No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits
Abstract
Background:
Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ).
Objective:
The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits.
Methods:
Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments.
Results:
Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency.
Conclusions:
These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.
... Even though this intervention may have raised tryptophan levels, it acted similarly to tryptophan depletion ot loss of serotonin producing cells in that the tryptophan metabolite 5HT was missing allowing for proliferation. "Serotonin degeneration " bas been implicated in cognitive declines [158] and it may not be clear in which direction cause and effect operate but degeneration in response to limited tryptophan would be quite plausible. Skin ecology may involve many factors and exposure to ketoconazole may have favored C. acnes for unclear reasons although biotin synthesis was considered [53]. ...
This is an alternative analysis of a simple differential abundance measure between control and AD brains from one recent publication [111]. The differential abundances suggest loss of beneficial organisms maybe acquired at conception. The title derives from literature on some of these organisms being symbionts with plants. As soon as I can figure out how to download the Bioproject data I hope to look at sequence level analysis. This may be another case of the mixed taxonomy getting in the way of seeing what is really there. A good database on metabolism may be helpful too. If nothing else, compare the list here to those most abundant in the endometrium [189]. Also repeats warnings on static measures of all kinds :) This is just released in current form due to hitting a time constraint. It seems to motivate important speculation with acceptable editing issues for now. This is a draft and has not been peer reviewed or completely proof read but released in some state where it seems worthwhile given time or other constraints. Typographical errors are quite likely particularly in manually entered numbers. This work may include output from software which has not been fully debugged. For information only, not for use for any particular purpose see fuller disclaimers in the text. Caveat Emptor. I am not a veterinarian or a doctor or health care professional and this is not particular advice for any given situation. Read the disclaimers in the appendicies or text, take them seriously and take prudent steps to evaluate this information. This work addresses a controversial topic and likely advances one or more viewspoints that are not well accepted in an attempt to resolve confusion. The reader is assumed familiar with the related literature and controversial issues and in any case should seek additional input from sources the reader trusts likely with differing opinions. For information and thought only not intended for any particular purpose. Caveat Emptor
Multiple studies over the last decade have established that Alzheimer's disease and related dementias (ADRD) are associated with changes in the gut microbiome. These alterations in organismal composition result in changes in the abundances of functions encoded by the microbial community, including metabolic capabilities, which likely impact host disease mechanisms. Gut microbes access dietary components and other molecules made by the host and produce metabolites that can enter circulation and cross the blood-brain barrier (BBB). In recent years, several microbial metabolites have been associated with or have been shown to influence host pathways relevant to ADRD pathology. These include short chain fatty acids, secondary bile acids, tryptophan derivatives (such as kynurenine, serotonin, tryptamine, and indoles), and trimethylamine/trimethylamine N-oxide. Notably, some of these metabolites cross the BBB and can have various effects on the brain, including modulating the release of neurotransmitters and neuronal function, inducing oxidative stress and inflammation, and impacting synaptic function. Microbial metabolites can also impact the central nervous system through immune, enteroendocrine, and enteric nervous system pathways, these perturbations in turn impact the gut barrier function and peripheral immune responses, as well as the BBB integrity, neuronal homeostasis and neurogenesis, and glial cell maturation and activation. This review examines the evidence supporting the notion that ADRD is influenced by gut microbiota and its metabolites. The potential therapeutic advantages of microbial metabolites for preventing and treating ADRD are also discussed, highlighting their potential role in developing new treatments.
Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota–gut–brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.
Introduction:
Depression has been associated with cognitive performance, but whether sociodemographic and clinical characteristics might influence this association is not well elaborated. This study aimed to further explore this relationship in older adults.
Methods:
This cross-sectional study is based on data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. A total of 1,433 individuals with complete information on depressive symptoms and cognitive function variables were included in this study. Patient Health Questionnaire 9 (PHQ-9) score ≥10 as the cutoff to identify cases of depression in our study. We defined poor cognitive performance as a composite cognitive score <47. Logistic regression models were used to examine the association of depression with cognitive performance (model 1). We progressively adjusted the covariates as confounders (model 2: model 1 + age, and gender; model 3: model 2 + race, education level, family income, drinking, and smoking; model 4: model 3 + overweight, arthritis, hyperlipidemia, diabetes, hypertension, heart failure, coronary heart disease, heart attack, stroke, and cancer). We then conducted subgroup, interaction, and restricted cubic spline (RCS) analyses to examine this association.
Results:
The prevalence of poor cognitive performance was 36.6% (53/145) in the depression group and 14.1% (182/1,288) in the non-depression group. In the fully adjusted model, depression was significantly associated with poor cognitive performance (adjusted odds ratio: 2.25; 95% confidence interval: 1.31-3.81). The results were robust to sensitivity analyses. Gender and education level may modify the association between depression and poor cognitive performance. RCS analysis revealed that the PHQ-9 score was related to poor cognitive performance in a nonlinear manner (p for nonlinearity <0.001), and exhibited a J-shaped curve.
