe and effective approach to treat this global health concern. Funding National Institute on Aging, R01AG050515

Agitation is a common complication of Alzheimer’s dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

In this article, a clinical protocol for delivering a flexible, spiritually integrated cognitive-behavioral therapy, called spiritual psychotherapy for inpatient, residential, and intensive treatment (SPIRIT), is presented, and its implementation is described.

Highlights • In the midst of the COVID-19 pandemic, how have researchers, clinicians, and participants of geriatric clinical trials been affected, and what are the implications for post-pandemic research of neurocognitive disorders? • Rapidly shifting institutional, sponsor, state and federal guidelines have resulted in halted enrollments, missed visits, interrupted medication delivery and delayed infusions and have challenged the limits of tolerance for continuing key studies on potentially disease-modifying treatments for Alzheimer's. Clinicians, research coordinators, and participants have responded to the chaotic environment by testing new models of care and assessment, pushing for creative adaptations in research methodology and data collection. • Researching treatments for a devastating disease during a global emergency carries unforeseen challenges, limitations, risks, and psychosocial consequences, but may lead to new strategies that improve efficiency, and are more crisis-resistant in the future., Advances in treating and preventing Alzheimer's 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 we 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 towards discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

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.

Introduction Alzheimer's disease (AD) is a debilitating neurodegenerative disease accounting for 60-80% of dementia cases worldwide. In the United States alone, 13.8 million Americans are predicted to develop AD by 2050. The neuropsychiatric symptoms (NPS) of dementia affect up to 97% of AD patients over the course of their disease. A common NPS is agitation, characterized by problem behaviors that include combativeness and restlessness. Agitation is commonly associated with greater caregiver burden, shorter time to institutionalization, and anxiety. Anxiety symptoms affect 25-70% of the dementia population, and this wide range speaks to the inability to discern anxiety from agitation. Despite the pervasiveness of anxiety and agitation in the AD population, there are no FDA-approved medications that treat the behavioral symptoms of AD. Current treatments for these symptoms include time-intensive behavioral therapies and prescription of off-label antipsychotic medications that include an FDA warning of increased mortality in this population. Thus, the need for developing safe and efficacious treatments for anxiety and agitation in AD is dire. One potential treatment is cannabidiol (CBD), the major non-intoxicating constituent of cannabis sativa and industrial hemp, a variety of the cannabis plant that contains Methods An 8-week open-label clinical trial of an industrial hemp-derived custom-formulated high-CBD/low-THC sublingual solution developed by Dr. Staci Gruber, PhD, at McLean Hospital. We will recruit 12 research participants with mild to moderate Alzheimer's dementia and behavioral symptoms of anxiety with or without agitation. Our primary efficacy outcome measures are the anxiety domain of the Neuropsychiatric Inventory-Clinician Version (NPI-C) and the Generalized Anxiety Disorder-7 Item Scale (GAD-7). Our secondary safety outcome measures include continuous monitoring for serious adverse events and medication side effects, cognitive decline estimates from the Mini Mental Status Exam (MMSE), and the emergence of possible delirium from the 3D-Confusion Assessment Method (3D-CAM). Agitation and aggression domains on the NPI-C, scores on the Cohen-Mansfield Agitation Inventory (CMAI), and caregiver burden estimates from the Zarit Caregiver Burden Interview will be included as additional exploratory measures. Results Dr. Gruber's team is currently conducting a clinical trial for the treatment of anxiety in adults with moderate to severe anxiety using a similar custom-formulated high-CBD/low-THC sublingual solution. Preliminary analyses of Dr. Gruber's ongoing trial reveal that subjects experience significant reduction in anxiety symptoms along with improvements in mood, quality of life, and executive function over 4 weeks of treatment. Given these data and evidence of CBD's anxiolytic effects, we hypothesize that twice daily treatment with a high-CBD/low-THC solution in older adults with AD for 8 weeks will be associated with a statistically significant reduction in anxiety and agitation symptoms compared to baseline, as measured by our efficacy outcome measurements. We predict that the solution will be well-tolerated by the study population, as measured by our safety outcome measurements. Conclusions We seek a safe and effective treatment for the neuropsychiatric symptoms of anxiety and agitation in older adults with AD. With no current FDA-approved treatments for these behavioral symptoms, patients with AD risk ineffective therapies or mortality-associated antipsychotic treatments to address their NPS. Treating anxiety and agitation in these patients not only alleviates their symptoms but could also reduce caregiver burden and lengthen the time to institutionalization. CBD is a promising anxiolytic treatment that could advance our available treatment options for anxiety and agitation in AD. Funding The Spier Family Foundation

