Molecular imaging of serotonin degeneration in mild cognitive impairment.

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system, as indicated by the observation of lower serotonin transporters in MCI relative to healthy controls.

Association between serotonin denervation and resting-state functional connectivity in mild cognitive impairment.

Resting-state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting-state functional MRI) in 20 participants with MCI and 21 healthy controls. Two SERT regions of interest were selected for the analysis: the Dorsal Raphe Nuclei (DRN) and the precuneus which represent the cell bodies of origin and a cortical target of projections of the serotonin system, respectively. Both regions show decreased SERT in MCI compared to controls and are the site of early AD pathology. Average resting-state functional connectivity did not differ between MCI and controls. Decreased SERT in DRN was associated with lower hippocampal resting-state connectivity in MCI participants compared to controls. Decreased SERT in the right precuneus was also associated with lower resting-state connectivity of the retrosplenial cortex to the dorsal lateral prefrontal cortex and higher resting-state connectivity of the retrosplenial cortex to the posterior cingulate and in patients with MCI but not in controls. These results suggest that a serotonergic mechanism may underlie changes in brain functional connectivity in MCI. Hum Brain Mapp 38:3391-3401, 2017. © 2017 Wiley Periodicals, Inc.

Structural imaging in late-life depression: association with mood and cognitive responses to antidepressant treatment.

OBJECTIVES: Recent positron emission tomography studies of cerebral glucose metabolism have identified the functional neural circuitry associated with mood and cognitive responses to antidepressant treatment in late life depression (LLD). The structural alterations in these networks are not well understood. The present study used magnetic resonance (MR) imaging and voxel-based morphometry to evaluate the association between gray matter volumes and changes in mood symptoms and cognitive function with treatment with the antidepressant citalopram. DESIGN: Open-label trial with baseline brain MR scan. Mood and cognitive assessments performed at baseline and during citalopram treatment. SETTING: Outpatient clinics of an academic medical center. PARTICIPANTS: 17 previously unmedicated patients age 55 years or older with a major depressive episode and 17 non-depressed comparison subjects. INTERVENTION: 12-week trial of flexibly dosed citalopram. MEASUREMENTS: Gray matter volumes, Hamilton Depression Rating Scale, California Verbal Learning Test, Delis-Kaplan Executive Function System. RESULTS: In LLD, higher gray matter volumes in the cingulate gyrus, superior and middle frontal gyri, middle temporal gyrus, and precuneus was associated with greater mood improvement. Higher gray matter volumes in primarily frontal areas were associated with greater improvement in verbal memory and verbal fluency performance. CONCLUSIONS: Associations with antidepressant induced improvements in mood and cognition were observed in several brain regions previously correlated with normalization of glucose metabolism after citalopram treatment in LLD. Future studies will investigate molecular mechanisms underlying these associations (e.g., beta-amyloid, inflammation, glutamate).

Depression in cognitive impairment.

Depression and cognitive disorders, including dementia and mild cognitive impairment, are common in the elderly. Depression is also a common feature of cognitive impairment although the symptoms of depression in cognitive impairment differ from depression without cognitive impairment. Pre-morbid depression approximately doubles the risk of subsequent dementia. There are two predominant, though not mutually exclusive, constructs linking pre-morbid depression to subsequent cognitive impairment: Alzheimer's pathology and the vascular depression hypothesis. When evaluating a patient with depression and cognitive impairment, it is important to obtain caregiver input and to evaluate for alternative etiologies for depressive symptoms such as delirium. We recommend a sequential approach to the treatment of depression in dementia patients: (1) a period of watchful waiting for milder symptoms, (2) psychosocial treatment program, (3) a medication trial for more severe symptoms or failure of psychosocial interventions, and (4) possible ECT for refractory symptoms.

Longitudinal studies of cerebral glucose metabolism in late-life depression and normal aging.

OBJECTIVE: Late-life depression (LLD) has a substantial public health impact and is both a risk factor for and a prodrome of dementia. Positron emission tomography (PET) studies of cerebral glucose metabolism have demonstrated sensitivity in evaluating neural circuitry involved in depression, aging, incipient cognitive decline, and dementia. The present study evaluated the long term effects of a course of antidepressant treatment on glucose metabolism in LLD patients. METHODS: Nine LLD patients and seven non-depressed control subjects underwent clinical and cognitive evaluations as well as brain magnetic resonance imaging and PET studies of cerebral glucose metabolism at baseline, after 8 weeks of treatment with citalopram for a major depressive episode (patients only), and at an approximately 2-year follow-up. RESULTS: The majority of LLD patients were remitted at follow-up (7/9). Neither patients nor controls showed significant cognitive decline. The patients showed greater increases in glucose metabolism than the controls in regions associated with mood symptoms (anterior cingulate and insula). Both groups showed decreases in metabolism in posterior association cortices implicated in dementia. CONCLUSIONS: Longitudinal changes in cerebral glucose metabolism are observed in controls and in LLD patients without significant cognitive decline that are more extensive than the decreases in brain volume. Longer duration follow-up studies and the integration of other molecular imaging methods will have implications for understanding the clinical and neurobiological significance of these metabolic changes.