Conclusion:
Depression is associated with poor cognitive performance in US older adults. Early recognition and treatment of depression may be potential intervention strategies to protect cognitive health.
Introduction:
For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo.
Methods:
We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD.
Results:
Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume.
Conclusion:
These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.
Beta-amyloid deposition (Aβ) is one of the earliest pathological markers associated with Alzheimer’s disease. Mild cognitive impairment in the setting of Aβ pathology is widely considered to represent a preclinical manifestation of Alzheimer’s disease. In-vivo imaging studies are unique in their potential to advance our understanding of the role of Aβ in cognitive deficits in Alzheimer’s disease and in mild cognitive impairment. Previous work has shown an association between global cortical measures of Aβ (“amyloid positivity”) in mild cognitive impairment with greater cognitive deficits and greater risk of progression to Alzheimer’s disease. The focus of the present study was to examine the relationship between the regional distribution of Aβ and specific cognitive deficits in people with mild cognitive impairment and cognitively normal elderly individuals. Forty-seven participants with multi-domain, amnestic mild cognitive impairment (43% female, aged 57-82 years) and thirty-seven healthy, cognitively normal comparison subjects (42% female, aged 55-82 years) underwent clinical and neuropsychological assessments and high-resolution positron emission tomography with the radiotracer [11C]PiB to measure Aβ. Brain-behavior partial least squares analysis was conducted to identify spatial patterns of Aβ that correlated with performance on neuropsychological assessments. Partial least squares analysis identified a single significant (p < 0.001) latent variable which accounted for 80% of the covariance between demographic and cognitive measures and Aβ. Performance in immediate verbal recall (R = -0.46 ± 0.07, p < 0.001), delayed verbal recall (R = -0.39 ± 0.09, p < 0.001), immediate visual-spatial recall (R = -0.39 ± 0.08, p < 0.001), delayed visual-spatial recall (R = -0.45 ± 0.08, p < 0.001) and semantic fluency (R = -0.33 ± 0.11, p = 0.002) but not phonemic fluency (R = -0.05 ± 0.12, p < 0.705) negatively covaried with Aβ in the identified regions. Partial least squares analysis of the same cognitive measures with gray matter volumes showed similar associations in overlapping brain regions. These findings suggest that the regional distribution of Aβ and gray matter volumetric decreases are associated with deficits in executive function and memory in mild cognitive impairment. Longitudinal analysis of these relationships may advance our understanding of the role of Aβ in relation to gray matter volumetric decreases in cognitive decline.
Depression in late-life is associated with increased risk of cognitive decline and development of all-cause dementia. The neurobiology of late-life depression (LLD) may involve both neurochemical and neurodegenerative mechanisms that are common to depression and dementia. Transgenic amyloid mouse models show evidence of early degeneration of monoamine systems. Informed by these preclinical data, the hypotheses were tested that a spatial covariance pattern of higher beta-amyloid (Aβ) and lower serotonin transporter availability (5-HTT) in frontal, temporal, and parietal cortical regions would distinguish LLD patients from healthy controls and the expression of this pattern would be associated with greater depressive symptoms. Twenty un-medicated LLD patients who met DSM-V criteria for major depression and 20 healthy controls underwent PET imaging with radiotracers for Aβ ([11C]-PiB) and 5-HTT ([11C]-DASB). A voxel-based multi-modal partial least squares (mmPLS) algorithm was applied to the parametric PET images to determine the spatial covariance pattern between the two radiotracers. A spatial covariance pattern was identified, including higher Aβ in temporal, parietal and occipital cortices associated with lower 5-HTT in putamen, thalamus, amygdala, hippocampus and raphe nuclei (dorsal, medial and pontine), which distinguished LLD patients from controls. Greater expression of this pattern, reflected in summary 5-HTT/Aβ mmPLS subject scores, was associated with higher levels of depressive symptoms. The mmPLS method is a powerful approach to evaluate the synaptic changes associated with AD pathology. This spatial covariance pattern should be evaluated further to determine whether it represents a biological marker of antidepressant treatment response and/or cognitive decline in LLD patients.
This study investigated the effects of vortioxetine on cognitive function in adults with mild cognitive impairment (MCI). This single-arm, open-label, phase II study enrolled 111 adults with MCI without depressive symptoms to receive 5-10 mg/day vortioxetine for 6 months. Main outcomes assessed: cognitive function [Montreal Cognitive Assessment (MoCA); Digit Symbol Substitution Test (DSST)], disease severity [Clinical Dementia Rating (CDR)], clinician-assessed improvement and safety. Mean MoCA score increased from 24.2 points (baseline) to 29.7 points (month 6), placing most subjects within the cognitively normal range (≥26 points). Compared with baseline, MoCA and DSST scores were significantly improved at months 1, 3 and 6 (P < 0.001 for all). Global CDR scores significantly improved from baseline to month 6 (mean change -0.37 points; P < 0.001), representing an improvement from very mild impairment (0.50 points) to cognitively normal status (0.13 points), mainly in CDR memory scores. At month 6, 89.6% of subjects had improved disease severity. Adverse events and adverse drug reactions were reported in 9.9% (n = 11) and 2.7% (n = 3) of subjects, respectively. Vortioxetine treatment was associated with significant improvement in cognitive function and a favorable safety profile in community-dwelling older adults with MCI. Given the lack of evidence for efficacious pharmacologic interventions for MCI, our results are encouraging and warrant further investigation.