Introduction Bipolar disorder can impair executive functioning and social cognition which refers to the cognitive processes involved in understanding social cues (this includes theory of mind). However, little is known about the degree to which subclinical manic symptoms can impact social cognition in older adults and the role of executive functioning in this interaction. This cross-sectional study examined if transdiagnostic subclinical manic symptoms in older adults with mood disorders were related to impaired social cognition and if this relationship was mediated by executive functioning. Methods Ninety-five mood disorder patients (43 patients with bipolar disorder, 50 with major depressive disorder, 2 with schizoaffective disorder) ages 55 and above completed a battery of neuropsychological tests, mood and anxiety rating scales, clinical rating scales, functional and medical assessments. Total scores from the Mind in the Eyes task were used to assess social cognition. Executive functioning was assessed using the total correct scores from the Wisconsin Card Sorting Task (WCST). The Young Mania Rating Scale (YMRS), the Generalized Anxiety Disorder 7-item (GAD-7) scale and the Montgomery-Asberg Depression Rating Scale (MADRS) were used to assess mood and anxiety symptoms. Results All participants had subclinical manic symptoms based on the YMRS scores independent of their diagnosis. We used linear regressions to test mediation following the Baron and Kenny (1986) method. We found that greater subclinical manic symptoms (YMRS) were related to reduced executive functioning (path a, p=.043), and lower social cognitive functioning (Mind in the Eyes task), when controlling for depression and anxiety symptoms (path c, p = .002). The association between manic symptoms and social cognition was fully mediated by performance on an executive functioning task (the Wisconsin Card Sorting Task total correct scores, path b, p=.010, path c’ p= .375). Mood diagnosis, depression and anxiety symptoms were not significantly related to performance on social cognitive or executive functioning tasks. Conclusions Executive functioning could explain social cognitive impairment related to subclinical manic symptoms. Our findings shed some light into the neuropsychological features of subclinical manic symptoms in older adults. Funding The Rogers Family Foundation

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.

Introduction Affecting 5.8?million individuals in the U.S. alone, the impact of Alzheimer's disease (AD) is several-fold; it increases patient morbidity and mortality, contributes to caregiver burden, increases public health burden, and comes at a staggering combined cost of over half a trillion dollars per year in health care and unpaid caregiving. Unfortunately, the behavioral symptoms of dementia (BPSD) such as agitation and aggression that largely contribute to the morbidity and burden of the disease remain neglected in the sphere of research. As the number of patients impacted by this disease rises to a predicted 13.8?million by 2050, the need for novel interventions to mitigate these BPSD contributing to the AD epidemic remains unmet. Current non-pharmacological interventions require substantial time to take effect and do not address the most severe, treatment refractory cases of BPSD. Pharmacological interventions, on the other hand, most commonly antipsychotics, have limited efficacy and are linked to substantial risks that elevate patient mortality. The limitations of these existing interventions have prompted the search for faster, safer, and more effective methods of managing BPSD in the AD population. In the past few decades, there has been growing evidence to support electroconvulsive therapy (ECT) as a safe and effective treatment to mitigate agitation in AD patients who are refractory to traditional interventions. This poster reports the results from a systematic review of the current evidence for ECT as an intervention for the mitigation of intractable BPSD in AD patients. Methods The authors conducted a literature search on Google Scholar, Medline, PubMed, and PsychInfo of the following search terms: “ECT aggression dementia,” “ECT Behavior and Psychological Symptoms of Dementia,” and “ECT BPSD.” The term “dementia” is also interchanged with “Major Neurocognitive Disorder.” The timeline for these searches was restricted to the past 30?years, allowing a list of publications between 1989-2019 to populate. Papers with only abstracts available were excluded, as were any duplicates between the searches. Results The authors reviewed 17 papers with a total (N) of 181 patients diagnosed with dementia and exhibiting severe agitation and aggression. These patients received various types of electroconvulsive therapy including: brief pulse (>0.5 msec) bitemporal (BP-BT), brief pulse right unilateral (BP-RUL) and ultrabrief pulse ( Conclusions This review of the current evidence for ECT in the treatment of severe agitation and aggression in AD, increasingly apparent is the large body of evidence for the efficacy of ECT for this indication. This review has brought to attention, however, the lack of safety data to accompany these findings on efficacy. As future prospective studies are developed to address this area of research with more robust parameters and objective scales, the studies reviewed thus far indicate a favorable risk/benefit ratio for the use of ECT in managing treatment refractory BPSD in patients with AD. This research was funded by: The National Institute of Aging (NIA 1 R01 AG061100-01)

Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean±SD age: 43.4±13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0±12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, proton-phosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major 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

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.

Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging, affecting approximately 5.4 million individuals in the US, and predicted to increase to 13.8 million by 2050. Occurring in over 90% of AD patients, neuropsychiatric symptoms such as agitation, depression and apathy, contribute to caregiver burden and increase patient morbidity and mortality. With no FDA-approved options available, treatments for severe agitation in people with advanced dementia are limited, with modest evidence for efficacy and substantial safety concerns. Behavioral therapies are recommended as first-line treatments for agitation in AD; however, they require substantial time to take effect and may be less efficacious for the most severely agitated patients. Psychotropic medications, especially antipsychotics, are widely used off-label to treat agitation in AD even with documented limitations in efficacy and safety concerns. Therefore, new treatments for severe agitation in AD refractory to standard interventions are timely and warranted. Randomized controlled trials have demonstrated the safety and efficacy of electroconvulsive therapy (ECT) for the treatment of severe psychiatric disorders of late life, including depression, mania and psychosis. Recently, small open label studies suggest efficacy and safety of ECT for agitation in individuals with AD who are refractory to standard therapies. The present randomized controlled trial builds upon prior work and aims to determine the efficacy and safety of ECT for severe agitation in moderate to severe stage AD, while also examining the durability of the acute treatment effect in an exploratory maintenance naturalistic design. Methods We describe an NIA-funded multi-site, single blind, randomized trial of ECT plus usual care (UC) versus Simulated-ECT (S-ECT) plus UC. We will enroll 200 inpatients with severe agitation and moderate to severe dementia, who have not responded well to prior trials of psychotropic medications. Our primary efficacy outcome measure is the Cohen Mansfield Agitation Inventory (CMAI), and the Neuropsychiatric Inventory – Clinician Version (NPI-C), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC), and Pittsburgh Agitation Scale (PAS) will be secondary measures. Safety and tolerability will be assessed with the Severe Impairment Battery – 8 item (SIB-8), the Confusion Assessment Method (CAM), and adverse event monitoring. Results Preliminary open-label data from our team suggests acute ECT treatment is safe and effective in reducing agitation in this population as measured by the CMAI, PAS, CGI, and adverse event monitoring. A multi-site, prospective case series investigated ECT treatment in 23 consecutive inpatients with dementia and severe agitation who did not benefit from standard behavioral interventions and pharmacotherapy. Eighteen of the 23 subjects experienced a significant reduction in agitation from baseline to discharge on the CMAI. In a retrospective chart review study of 16 patients undergoing ECT for agitation related to AD, only two experienced more than transient confusion post-ECT that required treatment, and no other clinically significant adverse events were noted in this group. We hypothesize ECT+UC will be more efficacious in reducing severe agitation in AD subjects than S-ECT+UC, as measured by our primary and secondary efficacy measures, and that there will be no difference in tolerability/safety outcomes for ECT+UC and S-ECT+UC as measured by cognitive decline (SIB-8), development of delirium (CAM), and serious adverse event monitoring. Conclusions This innovative study will fill a gap in the current clinical practice of treating severe agitation in AD using a rigorous methodological approach thus providing evidence for a new therapeutic application (severe agitation in AD) of a well-studied, established, and safe treatment (ECT). Study findings may demonstrate support for a new therapeutic use of ECT for severe agitation in AD. Successful management of neuropsychiatric symptoms reduces long-term care placement, decreases the risk of mortality, and enhances patient and caregiver quality-of-life. Such an approach has the potential to offer enormous relief to the substantial socioeconomic burden of AD-related behavioral disturbances. This research was funded by National Institute of Aging R01 AG061100-01

