Background

Cholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer's disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood.

Methods

This study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer's disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4β2 nicotinic cholinergic receptor binding (V_T/fp) was measured using 2-[¹⁸F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest.

Results

SPM analysis showed the group V_T/f_p binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p < .05, FWE-corrected). Pairwise comparisons revealed lower binding in the AD group compared to the CU group in similar regions. Binding in the entorhinal cortex was lower in the MCI group than in the CU group; binding in the hippocampus was lower in the AD group than in the MCI group. AD participants taking cholinesterase inhibitor medication had lower 2FA binding in the bilateral hippocampus and thalamus compared to those not taking medication. In the CU group, age was negatively associated with 2FA binding in each region of interest (r_s = - .33 to - .59, p < .05 for each, uncorrected). Attention, immediate recall, and delayed recall scores were inversely associated with 2FA binding in most regions across the full sample. In the combined group of CU and MCI participants, attention was inversely associated with 2FA binding in most regions, beyond the effect of hippocampal volume.

Conclusions

Nicotinic cholinergic receptor binding in specific limbic and subcortical regions is lower in MCI and further reduced in AD dementia, compared to CU older adults, and is related to cognitive deficits. Cognitive decline with age may be a consequence of reduced cholinergic receptor density or binding affinity that may also promote vulnerability to other Alzheimer's processes. Contemporary modification of the "cholinergic deficit" of aging and AD may reveal opportunities to prevent or improve clinical symptoms.

Patients with Alzheimers Disease (AD) show difficulties with attention. Cognitive neuroscience models posit that attention can be broken down into alerting, orienting, and executive networks. We used the Stroop Color-Word test to interrogate the neural correlates of attention deficits in AD. We hypothesized that the Word, Color, and Color-Word conditions of the Stroop would all tap into the alerting and orienting networks. The Color-Word condition would additionally tap into the executive network. A ratio of Color-Word to Color naming performance would isolate the executive network from the others. To identify the neural underpinnings of attention in AD we correlated performance on the Stroop with brain metabolic activity. Sixty-six patients with probable AD completed [18F] fluorodeoxyglucose PET scanning and neuropsychological testing. Analysis was conducted with SPM12 (p<0.001 uncorrected, extent threshold 50 voxels). Performance on the Word, Color, and Color-Word conditions directly correlated with metabolic rate in right inferior parietal lobules/intraparietal sulci. The Color-Word/Color ratio revealed associations with metabolic rate in right medial prefrontal cortex and insula/operculum. Overall findings were largely consistent with the hypothesized neuroanatomical substrates of the alerting, orienting, and executive networks. As such, attention deficits in AD reflect compromise to multiple large-scale networks.

Objectives

Depression is related to increased risk for dementia, possibly through links with cerebrovascular disease. Blood pressure variability is an emerging risk factor for cerebrovascular disease and dementia, but relationships with affective symptoms remain understudied.

Design

Retrospective analysis of prospective cohort study.

Setting

Alzheimer's Disease Neuroimaging Initiative.

Participants

505 older adults without history of dementia or recent depression underwent three to four blood pressure measurements over 12 months and completed a self-report measure of depressive symptoms (Geriatric Depression Scale - 15 Item) at study baseline and 24-months follow-up.

Measurements

Blood pressure variability was calculated as variability independent of mean and maximum minus minimum. Regression models investigated relationships between blood pressure variability and severity of self-reported depressive symptoms at 24-months follow-up after controlling for several variables, including average blood pressure, antihypertensive use, antidepressant use, and baseline depressive symptom severity.

Results

Elevated diastolic blood pressure variability was related to greater total depressive symptom score at follow-up (ß = .16 [95% CI 0.02, .30]; p = 0.03), with specific contribution from increased severity of symptoms of dysphoria (odds ratio = 1.35 [95% CI 1.07, 1.75]; p = 0.02). Blood pressure variability was not significantly related to other symptom subscales, including those reflecting life satisfaction or withdrawal.

Conclusions

Findings suggest that elevated diastolic blood pressure variability is related to subthreshold depressive symptomatology in older adults without history of dementia or recent depression, independent of average blood pressure. Blood pressure variability may be an understudied vascular risk factor linked with depression and cognitive impairment, with potential therapeutic implications.

The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety.

Objective

Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This study's goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms.

Methods

In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. (18)F-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2.

Results

Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight.

Conclusion

Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor and is now reducing PTSD symptoms in the first patient enrolled in an early-phase safety trial.

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor and is now reducing PTSD symptoms in the first patient enrolled in an early-phase safety trial.