The pathogenesis of Alzheimer's disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression of AD. In physiological conditions, all neurotransmitter systems function in concert and are interdependent at both the neuroanatomical and molecular levels. Through their early involvement in AD, cognitive and behavioral abilities that rely on their interactions also become disrupted. Considering that serotonin (5HT) regulates the release of noradrenaline (NA), dopamine (DA) and acetylcholine (ACh), any alteration in 5HT levels leads to disturbance of NA, DA, and ACh homeostasis in the brain. One of the earliest pathological changes during the prodromal phase of AD is a decrease of serotonergic transmission throughout the brain, with serotonergic receptors being also affected. Additionally, serotonergic and noradrenergic as well as serotonergic and dopaminergic nuclei are reciprocally interconnected. As the serotonergic dorsal raphe nucleus (DRN) is affected by pathological changes early in AD, and the noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental area (VTA) exhibit AD-related pathological changes, their connectivity also becomes altered in AD. Such disrupted interactions among neurotransmitter systems in AD can be used in the development of multi-target drugs. Some of the potential AD therapeutics (such as ASS234, RS67333, tropisetron) target multiple neurotransmitter systems to achieve the best possible improvement of cognitive and behavioral deficits observed in AD. Here, we review how serotonergic system interacts with other subcortical modulatory systems (noradrenergic, dopaminergic, cholinergic, and opioid systems) during AD.
Background
Discrepant and often contradictory results have accumulated regarding the antidepressant and pro-cognitive effects of serotonin transporter (SERT) antagonists in Alzheimer’s disease.
Methods
To address the discrepancy, we measured the activity and density of SERT in the neocortex of 3–24-month-old APPswe/PS1dE9 and wild-type littermate mice, by using [³H]DASB autoradiography and the [³H]5-HT uptake assay. Levels of soluble amyloid-β (Aβ), and pro-inflammatory cytokines that can regulate SERT function, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were measured in parallel. Neuroinflammation in aging APPswe/PS1dE9 mice was further evaluated by [³H]PK11195 autoradiography.
Results
Decreased SERT density was observed in the parietal and frontal cortex of 18–24-month-old APPswe/PS1dE9 mice, compared to age-matched, wild-type animals. The maximal velocity uptake rate (Vmax) of [³H]5-HT was reduced in neocortical preparations from 20-month-old transgenic vs. wild-type mice. The reduction was observed when the proportion of soluble Aβ40 in the Aβ40/42 ratio increased in the aged transgenic brain. At concentrations compatible with those measured in 20-month-old APPswe/PS1dE9 mice, synthetic human Aβ40, but not Aβ42, reduced the baseline Vmax of [³H]5-HT by ~ 20%. Neuroinflammation in APPswe/PS1dE9 vs. wild-type mice was evidenced by elevated [³H]PK11195 binding levels and increased concentration of IL-1β protein, which preceded the reductions in neocortical SERT density and activity. Age-induced increases in the levels of IL-1β, IL-6, and TNF were observed in both transgenic and wild-type animals.
Conclusions
The progression of cerebral amyloidosis is associated with neuroinflammation and decreased presynaptic markers of serotonergic integrity and activity. The Aβ40-induced reduction in the uptake kinetics of [³H]5-HT suggests that the activity of SERT, and potentially the effects of SERT antagonism, depend on the levels of interstitial Aβ40.
Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition.
Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines.
Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity.
Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.
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, as well as the cell bodies of origin (raphe nuclei).
Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET) with ^{11}carbon-labelled Pittsburgh Compound-B ( 11 C-PIB), the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (A β ) deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.
Introduction:
Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study.
Methods:
We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences.
Results:
Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers.
Discussion:
The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.
Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer's disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram's effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.