Early intervention in Alzheimer’s Disease (AD) requires novel biomarkers that can capture changes in brain activity at an early stage. Current AD biomarkers are expensive and/or invasive and therefore unsuitable for use as screening tools, but a non-invasive, inexpensive, easily accessible screening method could be useful in both clinical and research settings. Prior studies suggest that especially paired-associate learning tasks may be useful in detecting the earliest memory impairment in AD. Here, we investigated the utility of functional Near Infrared Spectroscopy in measuring brain activity from prefrontal, parietal and temporal cortices of healthy adults (n = 19) during memory encoding and retrieval under a face-name paired-associate learning task. Our findings demonstrate that encoding of novel face-name pairs compared to baseline as well as compared to repeated face-name pairs resulted in significant activation in left dorsolateral prefrontal cortex while recalling resulted in activation in dorsolateral prefrontal cortex bilaterally. Moreover, brain response to recalling was significantly higher than encoding in medial, superior and middle frontal cortices for novel faces. Overall, this study shows that fNIRS can reliably measure cortical brain activation during a face-name paired-associate learning task. Future work will include similar measurements in populations with progressing memory deficits.

Living from 1818 to 1889, the story of Franciscus Donders covers much of the nineteenth century. It was a time of enormous confusion regarding many aspects of ophthalmology. Thomas Young’s work in the late eighteenth century proving that the lens rounded up in accommodation was ignored and forgotten. Hypermetropia and its relationship to accommodation was unknown prior to the middle of the century when Donders and Helmholtz would finally unravel the mysteries of this complex physiologic science. Refractive error correction with both concave and convex lenses was thought likely to lead to serious and permanent amblyopia. Donders, receiving a classical education, ultimately chose a scientific career path that lead to ophthalmology. His enduring devotion to both the teaching and practice of this medical and surgical subspecialty resulted in the publication, in 1864, of the most practical and in depth textbook of ophthalmologic refractive science of the nineteenth century. This enduring contribution changed the face of ophthalmology forever.

STUDY OBJECTIVES A principal function of sleep may be restoration of brain energy metabolism caused by the energetic demands of wakefulness. Because energetic demands in the brain are greater in gray than white matter, this study used linear mixed-effects models to examine tissue-type specific changes in high-energy phosphates derived using 31P magnetic resonance spectroscopy (MRS) after sleep deprivation and recovery sleep. DESIGN Experimental laboratory study. SETTING Outpatient neuroimaging center at a private psychiatric hospital. PARTICIPANTS A total of 32 MRS scans performed in eight healthy individuals (mean age 35 y; range 23-51 y). INTERVENTIONS Phosphocreatine (PCr) and β-nucleoside triphosphate (NTP) were measured using 31P MRS three dimensional-chemical shift imaging at high field (4 Tesla) after a baseline night of sleep, acute sleep deprivation (SD), and 2 nights of recovery sleep. Novel linear mixed-effects models were constructed using spectral and tissue segmentation data to examine changes in bioenergetics in gray and white matter. MEASUREMENTS AND RESULTS PCr increased in gray matter after 2 nights of recovery sleep relative to SD with no significant changes in white matter. Exploratory analyses also demonstrated that increases in PCr were associated with increases in electroencephalographic slow wave activity during recovery sleep. No significant changes in β-NTP were observed. CONCLUSIONS These results demonstrate that sleep deprivation and subsequent recovery-induced changes in high-energy phosphates primarily occur in gray matter, and increases in PCr after recovery sleep may be related to sleep homeostasis.

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.

