A randomized feasibility trial of the modified Atkins diet in older adults with mild cognitive impairment due to Alzheimer's disease.

Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action. Methods: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time. Results: A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's D = 0.57, 95% CI: -0.67, 1.33). In the 15 participants (nine MAD, six control) assessed for lipidomic and metabolomic-lipidomics and metabolomics, 13 metabolites and 10 lipids showed significant changes from baseline to 12 weeks, including triacylglycerols (TAGs, 50:5, 52:5, and 52:6), sphingomyelins (SM, 44:3, 46:0, 46:3, and 48:1), acetoacetate, fatty acylcarnitines, glycerol-3-phosphate, and hydroxy fatty acids. Conclusions: Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined a priori, lipidomic and metabolomic analyses indicate significant changes from baseline in circulating lipids and metabolites between MAD and control participants at 12-week postrandomization, and MAD participants showed greater, albeit nonsignificant, improvement in memory.

Thin-Film Organic Heteroepitaxy.

Incorporating crystalline organic semiconductors into electronic devices requires understanding of heteroepitaxy given the ubiquity of heterojunctions in these devices. However, while rules for commensurate epitaxy of covalent or ionic inorganic material systems are known to be dictated by lattice matching constraints, rules for heteroepitaxy of molecular systems are still being written. Here, it is found that lattice matching alone is insufficient to achieve heteroepitaxy in molecular systems, owing to weak intermolecular forces that describe molecular crystals. It is found that, in addition, the lattice matched plane also must be the lowest energy surface of the adcrystal to achieve one-to-one commensurate molecular heteroepitaxy over a large area. Ultraviolet photoelectron spectroscopy demonstrates the lattice matched interface to be of higher electronic quality than a disordered interface of the same materials.

Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients.

A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55-90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21-all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers-four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy-even with abundant co-morbidity.

Multidomain cognitive dysfunction after minor stroke suggests generalized disruption of cognitive networks.

OBJECTIVE: Although small strokes typically result in "good" functional outcomes, significant cognitive impairment can occur. This longitudinal study examined a cohort of patients with minor stroke to determine the pattern of deficits, evolution over time, and factors associated with outcome. METHODS: Patients admitted to the hospital with their first clinical minor stroke (NIH Stroke Scale [NIHSS] ≤ 10, absence of severe hemiparesis, aphasia, or neglect) were assessed at 1 month post-infarct, and a subset were followed over time (with 6- and 12-month evaluations). Composite scores at each time point were generated for global cognition, verbal memory, spatial memory, motor speed, processing speed, and executive function. Paired t-tests evaluated change in scores over time. Regression models identified factors associated with initial performance and better recovery. RESULTS: Eighty patients were enrolled, evaluated at 1 month, and prospectively followed. The average age of the participants was 62.3 years, and mean education was 13.5 years. The average stroke volume was 6.6 cc; mean NIHSS score was 2.8. At 1 month, cognitive scores were below the normative range and > 1 standard deviation below the patient's peak ("recovery") score for every cognitive domain, strongly suggesting that they were well below patients' prestroke baselines. Forty-eight patients followed up at 6 months, and 39 at 12 months. Nearly all (98%) patients significantly improved in global cognition (averaged across domains) between 1 and 6 months. Between 6 and 12 months, recovery was variable. Higher education, occupational class, and Caucasian race were associated with higher recovery scores for most domains. CONCLUSIONS: Cognitive impairment across multiple domains is common following minor stroke regardless of infarct location, suggesting a global process such as network dysfunction that improves over 6 months. Degree of recovery can be predicted using baseline factors.

Dementia in late-onset epilepsy: The Atherosclerosis Risk in Communities study.