There is an increasing demand for alternate-form neuropsychological tests that can be used in clinical trials with little risk of direct practice effect. Although the Brief Visuospatial Memory Test ( BVMT ) includes six equivalent alternate forms, its administration is limited to an immediate and 25-min delayed free-recall trial. We now present a revised version of the BVMT called the Brief Visuospatial Memory Test—Revised (BVMT-R) that includes three learning trials, a 25-min delayed recall trial, and a delayed yes/ no recognition task. A new scoring system, which accounts for the location of test stimuli as well as the accuracy of recall, is also introduced. Using these new administration and scoring procedures, we administered the BVMT-R to 261 neuropsychiatric patients and 456 normal healthy adults. The results indicated that the test has excellent interform reliability, and the construct and criterion-related validity of the test were supported in studies using clinical samples. Although the BVMT-R is not without its limitations, the test's brevity and alternate-form capacity make it a valuable instrument for serial neuropsychological assessments. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Growing evidence suggests that a compromised serotonergic system plays an important role in the pathophysiology of Alzheimer's disease (AD). We assessed the expression of 5-HT(1B/1D) and 5-HT(6) receptors and cholinacetyltransferase (ChAT) activity in post-mortem frontal and temporal cortex from AD patients who had been prospectively assessed for cognitive function using the Mini-Mental State Examination (MMSE) and behavioral changes using the Present Behavioral Examination (PBE). 5-HT(1B/1D) and 5-HT(6) receptor densities were significantly reduced in both cortical areas. 5-HT(1B/1D) receptor density was correlated to MMSE decline in the frontal cortex, supporting its implication in memory impairment. The best predictor for lowered 5-HT(6) receptor density in the temporal cortex was the PBE measure of overactivity. The 5-HT(6)/ChAT ratio was related to aggression both in the frontal and temporal cortex. Therefore, antagonists acting at 5-HT(6) receptors could be useful in the treatment of non-cognitive symptoms associated to AD.
Mild cognitive impairment (MCI) is considered to be an early stage of a neurodegenerative disorder, particularly Alzheimer's disease, and the clinical diagnosis requires the objective demonstration of cognitive deficits. The aim of the present study was to evaluate the predictive value of MCI for the conversion to dementia when using four different verbal memory tests (Logical Memory, LM; California Verbal Learning Test, CVLT; Verbal Paired-Associate Learning, VPAL; and Digit Span, DS) in the MCI criteria.
Participants were consecutive patients with subjective cognitive complaints who performed a comprehensive neuropsychological evaluation and were not demented, observed in a memory clinic setting.
At baseline, 272 non-demented patients reporting subjective cognitive complaints were included. During the follow-up time (3.0 ± 1.9 years), 58 patients converted to dementia and 214 did not. Statistically significant differences between the converters and non-converters were present in LM, VPAL, and CVLT. A multivariate Cox regression analysis combining the four memory tests revealed that only the CVLT test remained significant as a predictor of conversion to dementia. Non-demented patients with cognitive complaints diagnosed as having MCI according to abnormal (<1.5 SD) learning in the CVLT test had a 3.61 higher risk of becoming demented during the follow-up.
The verbal memory assessment using the CVLT should be preferred in the diagnostic criteria of MCI for a more accurate prediction of conversion to dementia.
Alzheimer's disease (AD) is a slowly progressing form of dementia characterized in its earliest stages as a loss of memory. Individuals with amnestic mild cognitive impairment (aMCI) may be in the earliest stages of the disease and represent an opportunity to identify pathological changes related to the progression of AD. Synaptic loss is one of the hallmarks of AD and associated with cognitive impairment. The inferior temporal gyrus plays an important role in verbal fluency, a cognitive function affected early in the onset of AD. Unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the inferior temporal gyrus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI had significantly fewer synapses (36%) compared to individuals with no cognitive impairment. Individuals with AD showed a loss of synapses very similar to the aMCI cohort. Synaptic numbers correlated highly with Mini Mental State Examination scores and a test of category verbal fluency. These results demonstrate that the inferior temporal gyrus is affected during the prodromal stage of the disease and may underlie some of the early AD-related clinical dysfunctions.
Behavioral markers measured through neuropsychological testing in mild cognitive impairment (MCI) were analyzed and combined in multivariate ways to predict conversion to Alzheimer's disease (AD) in a longitudinal study of 43 MCI patients. The test measures taken at a baseline evaluation were first reduced to underlying components (principal component analysis, PCA), and then the component scores were used in discriminant analysis to classify MCI individuals as likely to convert or not. When empirically weighted and combined, episodic memory, speeded executive functioning, recognition memory (false and true positives), visuospatial memory processing speed, and visuospatial episodic memory were together strong predictors of conversion to AD. These multivariate combinations of the test measures achieved through the PCA were good, statistically significant predictors of MCI conversion to AD (84% accuracy, 86% sensitivity, and 83% specificity). Importantly, the posterior probabilities of group membership that accompanied the binary prediction for each participant indicated the confidence of the prediction. Most of the participants (81%) were in the highly confident probability bins (.70-1.00), where the obtained prediction accuracy was more than 90%. The strength and reliability of this multivariate prediction method were tested by cross-validation and randomized resampling.
Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.
To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD.
A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).
The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri.
One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline.
Progression from CDR 0 to CDR 0.5 status (very mild dementia).
Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0.
Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.
In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, neuroimaging, biomarker, neuropathological, disease mechanism, and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.
Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET) with (11)carbon-labelled Pittsburgh Compound-B ((11)C-PIB), the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Abeta) deposits, and is a sensitive marker for Abeta pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.
Alzheimer's disease (AD) is a progressive and irreversible disease. There is strong evidence that the progression of the phospho-tau neurofibrillary cytoskeletal changes, rather than the beta-amyloid burden, is crucial in determining the severity of the dementia in AD. The Braak and Braak staging system (BB) focuses mainly on the cortical cytoskeletal pathology and classifies this progressive pathology into six stages, spreading from the transentorhinal region to primary cortices. Although it is reported elsewhere that the midbrain's dorsal raphe nucleus (DR), which is connected with those areas of the cerebral cortex undergoing early changes during BB I and II, exhibits AD-related cytoskeletal pathology, this nucleus has not been considered by the BB.
To determine during which BB stage and how frequently the DR is affected by AD-related neurofibrillary changes, we studied the DR of 118 well-characterized individuals of the Brain Bank of the Brazilian Aging Brain Study Group categorized according to the BB. Thirty-eight of these individuals were staged as BB = 0, and 80 as BB >or= 1.
In all of the BB >or= 1 individuals (cortical neurofibrillary changes were present at least in the transentorhinal region) and in more than 1/5 of the BB = 0 individuals neurofibrillary changes were detected in the supratrochlear subnucleus of the DR.
These observations: (i) support the hypothesis of transneuronal spread of neurofibrillary changes from the DR to its interconnected cortical brain areas; and (ii) indicate that the supratrochlear subnucleus of the DR is affected by neurofibrillary changes before the transentorhinal cortex during the disease process underlying AD.
The original conceptualization of mild cognitive impairment (MCI) was primarily as an amnestic disorder representing an intermediate stage between normal aging and Alzheimer's dementia (AD). More recently, broader conceptualizations of MCI have emerged that also encompass cognitive domains other than memory. These characterizations delineate clinical subtypes that commonly include amnestic and non-amnestic forms, and that involve single and multiple cognitive domains. With the advent of these broader classifications, more specific information is emerging regarding the neuropsychological presentation of individuals with MCI, risk for dementia associated with different subtypes of MCI, and neuropathologic substrates connected to the clinical subtypes. This review provides an overview of this burgeoning literature specific to clinical subtypes of MCI. Focus is primarily on neuropsychological and structural neuroimaging findings specific to clinical subtypes of MCI as well as the issue of daily functioning. Although investigations of non-amnestic subtypes using advanced neuroimaging techniques and clinical trials are quite limited, we briefly review these topics in MCI because these data provide a framework for future investigations specifically examining additional clinical subtypes of MCI. Finally, the review comments on select methodological issues involved in studying this heterogeneous population, and future directions to continue to improve our understanding of MCI and its clinical subtypes are offered.
The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.
beta-Amyloid (Abeta) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of Abeta pathology, including Abeta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Abeta neurotoxicity indicated by in vitro studies, mouse models with significant Abeta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Abeta pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1DeltaE9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Abeta deposition in the APPswe/PS1DeltaE9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (approximately 50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local Abeta or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of Abeta pathology develops progressive MAergic neurodegeneration occurring in AD cases.
Episodic (recall of passages) and semantic (letter and category fluency) memory tasks were administered to Alzheimer's Disease (early stages), Huntington's Disease (HD), and alcoholic Korsakoff patients matched for overall severity of dementia. Although all three patient groups were severely (and equally) impaired on memory for passages, only the Alzheimer and Korsakoff patients emitted numerous intrusion errors. On the fluency tasks, the performance of the mild Alzheimer patients was distinguishable from that of the other two patient groups. On both fluency tasks, the HD and Korsakoff patients demonstrated severe and moderate deficits, respectively, whereas the mild Alzheimer patients were impaired only on the category fluency task. As with the episodic memory test, the Alzheimer and Korsakoff patients made more perseverative errors than did the HD patients on letter fluency. These findings suggest that Alzheimer and HD patients' impairments on episodic and semantic memory tasks reflect different underlying processes. The performance of Alzheimer patients is affected by their language dysfunction and an increased sensitivity to proactive interference; the deficits of the HD patients appear due to a general retrieval problem. Similarities in the error patterns (i.e., perseveration errors) of Alzheimer and Korsakoff patients are discussed with regard to recent neuropathological findings.
To better define treatment-resistant depression (TRD) so as to assist clinical management and refine treatment guidelines.
In this study, we examine a broad range of clinical variables in depressed patients (n=196) referred to a tertiary referral Mood Disorders Unit (MDU). Information was collected from patients, referrers and assessors over a period of 32 months and included evaluations of treatments, treatment resistance and related variables. Data were analysed across trichotomized 'high', 'low' and 'no' treatment resistance groupings of patients.
A significantly greater proportion of patients with melancholia were amongst the high TRD group, and this was consistent across different strategies for evaluating melancholia.