Bipolar disorder (BD) is a prevalent mental disorder that causes disability throughout the life-span. Because of demographic trends, there is a growing population of individuals with older-age bipolar disorder (OABD). This symposium, presented by members of the International Society of Bipolar Disorders OABD taskforce, will highlight new data relevant to OABD and to aging with BD. The session chair, Martha Sajatovic, will first speak about the development of the Aging and Geriatric Experiments in BD (AGE-BD) integrated dataset, and present initial results regarding the interplay of clinical, demographic, and medical variables across adulthood. Second, Lisa Eyler will discuss the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) BD Working Group, a large, ecologically-valid sample of 3020 participants from 13 sites worldwide and present her analysis of ENIGMA data that showed advanced “brain age” among those with BD compared to those without and examined clinical correlates of advanced brain age. The third speaker, David Harper, will present recently analyzed resting state fMRI data in older bipolar depressed individuals vs healthy controls. The fourth speaker, Ariel Gildengers, will present on the relationship between bipolar disorder and medical burden on cognition and brain health in older adults.

We have already entered a new, more exciting, and hopeful era in the treatment of late-life depression. The increasing numbers of older adults who are surviving to more advanced ages and the greater recognition of late-life depression’s prevalence and impact on quality of life emphasize how important it is to detect and treat this disorder. Our increasing repertoire of evidence-based psychotherapeutic, pharmacologic, and neurotherapeutic treatment interventions offers many treatment alternatives, allowing substantial individualization of treatment approach. Demonstration of the effectiveness of depression treatment in primary care suggests the feasibility of increasing our patients’ access to care. Growing appreciation of the pathophysiology of depression and its interrelationships with cognitive impairment may increase our ability to limit or delay certain aspects of cognitive impairment through more aggressive treatment of depression. Improved recognition and treatment of late-life depression holds great potential for improving physical and mental health in later life, reducing disability in later years, and improving quality of life.