Clinical evaluation and management of a 45-year-old man with confusion, psychosis, agitation, stereotyped behavior, and impaired speech.

Our patient Mr. A is a mentally and physically disabled gentleman. He was first diagnosed with bipolar disorder as a teenager. He incurred a lumbar spinal injury due to a motor vehicle incident in his 20s which led to weakness, numbness, and frequent infection over both of his lower extremities. He also developed alcohol addiction over the course of his life. Mr. A presented to our facility with complicated neuropsychiatric symptoms. By adopting various clinical strategies, we were able to control his symptoms of agitation, self-harm, mood swings, and stereotyped behavior. However, we were not able to improve his neurocognitive functioning or speech impairment which seemed to become severe and irreversible in a period of a few months. We felt disappointed and perplexed by the mixed treatment responses. To understand Mr. A's clinical presentation, various laboratory tests and imaging studies were performed. Different psychotropic medications were used to manage his symptoms. Gradually, we felt that we were able to understand this case better clinically and etiologically. His bipolar disorder, alcohol addiction, and physical injury had likely all contributed to his neuropsychiatric symptoms, directly or indirectly. It is highly possible that an alcohol-related progressive dementia along with his chronic bipolar disorder played a key role in the progression of his brain neurodegeneration. Also, Wernicke-Korsakoff syndrome could reasonably be considered having developed during his clinical course. Moreover, the fluctuation of the patient's neuropsychiatric symptoms we observed during his hospitalization reflects the increased vulnerability of the human brain under sustained neurodegeneration.

Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients.

OBJECTIVES: Both diabetes mellitus and magnetic resonance image (MRI) deep white matter hyperintensities (WMHs) are more common in bipolar disorder (BD) patients than in matched controls. Deep-as opposed to periventricular--WMHs and diabetes are associated with treatment resistance and poorer outcome. This study investigated whether brain glucose metabolism by the polyol pathway--a pathway linked to nervous tissue disease in diabetes--is related to deep WMH volume and treatment resistance in BD patients. METHODS: Volumes of fluid-attenuated inversion recovery WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 20 nondiabetic patients with BD and nondiabetic comparison subjects with schizophrenia (n = 15) or transient neurologic symptoms (neurologic controls, n = 15). RESULTS: BD patients, but not schizophrenic patients, had significantly greater volumes of deep but not periventricular WMHs compared to neurologic controls. BD subjects also had significantly greater CSF concentrations of sorbitol and fructose (the polyol pathway metabolites of glucose) compared to controls. Significant positive correlations between CSF metabolites and WMH volumes were found only in the BD group and were between deep WMH volumes and CSF sorbitol (rho = 0.487, p = 0.029) and fructose (rho = 0.474, p = 0.035). An index of treatment resistance correlated significantly with deep WMH volume (rho = 0.578, p = 0.008), sorbitol (rho = 0.542, p = 0.013), and fructose (rho = 0.692, p = 0.001) in BD subjects but not in other subjects. CONCLUSIONS: This is the first reported evidence of relationships between abnormal brain glucose metabolism and both deep WMHs and treatment resistance in a group of BD patients. Further studies are necessary to determine the significance of these findings to BD pathophysiology.

Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression.

Neuroimaging and postmortem studies suggest the involvement of white matter disease in schizophrenia, bipolar disorder, and unipolar major depression. To date there is no published, collective study of myelin staining in these three psychiatric disorders. Deep white matter lesions, potentially affecting corticolimbic circuits, have been particularly implicated in late life depression and poor outcome bipolar disorder. We hypothesized that individuals with these disorders would manifest reduced deep white matter myelin staining compared to normal controls. Sixty transverse sections of fixed dorsolateral prefrontal cortex - 15 from individuals with each psychiatric disorder and 15 from normal controls - were stained according to the method of Kluver and Barrera. Myelin staining intensity was quantified by digital image analysis and expressed as a percent of grey matter staining for a given section. Mean deep (but not gyral) white matter myelin staining was less intense in all three psychiatric groups compared to control. This difference was statistically significant for the bipolar and unipolar groups, with a strong trend toward attenuated staining in the schizophrenic group. Our findings are consistent with postmortem and neuroimaging studies of affective disorders that indicate an increased prevalence of deep white matter lesions in unipolar and bipolar affective disorders.

Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial.

OBJECTIVE: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed. METHOD: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each. RESULTS: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam. CONCLUSIONS: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.

Interventions for Neuropsychiatric Symptoms in Neurocognitive Impairment Due to Alzheimer's Disease: A Review of the Literature.