Melancholia perhaps provides a prototypic TRD subset that perhaps reflects some innate aspects of melancholic depression or factors such as the impact of ageing. Research into TRD is needed to both replicate this finding and perhaps explicate it further.
The human brainstem is a complex structure with several small nuclei and neural pathways of interest in the pathophysiology of central nervous system (CNS) disorders. In common with other monoaminergic systems, serotoninergic neurons originate from a group of nuclei located in the brainstem. The present study was designed to validate a user-independent approach for a detailed in vivo quantification of serotonin transporter (5-HTT) availability in the human brainstem using a template-based approach that consisted of three steps. First, 3T-MR images and parametric binding potential (BPND) [(11)C]MADAM images of ten healthy subjects were used to generate a PET template of 5-HTT availability. In the second step, volumes of interest (VOIs) for different brainstem nuclei were obtained using a method in which VOIs are initially delineated on MRI images using anatomical landmarks and then are finally tailored on the distribution of 5-HTT binding using a thresholding approach applied to the 5-HTT template. In the final step, the VOIs were transformed and applied individually to BPND images of 16 healthy subjects (14M/2F, 20-64 y). The in vivo distribution of BPND values obtained with the template-based method were in good agreement with an individual-based approach taken as gold-standard. Results were also in agreement with 5-HTT quantification using in vitro binding data obtained with autoradiography (ARG) studies using [(3)H]MADAM. The proposed template-based method can be applied to PET data acquired in several CNS-disorders in which serotonin neurons in the brainstem might be affected.
Alzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enhance serotonin concentration in the synaptic cleft have been debated as possible therapeutic strategies to slow the progression of AD. In this Viewpoint, we discuss exciting new insights regarding the modulation of serotonin signaling for AD prevention and therapy.
Serotonergic dysfunction is implicated in Alzheimer's disease (AD). In addition, reductions in brain of both monoamine synthesis and release have been reported. Serotonin 1B receptors (5-HT1B), along with serotonin transporter (SERT) are among the regulators of extracellular 5-HT levels. We investigated the effect of the familial AD APP (Amyloid precursor protein) K670N/M671L double mutation, APP Swedish mutation (APPswe), on the expression of 5-HT1B, SERT, MAOA, p11 and 5-HT and its metabolite 5-HIAA in SH-SY5Y human neuroblastoma cell line stably transfected with APPswe mutation. In addition, hippocampal expressions of 5-HT1B and SERT were assessed in wild type and transgenic mice expressing APPswe mutation (Tg2576) at different age groups. We found a reduction of 5-HT1B as well as SERT in both APPswe in vitro and ex vivo. P11 and 5HT were also reduced, whereas 5HT turnover and MAOA were increased. Our results indicate that APPswe induced decreased 5-HT1B expression and 5-HT release, as well as increased MAOA activity and 5-HT breakdown. Further studies to explore the detailed mechanism behind reduced 5-HT1B and SERT in AD and their clinical implications are needed.
Copyright © 2015. Published by Elsevier Ireland Ltd.
The promising β-amyloid PET imaging agent, [11C]-6-OH-BTA-1, has been radiolabelled in one step using [11C]-methyl triflate. No protection of the 6-hydroxy group is required, greatly simplifying the synthetic method. The reaction may be carried out in solution or by the captive solvent ‘loop’ method. Copyright © 2004 John Wiley & Sons, Ltd.
This paper presents a simple and widely ap- plicable multiple test procedure of the sequentially rejective type, i.e. hypotheses are rejected one at a tine until no further rejections can be done. It is shown that the test has a prescribed level of significance protection against error of the first kind for any combination of true hypotheses. The power properties of the test and a number of possible applications are also discussed.
The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-β (Aβ) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early Alzheimer disease (AD) patients in relation to cortical Aβ burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19-27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD patients and eight healthy controls additionally underwent a [11C]PIB PET scan to measure the cortical Aβ burden. When AD patients were defined on clinical criteria, no difference in cerebral 5-HT4 receptor binding between AD patients and healthy controls was found (p = 0.54). However, when individuals were reassigned to groups according to their amyloid status, the PIB-positive individuals had 13% higher 5-HT4 receptor levels than PIB-negative individuals (p = 0.02) and the importance of classification of groups is emphasized. The 5-HT4 receptor binding was a positively correlated to Aβ burden (p = 0.03) and negatively to MMSE score of the AD patients (p = 0.02). Our data suggests that cerebral 5-HT4 receptor upregulation starts at a preclinical stage of and continues while dementia is still at a mild stage, which contrasts other receptor subtypes. We speculate that this may either be a compensatory effect of decreased levels of interstitial 5-HT, an attempt to improve cognitive function, increase acetylcholine release or to counteract Aβ accumulation.