Alterations in membrane phospholipid composition may be related to the cognitive impairment associated with several brain diseases such as bipolar disorder, schizophrenia, Alzheimer’s disease, and multiple sclerosis (1). Phospholipids are major constituents of all mammalian cell membranes. There are different species of phospholipids, the most abundant being phosphatidylcholine (PtdCho), which makes up approximately 40-50% of total phospholipids, followed by phosphatidylethanolamine (PtdEtn) which constitutes 20-50% (2, 3). PtdCho is located in the outer leaflet and PtdEtn is primarily located in the inner leaflet of cellular membranes (4). While the former is more generally a precursor of second messengers (diacylglycerol, phosphatidic acid, and arachidonic acid) and is involved in the synthesis of acetylcholine, PtdEtn plays a more critical role in energy metabolism due to its abundance in mitochondrial membranes (3, 5). Different types of cells and tissues have characteristic phospholipid compositions that determine membrane fluidity, receptor function, optimal exchange of nutrients, and mitochondrial efficiency (6-9). Membrane phospholipids also serve as reservoirs for several intermediates of signal transduction across membranes, such as eicosanoids, diacylglycerol, and inositol 1,4,5-triphosphate (4, 10). 31-Phosphorus magnetic resonance spectroscopy (31P-MRS) can resolve phosphorus-containing metabolites into separate resonance peaks, including phospholipid anabolites [phosphomonoesters (PME)] such as phosphocholine (PCho) and phosphoethanolamine (PEtn), catabolites [phosphodiesters (PDE)] such as glycerophosphocholine (GPCho) and glycerophosphoethanolamine (GPEtn), inorganic phosphate (Pi), phosphocreatine (PCr), and high-energy phosphates such as adenosine triphosphate (ATP) (Fig. 1B). These metabolites are located within the cytosol and are 31P-MRS visible, whereas membrane-bound PtdCho or PtdEtn are 31P-MRS invisible (Fig. 1B). The 31P-MRS spectrum provides useful information relevant to phospholipid metabolism. Fig.1 Magnetic resonance images depicting 3 cm chemical shift imaging slab placement and grid alignment and an in vivo human brain sample phosphorus spectrum acquired from a single voxel at 4.0 Tesla. Spectrum (B) is displayed with 5 Hz exponential filtering ... The more abundant membrane phospholipids (PtdCho and PtdEtn) in mammalian cells are synthesized via the Kennedy cycle (11), which requires the pyrimidine nucleosides cytidine triphosphate (CTP) (Fig. 2) (5). Pyrimidine nucleosides can be synthesized either via a de novo pathway, which is ATP-dependent, or the less energy-consuming salvage pathway that recycles the circulating pyrimidines, such as uridine and cytidine, into nucleic acids to form nucleosides such as uridine triphosphate (UTP) and CTP (12). Specific kinases phosphorylate free choline and ethanolamine to PCho and PEtn, respectively. In a rate-determining step catalyzed by CTP:phosphocholine cytidylyl transferase (CCT), CTP combines with PME to form cytidine diphosphate (CDP)-choline or CDP-ethanolamine (11). The CDP-choline and CDP-ethanolamine moieties are transferred to diacylglycerol (DAG) to form PtdCho and PtdEtn, respectively (11). Fig. 2 Synthesis of phosphatidylcholine via the Kennedy Cycle. Uridine is the major circulating pyrimidine that is converted to cytidine triphosphate (CTP) in humans. Specific transporters facilitate the entry of uridine across the blood-brain barrier, where ... Both animal and human studies, by directly measuring brain phospholipids, have now established that pyrimidines such as cytidine can enhance phospholipid synthesis (13-16). In humans, cytidine is metabolized to uridine following oral administration (17). Uridine is efficiently transported across the blood-brain barrier through high-affinity nucleoside transporters and can be converted into CDP-choline in the human brain (18). In this study we used 31P-MRS to identify changes in phospholipid synthesis after one week of oral administration of uridine to healthy male volunteers. It was hypothesized that by measuring 31P-MRS visible metabolites we would be able to study indirect effects of uridine on membrane phospholipid metabolism. State-dependent alterations in membrane phospholipids have been reported in patients with bipolar disorder (19, 20). 31P-MRS studies in depressed bipolar disorder patients have reported higher PME levels compared to euthymic bipolar disorder patients, and unmedicated euthymic patients have lower PME than healthy adults (21-24). While some progress has been made toward understanding the pathophysiology of this disorder, existing treatments are still characterized by limited efficacy and tolerability. Recently, uridine was observed to act as an effective antidepressant in rat models of depression (25). Moreover, a Repligen-sponsored phase 2a clinical trial reported a significant decrease in the symptoms of depression in bipolar disorder patients (26). Currently a phase 2b multicenter clinical trial is underway to test the efficacy of uridine as an antidepressant in bipolar depressed patients. Results of this study would potentially provide an in vivo tool to indirectly monitor phospholipid changes after uridine treatment in bipolar disorder patients.

To investigate the association of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) and magnetic resonance imaging (MRI) measures of brain atrophy and white matter hyperintensities (WMH).Thirty-seven patients with probable AD received the Neuropsychiatric Inventory (NPI), the Mini Mental Status Exam (MMSE), and an MRI scan as part of their initial evaluation at the Outpatient Memory Diagnostic Clinic at McLean Hospital. MRI-based volumetric measurements of whole brain atrophy, hippocampal volumes, and WMH were obtained. Analysis of covariance models, using age as a covariate and the presence of specific BPSD as independent variables, were used to test for differences in whole brain volumes, hippocampal volumes and WMH volumes.Increased WMH were associated with symptoms of anxiety, aberrant motor behavior, and night time disturbance, while symptoms of disinhibition were linked to lower WMH volume. No associations were found for whole brain or hippocampal volumes and BPSD.These findings suggest that white matter changes are associated with the presence of BPSD in AD.

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 (31P) MRS. 31P 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 31P 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. Copyright © 2009 John Wiley & Sons, Ltd.