OBJECTIVE: To determine the risk of dementia after the development of late-onset epilepsy. METHODS: We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15,792 mostly Black and White men and women from 4 US communities. We identified late-onset epilepsy (LOE; seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance, and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics and vascular and Alzheimer disease risk factors. RESULTS: Of 9,033 ARIC participants with sufficient Medicare coverage data (4,980 [55.1%] female, 1993 [22.1%] Black), 671 met the definition of LOE. Two hundred seventy-nine (41.6%) participants with and 1,408 (16.8%) without LOE developed dementia (p < 0.001). After a diagnosis of LOE, the adjusted hazard ratio for developing subsequent dementia was 3.05 (95% confidence interval 2.65-3.51). The median time to dementia ascertainment after the onset of LOE was 3.66 years (quartile 1-3, 1.28-8.28 years). INTERPRETATION: The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Late-onset epilepsy and 25-year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVE: To define the association between late-onset epilepsy (LOE) and 25-year change in cognitive performance. METHODS: The Atherosclerosis Risk in Communities (ARIC) study is a multicenter longitudinal cohort study with participants from four U.S. communities. From linked Medicare claims, we identified cases of LOE, defined as ≥2 seizure-related diagnostic codes starting at age ≥67. The ARIC cohort underwent evaluation with in-person visits at intervals of 3-15 years. Cognition was evaluated 4 times over >25 years (including before the onset of seizures) using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT); a global z-score was also calculated. We compared the longitudinal cognitive changes of participants with and without LOE, adjusting for demographics and LOE risk factors. RESULTS: From 8033 ARIC participants with midlife cognitive testing and Medicare claims data available (4523 [56%] female, 1392 [17%] Black), we identified 585 cases of LOE. The rate of cognitive decline was increased on all measures in the participants who developed LOE compared to those without LOE. On the measure of global cognition, participants with LOE declined by -0.43 z-score points more over 25 years than did participants without epilepsy (95% confidence interval [CI] -0.59 to -0.27). Prior to the onset of seizures, cognitive decline was more rapid on the DWRT, DSST, and global z-scores in those who would later develop LOE than it was in non-LOE participants. Results were similar after excluding data from participants with dementia. SIGNIFICANCE: Global cognition, verbal memory, executive function, and word fluency declined faster over time in persons developing LOE than without LOE. Declines in cognition preceding LOE suggest these are linked; it will be important to investigate causes for midlife cognitive declines associated with LOE.

Identifying neuropsychologically impaired physicians.

Objective: With the increasing focus on reducing medical errors and the aging of the physician workforce has come growing concern for cognitive impairment among physicians. This study sought to establish and validate an approach to detecting neuropsychological impairment among physicians.Method: The neuropsychological test performance of 30 physicians referred clinically for neuropsychological evaluations was compared to that of 39 normal community-practicing urologists. We derived 9 key variables from the cognitive and motor tests as dependent variables. Impairment among the clinically-referred doctors was operationalized as scoring ≤5th percentile of the community physicians on at least 3, 4, 5, or 6 of the 9 variables. Using this approach, all clinically-referred physicians were classified as either "impaired" or "ambiguous."Results: A cutoff of ≥5 impaired test scores provided the best balance among competing models. Using this criterion, 14 of the clinically-referred doctors (46%) were impaired and 16 remained ambiguous. The impaired physicians: (1) were older, (2) were more often suspected of having a neurodegenerative disorder, and (3) were more likely to have discontinued practicing medicine. These findings serve as initial validation of our methodology.Conclusions: Using conservative criteria derived from normal community physicians, we could identify a substantial subgroup of clinically-referred physicians who are unambiguously neurocognitively impaired. Replication and refinement of our method with larger samples are recommended, as are the development of specialty-specific criteria for impairment.

Influence of sex differences in interpreting learning and memory within a clinical sample of older adults.

Sex is an important factor to consider when evaluating memory with older adults. This present study aimed to examine sex differences in memory within a clinical sample of older adults (N = 1084). Raw learning and recall scores on the Hopkins Verbal Learning Test, Revised (HVLT-R) and Brief Visuospatial Memory Test, Revised (BVMT-R) were compared between sexes within the entire sample and cohorts stratified by age. Within the entire sample, women outperformed men in HVLT-R learning and recall, and there were no sex differences in BVMT-R performance. These sex differences, however, were absent or reversed for those with impaired HVLT-R performance and functional deficits, indicating that women retain an early advantage in verbal memory, which is lost with greater indication of disease severity. These findings indicate that women retain an advantage in verbal learning and memory, at least before significant levels of impairment, within a sample of older adults seen at an outpatient neurology clinic, which may have implications for diagnosing memory disorders.