We previously demonstrated a 20-30% reduction in cortical 5-HT2A receptor binding in patients with mild cognitive impairment (MCI) as compared to healthy subjects. Here we present a two-year follow-up of 14 patients and 12 healthy age-matched subjects. Baseline and follow-up partial volume corrected levels of 5-HT2A in four neocortical lobes and the posterior cingulate gyrus were investigated using [18F]altanserin positron emission tomography with a bolus-infusion approach. In the two-year follow-up period, 8 of 14 patients with MCI had progressed to fulfill diagnostic criteria for probable Alzheimer's disease (AD). In both patients and healthy subjects, no significant change in 5-HT2A receptor binding was found as compared to baseline values. In MCI patients, the average BPP in neocortex ranged from 1.49 to 2.45 at baseline and 1.38 to 2.29 at two-year follow-up; and in healthy subjects BPP ranged from 1.85 to 3.10 at baseline and 1.81 to 2.98 at two-year follow-up. The BPP of the patients that converted to AD during the follow-up period did not differ significantly from the patients that had not (yet) converted, neither at baseline, nor at follow-up. We conclude that the reduced levels of 5-HT2A receptor binding in MCI patients decrease only slowly and non-significantly, even in patients who convert to AD. Our finding suggests that profoundly reduced cortical 5-HT2A receptor binding is an early feature in MCI whereas the clinical progression from MCI to AD is less associated with further decrease in binding.
We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.
The distribution of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) was mapped in 39 cortical areas of 11 brains of patients with Alzheimer's disease (AD). Whole hemisphere blocks were embedded in polyethylene glycol (Carbowax), sectioned coronally, and stained with thioflavin S and thionin. The densities of NFTs and NPs were assessed using a numerical rating scale for each area. Scores were grouped by type of cortex and by lobe for statistical analysis. Highly significant differences were obtained. For example, limbic periallocortex and allocortex had more NFTs than any other type of cortex. In descending order, the density of NFTs was as follows: periallocortex (area 28) greater than allocortex (subiculum/CA1 zones of hippocampal formation, area 51) greater than corticoid areas (accessory basal nucleus of amygdala, nucleus basalis of Meynert) greater than proisocortex (areas 11, 12, 24, 23, anterior insula, 38, 35) greater than nonprimary association cortex (32, 46, superior temporal sulcus, 40, 39, posterior parahippocampal cortex, 37, 36) greater than primary sensory association cortex (7, 18, 19, 22, 21, 20) greater than agranular cortex (44-5, 8, 6, 4) greater than primary sensory cortex (41-2, 3-1-2, 17). The laminar distribution of NFTs tended to be selective, involving primarily layers III and V of association areas and layers II and IV of limbic periallocortex. There were far more NFTs in both limbic and temporal lobes than in frontal, parietal, and occipital lobes. In general, NPs were more evenly distributed throughout the cortex, with the exceptions of limbic periallocortex and allocortex, which had notably fewer NPs than other cortical areas. Temporal and occipital lobes had the highest NP densities, limbic and frontal lobes had the lowest, and parietal lobe was intermediate. No significant left-right hemispheric differences for NFT or NP densities were found across the population, and there was no relationship between duration of illness and densities of NFTs or NPs. The regional and laminar distribution of NFTs (and, to a lesser degree, that of NPs) suggests a consistent pattern of vulnerability within the cerebral cortices that seems correlated to the hierarchies of cortico-cortical connections. The higher-order association cortices, especially those in the anterior and ventromedial sectors of temporal lobe, are the most vulnerable, while other cortices appear less vulnerable to a degree commensurate with their connectional "distance" (i.e., synapses removed) from the limbic areas.
Little systematic attention has been directed toward the subject of treatment-resistant depression. Although these patients constitute a distinct minority, their treatment consumes a major portion of the clinician's time. Thus, the authors address the problems of defining and treating the estimated 750,000 patients with treatment-resistant depression. Several major factors concerning treatment-resistant depression appear evident: (1) although there is an emerging consensus of what constitutes "adequate" treatment, the majority of patients receive suboptimal drug regimens; (2) misdiagnosis of depression subtypes can lead to suboptimal treatment and "pseudo-resistance" to drug therapy; (3) treatment strategies for resistant depression should use systematic algorithms to avoid confusion and limit "therapeutic nihilism" in the patient and physician; and (4) the patient's risk/benefit ratio for each successive treatment application must be considered with the potential benefit weighed against the increasing risk of illness morbidity and likelihood of adverse events and/or suicide.
Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)
The high-affinity binding of thirteen ligands to putative neurotransmitter receptors was studied in temporal cortex of control and Alzheimer-type dementia (ATD) patients. A selective reduction of serotonin S2 receptors was observed in the ATD patients, to 57% of controls with no change in S1 receptors. Of the other ligand binding sites studied, only 3H-flunitrazepam binding was significantly reduced, to 84% of controls. Ligand binding sites which were unchanged in ATD temporal cortex included those labelled by adrenergic, adenosine, histamine, opiate, GABA, benzodiazepine and cholinergic ligands.