Introduction We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12-week treatment trial of sertraline. Methods Thirteen older adults, age ≥55, with Major Depressive Disorder (HAMD17 score of ≥18) were recruited along with ten age-matched controls. The depression subjects had a pre- and post-treatment 4T 31P-MRS scan using a three-dimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre-treatment and post-treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg++). Results Total tissue beta-NTP (−8%, t(18.66) = 3.50; p = 0.0024) and total tissue total NTP (−6%, t(17.41) = 2.68; p = 0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total-NTP changed significantly with treatment (−2%, t(14.84) = −2.47; p = 0.0259). Total NTP was reduced in the WM, but not the GM, in the pre-treatment depression group (t(51.65) = 4.02; p = 0.0002). Intracellular pH was higher in the GM of subjects with pre-treatment depression (t(1133.84) = −2.10; p = 0.0353) and decreased to approximate control levels after treatment (t(648.86) = −2.53; p = 0.0115). Discussion These findings demonstrate bioenergetic changes including tissue specific differences in 31P-MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function. Copyright © 2009 John Wiley & Sons, Ltd.

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain-behaviour relationships in the human.

Although bipolar disorder (BD) often presents in young adulthood, most individuals experience recurrent mood episodes, psychosocial deficits and high utilization of health services that persist into later life.1 Bipolar depression represents the predominant and least successfully treated phase of this illness. Individuals with BD spend more time ill with depressive symptoms than with manic/hypomanic or with cycling/mixed symptoms,2-4 and the proportion of time spent in depressive episodes to time spent in manic episodes increases with age. The few medications (quetiapine, lurasidone, olanzapine-fluoxetine) FDA-approved for treatment of bipolar depression were studied in predominantly middle-adult-aged cohorts. The clinical management of bipolar disorder in later life is also complicated by medical co-morbidity, cognitive impairment and polypharmacy.5 Furthermore, the neurobiological mechanisms that underlie bipolar depression may change with age and resistance to current treatments is high.6,7 Over the past decade there has been increasing evidence8 that implicates alterations in bioenergetic metabolism and enhanced oxidative stress in the neurobiology of bipolar disorder.9 Although the degree of mitochondrial dysfunction does not produce a substantial systemic metabolic disorder, it is likely sufficient to impact the CNS, as the brain requires twenty-fold the energy production of the rest of the body.9 Furthermore, the efficiency of mitochondrial energy production declines with age, an effect seen both in CNS and peripheral tissue. Successful treatment strategies for late life bipolar disorder may depend on developing novel ways to address reduced mitochondrial ATP (adenosine triphosphate) production. Coenzyme Q10 (CoQ10) is present in the phospholipid bilayers of mitochondria,10 shuttling electrons within the mitochondrial electron transport chain to generate ATP and serving as a potent antioxidant.11 CoQ10has been studied as a treatment for disorders implicating mitochondrial impairment, including congestive heart failure, diabetes, and degenerative neurological conditions.12-15 We now present the results from an open-label study of CoQ10 (added to existing treatment at a dosage of 800 mg/day for 4 weeks) for the treatment of older adults with a current episode of bipolar depression. We hypothesized that CoQ10 would reduce depressive symptoms as measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Background: Neuroinflammation contributes to the pathogenesis of Alzheimer’s disease (AD). Increased pro-inflammatory cytokine levels have been reported in the brain and cerebro-spinal fluid of individuals affected by this neurodegenerative disorder. These same cytokines, including interleukin -1, interleukin-6 and tumor necrosis factor-α, are also believed to be involved in thermoregulation. Furthermore, their effects are thought to be mediated through the induction of cyclooxygenases resulting in increased production of inflammatory prostaglandins. Such increases have been observed in AD brains. We hypothesized that these increased levels of inflammatory mediators could lead to an increase in core body temperature in AD patients. Objective: To determine whether clinical signs of AD are accompanied by an increase in core body temperature. Methods: Analysis of the scientific literature identified six studies that used continuous rectal measurements of core body temperature in AD and control patients. Meta-analysis was performed on these published data. Results: Meta-analysis showed that the mean core body temperature in AD patients was significantly increased by 0.10°C when compared to healthy elderly subjects. The two-sided p value was 0.0355, and the 95% confidence interval was 0.0068–0.1950. The severity of AD pathology did not appear to contribute significantly (p = 0.235) to the heterogeneity in the core body temperature among different groups of AD patients. Conclusion: The significant increase in core body temperature in AD patients could be a direct consequence of local inflammatory reactions in the brain. Although the changes observed are probably too small to be of any diagnostic value, these observations lend further support to the neuroinflammatory hypothesis of AD pathology.

Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. Although the sleep disturbances of AD and DLB are qualitatively similar, they appear to be more prominent in patients with DLB. Disturbance of the circadian rhythm has been noted and is a potential factor underlying the nocturnal sleep fragmentation and daytime sleepiness observed in these patients. We studied the circadian variation of core-body temperature and motor activity in a total of 32 institutionalized patients with probable AD by NINCDS-ADRDA criteria, 9 of whom also met pathologic criteria for DLB. Eight, healthy, elderly male controls were studied on a clinical research unit designed to simulate the hospital environment where the dementia patients were studied. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that central changes mediate circadian disturbances in AD and DLB. Patients with a postmortem diagnosis of DLB manifested greater disturbances of locomotor activity circadian rhythms than patients with AD, possibly reflecting the greater sleep disturbances seen in this population, but the differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar.

Since at least the 16th century, many investigators have speculated on the presence of a specialized muscle in the front of the eye designed to somehow alter its disposition to bring about changes in focus. By the 1850s, when Hermann von Helmholtz offered the first plausible theory of accommodation, the anatomy of the ciliary muscle was well known. The credit for this knowledge is generally given to Ernst Brücke and William Bowman, who published their observations on the muscle independently in the 1840s. In fact, not only were Bowman and Brücke wrong about the role of the ciliary muscle in accommodation, and for different reasons, but they shared this distinction with at least 3 investigators who came before them. In the 3 decades before 1840, Philip Crampton, Robert Knox, and William Wallace had all zeroed in on the ciliary muscle, describing its anatomy in varying detail. If none understood its precise role in accommodation--all ignored the work of Thomas Young, who by 1800 had proved that the lens must somehow round up to achieve near vision--each deserves a share of the credit for its discovery.

Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), the putative site of the hypothalamic circadian pacemaker, to determine the nature and degree of pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history of severe dementia, 22 had Braak and Braak stage V-VI Alzheimer disease, 3 had combined Alzheimer and Parkinson disease, 3 had Pick disease and 2 had severe hippocampal sclerosis. Comparisons were made with a control group composed of 13 age-matched patients with no clinical or pathological evidence of dementia or other CNS disorders. To determine the pathologic involvement within the SCN, human hypothalami were stained with: Nissl, Bielchowsky silver, thioflavin S and specific antibodies directed against vasopressin (VP), neurotensin (NT), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), beta-amyloid (B/A4) and glial fibrillary acidic protein (GFAP). Pathologic damage was primarily limited to neuronal loss and neurofibrillary tangle formation. Only rare diffuse plaques were noted. The pathologic changes within the SCN were less severe than in the other brain regions. Morphometric analysis was accomplished using a stereological approach to sample the average total number of positively stained neurons and astrocytes in 10 different 0.1mm2 microscopic fields in the dorsal subdivision of the SCN. Patients with Alzheimer disease exhibited a significant decrease in vasopressin (9.75 vs 16.7, p < 0.001) and neurotensin (6.82 vs 9.63, p < 0.002) neurons, as well as a corresponding increase in the GFAP-stained astrocyte/Nissl-stained neuron ratio (0.54 vs 0.10, p < 0.009). These studies provide evidence that both vasopressin and neurotensin neurons are lost in Alzheimer disease, and that the astrocyte/neuron ratio is a reliable indicator of disease-related pathology within the SCN. Taken collectively, our data support the hypothesis that damage to the SCN may be an underlying anatomical substrate for the clinically observed changes in circadian rhythmicity that have been observed in Alzheimer patients.

Alzheimer's disease (AD) causes sleep and behavioral disturbares which may be related to abnormalities of circadian rhythms caused by damage of the suprachiasmatic nucleis. Exposure to bright light may compensate for this danlage by improving synchronization, timing and amplijude of circadian rhythms. Three case studies, presented in this paper, demonstrate the beneficial effect of light therapy on sleep and one of the cases also suggests that light therapy may be effective in the treatment of agitated behavior. The clinical observations also suggest a need for increased level of lighting in long term care facilites.