Background: Combat post-traumatic stress disorder (PTSD) involves significant suffering, impairments in social and occupational functioning, substance use and medical comorbidity, and increased mortality from suicide and other causes. Many veterans continue to suffer despite current treatments. Deep brain stimulation (DBS) has shown promise in refractory movement disorders, depression and obsessive-compulsive disorder, with deep brain targets chosen by integration of clinical and neuroimaging literature. The basolateral amygdala (BLn) is an optimal target for high-frequency DBS in PTSD based on neurocircuitry findings from a variety of perspectives. DBS of the BLn was validated in a rat model of PTSD by our group, and limited data from humans support the potential safety and effectiveness of BLn DBS.Methods/Design: We describe the protocol design for a first-ever Phase I pilot study of bilateral BLn high-frequency DBS for six severely ill, functionally impaired combat veterans with PTSD refractory to conventional treatments. After implantation, patients are monitored for a month with stimulators off. An electroencephalographic (EEG) telemetry session will test safety of stimulation before randomization to staggered-onset, double-blind sham versus active stimulation for two months. Thereafter, patients will undergo an open-label stimulation for a total of 24 months. Primary efficacy outcome is a 30% decrease in the Clinician Administered PTSD Scale (CAPS) total score. Safety outcomes include extensive assessments of psychiatric and neurologic symptoms, psychosocial function, amygdala-specific and general neuropsychological functions, and EEG changes. The protocol requires the veteran to have a cohabiting significant other who is willing to assist in monitoring safety and effect on social functioning. At baseline and after approximately one year of stimulation, trauma script-provoked 18FDG PET metabolic changes in limbic circuitry will also be evaluated.Discussion: While the rationale for studying DBS for PTSD is ethically and scientifically justified, the importance of the amygdaloid complex and its connections for a myriad of emotional, perceptual, behavioral, and vegetative functions requires a complex trial design in terms of outcome measures. Knowledge generated from this pilot trial can be used to design future studies to determine the potential of DBS to benefit both veterans and nonveterans suffering from treatment-refractory PTSD.

Background

Combat post-traumatic stress disorder (PTSD) involves significant suffering, impairments in social and occupational functioning, substance use and medical comorbidity, and increased mortality from suicide and other causes. Many veterans continue to suffer despite current treatments. Deep brain stimulation (DBS) has shown promise in refractory movement disorders, depression and obsessive-compulsive disorder, with deep brain targets chosen by integration of clinical and neuroimaging literature. The basolateral amygdala (BLn) is an optimal target for high-frequency DBS in PTSD based on neurocircuitry findings from a variety of perspectives. DBS of the BLn was validated in a rat model of PTSD by our group, and limited data from humans support the potential safety and effectiveness of BLn DBS.

Methods/design

We describe the protocol design for a first-ever Phase I pilot study of bilateral BLn high-frequency DBS for six severely ill, functionally impaired combat veterans with PTSD refractory to conventional treatments. After implantation, patients are monitored for a month with stimulators off. An electroencephalographic (EEG) telemetry session will test safety of stimulation before randomization to staggered-onset, double-blind sham versus active stimulation for two months. Thereafter, patients will undergo an open-label stimulation for a total of 24 months. Primary efficacy outcome is a 30% decrease in the Clinician Administered PTSD Scale (CAPS) total score. Safety outcomes include extensive assessments of psychiatric and neurologic symptoms, psychosocial function, amygdala-specific and general neuropsychological functions, and EEG changes. The protocol requires the veteran to have a cohabiting significant other who is willing to assist in monitoring safety and effect on social functioning. At baseline and after approximately one year of stimulation, trauma script-provoked 18FDG PET metabolic changes in limbic circuitry will also be evaluated.

Discussion

While the rationale for studying DBS for PTSD is ethically and scientifically justified, the importance of the amygdaloid complex and its connections for a myriad of emotional, perceptual, behavioral, and vegetative functions requires a complex trial design in terms of outcome measures. Knowledge generated from this pilot trial can be used to design future studies to determine the potential of DBS to benefit both veterans and nonveterans suffering from treatment-refractory PTSD.

Trial registration

PCC121657, 19 March 2014.

Poor executive functioning increases risk of decline in Mild Cognitive Impairment (MCI). Executive functioning can be conceptualized within the framework of working memory. While some components are responsible for maintaining representations in working memory, the central executive is involved in the manipulation of information and creation of new representations. We aimed to examine the neural correlates of these components of working memory using a maintenance working memory and visuospatial reasoning task. Twenty-five patients with amnestic MCI and 19 elderly controls (EC) completed functional MRI during reasoning and maintenance working memory tasks. In MCI, maintenance working memory was associated with hypoactivation of right frontoparietal regions and hyperactivation of left prefrontal cortex, coupled with attenuation of default mode network (DMN) relative to EC. During reasoning, MCI showed hypoactivation of parietal regions, coupled with attenuation of anterior DMN and increased deactivation of posterior DMN relative to EC. Comparing the reasoning task to the maintenance working memory task yields the central executive. In MCI, the central executive showed hypoactivation of right parietal lobe and increased deactivation of posterior DMN compared to EC. Consistent with prior work on executive functioning, MCI show different neural circuitry during visuospatial reasoning, including changes to both task positive frontoparietal regions, as well as to deactivation patterns within the DMN. Both hyperactivation of task positive networks and increased deactivation of DMN may be compensatory.