A review of the anatomic organization of ascending serotonin projections is followed by recent findings showing that these axonal projections are not diffuse but have an intricate and orderly pattern. The dorsal and median raphe nuclei and the B9 cell group have overlapping but differential projections to all parts of the forebrain. While most raphe projections extensively overlap, the dorsal raphe projects most heavily to frontal cortex and striatum, while the median raphe predominantly innervates hippocampus and septum. Small clusters of raphe cells project in a mosaic pattern to multiple, widely distributed islands of cortex. Yet, a coarse topographic order is preserved in the ascending dorsal raphe projections. Recent studies demonstrate two classes of serotonin axon terminals that differ in axon morphology, cells of origin, regional distribution, and response to psychotropic drugs. Dorsal raphe axons are extremely fine and highly vulnerable to certain neurotoxic amphetamines, e.g., 3,4-methylenedioxymethamphetamine; median raphe axons have large varicosities and are resistant to these mood-elevating drugs. We propose that there are two anatomically and functionally distinct serotonergic projections to cortex and that neurons in the dorsal raphe nucleus appear to play a major role in the control of affective state.
The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.
We present a technique for automatically assigning a neuroanatomical label to each voxel in an MRI volume based on probabilistic information automatically estimated from a manually labeled training set. In contrast to existing segmentation procedures that only label a small number of tissue classes, the current method assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a registration procedure that is robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging. The technique is shown to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume of noncortical structures that presage the onset of probable Alzheimer's disease.
3-Amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, labeled with carbon-11 ([11C]-DASB), is a recently introduced radiotracer for imaging the serotonin transporter (SERT) by positron emission tomography (PET). A series of in vitro and in vivo experiments were performed to further characterise the properties of [11C]-DASB as an in vivo imaging agent for SERT. In vitro binding assays confirmed that DASB binds specifically to SERT with nanomolar affinity and high selectivity over a large number of other receptors, ion-channels and enzymes in the central nervous system. Ex vivo, [11C]-DASB binding in rat brain was shown to be saturable (ED(50) of 56 nmoles/kg), and sensitive to both the number of available SERT binding sites and the number of viable serotonin neurons. Estimates of the radiation dose in man were extrapolated from rat biodistribution data (effective dose 5.5 E-03 mSv/MBq; critical organ --urinary bladder wall). Together with previous studies, the present findings indicate that [11C]-DASB is a very useful radiopharmaceutical for probing changes in SERT densities using PET imaging in the living human brain.
Cell counts in the cholinergic nucleus basalis (NB), noradrenergic locus coeruleus (LC), dopaminergic substantia nigra (SN), and the serotonergic dorsal raphe nucleus (DRN) were assessed from primary-level reports in patients with Alzheimer disease (AD) and in controls. Sixty-seven studies that covered about 20 years were included in the meta-analysis. Effect sizes were computed as a standardized mean difference (d) in cell counts between AD and controls. Effect sizes were largest in magnitude for the NB (mean d=2.48, 33 studies, N=585), and the LC (d=2.28, 24 studies, N=545), then the DRN (d=1.79, 11 studies, N=234), and were smallest for the SN (d=0.61, 14 studies, N=440). In general, the overall effect size estimates for the four cell areas were reliable. Using effect size magnitude in the SN as a referent, cell loss was about three times greater in the DRN and four times greater in the NB and LC. Symptomatic drug treatment for AD might be beneficially directed toward ameliorating multiple neurotransmitter deficiencies, particularly cholinergic and noradrenergic.
Several neurochemical in vitro and in vivo imaging studies have been aimed at characterizing the localization of serotonin receptors and transporters in the human brain. In this study, a detailed comparison of the distribution of a number of 5-HT receptor subtypes and the 5-HT transporter was carried out in vitro using human postmortem brain tissue. Anatomically adjacent whole hemisphere sections were incubated with specific radioligands for the 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(4) receptors and the 5-HT transporter. The autoradiograms revealed different laminar and regional distribution patterns in the isocortex, where 5-HT(1A) and 5-HT(4) receptor binding showed highest densities in superficial layers and 5-HT(2A) receptor binding was most abundant in middle layers. In cortical regions, 5-HT transporters were concentrated to several limbic lobe structures (posterior uncus, entorhinal, cingulate, insular and temporal polar regions). 5-HT(1A) receptor densities were also high in limbic cortical regions (hippocampus, posterior entorhinal cortex, and subcallosal area) compared to the isocortex. Subregionally different distribution patterns were observed in the basal ganglia with a trend toward higher levels in ventral striatal (5-HT(1B) receptors) and pallidal (5-HT transporters and 5-HT(1B) receptors) regions. The localization in regions belonging to limbic cortico-striato-pallido-thalamic circuits is in line with the documented role of 5-HT in modulation of mood and emotion, and the suggested involvement of this system in pathophysiology of various psychiatric disorders. The qualitative and quantitative information reported in this study might provide important complements to in vivo neuroimaging studies of the 5-HT system.
In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.