Neurocognitive impairment due to Alzheimer's disease (previously termed Alzheimer's dementia) (AD) is the most common form of cognitive impairment worldwide. Given the anticipated increase in the population aged 65 and over, the prevalence of persons with AD is expected to increase exponentially during the next 30 years. Noncognitive neuropsychiatric symptoms (NPS) commonly occur in AD and are associated with adverse outcomes for patients and their caregivers. This review summarizes randomized, controlled trials (RCTs) published between 2004 and 2014 with a primary outcome measure of change in symptom severity for NPS in AD. Of the 388 articles initially identified through a literature search, 33 trials met inclusion criteria. Fifteen of these studies had agitation/aggression as a targeted symptom. Twenty-eight evaluated pharmacologic treatments, including psychotropics, cognitive enhancers, stimulants, and nutraceuticals. Nonpharmacologic interventions included bright light, music, exercise, and cognitive-stimulation therapies. Among the pharmacologic interventions, modest efficacy was reported with aripiprazole, citalopram, trazodone, methylphenidate, and scheduled analgesics. Significant reduction in symptom severity was reported with nearly all the nonpharmacologic interventions. Variations in methodology such as inclusion criteria, study setting, and outcome measures limit the generalizability of these results. Barriers to the implementation of nonpharmacologic interventions in clinical settings include resource and training limitations. Electroconvulsive therapy and dronabinol are promising as emerging treatment strategies. Randomized clinical trials are needed in order to validate the utility of electroconvulsive therapy and dronabinol, including where and with whom these interventions will prove most valuable.

Oral glucose tolerance testing to modulate plasma amyloid levels: A novel biomarker.

INTRODUCTION: Plasma levels of amyloid-beta (Aß) do not correlate well with different stages of Alzheimer's disease (AD) in cross-sectional studies. Measuring the changes in Aß plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment; MCI) from normal controls. METHODS: 57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2 hour time period. Changes in plasma Aß40 and42 levels were measured from either baseline or 5 minutes to the 10 minute time point. RESULTS: Compared to normal controls, subjects with AD/MCI had significantly less change (Δ) in plasma levels for both Aß40(-3.13(40.93)pg/ml vs. 41.34(57.16)pg/ml;p=0.002) and Aß42(-0.15(3.77)pg/ml vs. 5.64(10.65)pg/ml; p=0.004). DISCUSSION: OGTT combined with measures of plasma Aß40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD.

The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging.

Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer׳s disease (AD). The underlying neurobiological mechanisms are poorly understood. Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD. Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD. Fasting serum glucose (FSG) in non-diabetic young (YC; n=20) and elderly controls (EC; n=12) and LLD patients (n=16) was correlated with PET scans of cerebral glucose metabolism on a voxel-wise basis. The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions. Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.

Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis.

BACKGROUND: Evidence is accumulating that mitochondrial dysfunction is involved in the pathophysiology of bipolar disorder and schizophrenia. Cerebrospinal fluid (CSF) concentration of lactate, a product of extra-mitochondrial glucose metabolism, is commonly elevated in individuals with mitochondrial disorders, especially those with neuropsychiatric symptoms. We tested the hypothesis that patients with bipolar disorder and schizophrenia would, on average, have elevated CSF lactate concentrations compared with healthy control subjects. METHODS: The CSF lactate and CSF and plasma glucose concentrations were measured with a YSI (YSI, Yellow Springs, Ohio) 2300 STAT Plus Glucose & Lactate Analyzer in 15 samples from each of three groups of subjects: bipolar I disorder patients, schizophrenic patients, and healthy control subjects. RESULTS: Mean CSF lactate concentrations were significantly higher in bipolar (1.76 +/- .38) and schizophrenic subjects (1.61 +/- .31) compared with control subjects (1.31 +/- .21 mmol/L). These differences persisted after adjusting means for CSF glucose concentration, which correlated positively with CSF lactate concentration. CONCLUSIONS: This is the first report of increased CSF lactate concentrations in patients with bipolar disorder and schizophrenia. Elevated CSF lactate indicates increased extra-mitochondrial and anaerobic glucose metabolism and is consistent with impaired mitochondrial metabolism. Measuring CSF lactate concentration might help identify bipolar and schizophrenic patients with mitochondrial dysfunction who might benefit from research to elucidate and ultimately rectify possible mitochondrial pathology underlying these disorders.

Increased plasma concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression.

OBJECTIVE: The therapeutic mechanism of electroconvulsive therapy (ECT) is unknown. Animal research supports a neurotrophic effect of ECT. To investigate a neurotrophic effect in humans, we examined whether plasma concentration of brain-derived neurotrophic factor (BDNF) increases in patients receiving ECT for major depression. METHOD: We conducted a prospective, self-controlled study of 15 patients with a DSM-IV diagnosis of major depressive episode who were referred for ECT at the University of Maryland Medical Center (Baltimore, Md.) between January 2004 and September 2005. Plasma BDNF concentration was measured by enzyme-linked immunosorbent assay before and during an acute course of ECT. Depression severity was measured using the 21-item Hamilton Rating Scale for Depression (HAM-D). RESULTS: ECT resulted in a significant increase in plasma BDNF (Z = 2.897, p = .004) from a pre-ECT median of 84.9 pg/mL to a post-ECT median of 141.2 pg/mL. This change was accompanied by a significant decrease in HAM-D score (Z = 3.411, p = .001) from a pre-ECT median of 30.0 to a post-ECT median of 9.0. BDNF increased in 13 (86.7%) of 15 subjects. CONCLUSION: This is the first report of an increase in plasma BDNF concentration in patients receiving ECT. These preliminary results encourage further investigation of a neurotrophic mechanism for the antidepressant effect of ECT.