Diet in Brain Health and Neurological Disorders: Risk Factors and Treatments.

The role of nutrition in health and disease has been appreciated from time immemorial [...].

Standardization of an Arabic-Language Neuropsychological Battery for Epilepsy Surgical Evaluations.

OBJECTIVES: This study provides a standardized Arabic language neuropsychological test battery and tests its ability to distinguish patients with left and right hemisphere epileptic foci who are candidates for surgical resection. METHODS: An Arabic language battery of 15 tests was developed based on the neuropsychological test battery used at the Johns Hopkins Hospital for surgical evaluation of patients undergoing temporal lobe resection. With modifications where culturally required, 11 tests were translated to Arabic by the principal investigator and back-translated by two bilingual health professionals; four tests were available in Arabic and added to the battery. The battery was administered to 21 Arabic-speaking patients with left temporal epileptic foci, 21 with right temporal epileptic foci, and 46 neurologically and psychiatrically healthy adults. RESULTS: Nearly all the Arabic test versions were capable of differentiating healthy controls and the temporal lobe epilepsy (TLE) groups. Tests known to distinguish left and right temporal lobectomy candidates, such as wordlist memory and prose recall, were able to do so as accurately as the English versions. Also, a roughly "culturally free" task (the Baltimore Board) and a newly developed version of the Boston Naming Test demonstrated some sensitivity to left temporal lobe involvement. CONCLUSIONS: Arabic-language neuropsychological tests for epilepsy surgical evaluations are made available, demonstrate cultural sensitivity and clinical validity, and require further psychometric property and normative research. (JINS, 2019, 25, 761-771).

Effect of STN DBS on vesicular monoamine transporter 2 and glucose metabolism in Parkinson's disease.

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment for Parkinson's Disease (PD). Despite the improvement of motor symptoms in most patients by sub-thalamic nucleus (STN) DBS and its widespread use, the neurobiological mechanisms are not completely understood. The objective of the present study was to elucidate the effects of subthalamic nucleus (STN) DBS in PD on the dopamine system and neural circuitry, employing high-resolution positron emission tomography (PET) imaging. The hypotheses tested were that STN DBS would decrease the striatal vesicular monoamine transporter (VMAT2), secondary to an increase in dopamine concentrations, and would decrease striatal cerebral metabolism and increase cortical cerebral metabolism. METHODS: PET imaging of the vesicular monoamine transporter (VMAT2) and cerebral glucose metabolism was performed prior to DBS surgery and after 4-6 months of STN stimulation in seven PD patients (mean age 67 ±â€¯7). RESULTS: The patients demonstrated significant improvement in motor and neuropsychiatric symptoms after STN DBS. Decreased VMAT2 was observed in the caudate, putamen and associative striatum and in extra-striatal, cortical and limbic regions. Cerebral glucose metabolism was decreased in striatal sub-regions and increased in temporal and parietal cortices and the cerebellum. Decreased striatal VMAT2 was correlated with decreased striatal and increased cortical and limbic metabolism. Improvement of depressive symptoms was correlated with decreased VMAT2 in striatal and extra-striatal regions and with striatal decreases and cortical increases in metabolism. CONCLUSIONS: The present results support further investigation of the role of VMAT2, and associated changes in neural circuitry in the improvement of motor and non-motor symptoms with STN DBS in PD.

Preliminary Report on the Feasibility and Efficacy of the Modified Atkins Diet for Treatment of Mild Cognitive Impairment and Early Alzheimer's Disease.

Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer's disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD.

Neuropsychological predictors of patient-reported cognitive decline after deep brain stimulation in Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is effective for treatment of motor complications of dopaminergic therapy in Parkinson's disease (PD) but occasionally has been associated with multidomain cognitive decline. Patient- and caregiver-reported cognitive decline are clinically meaningful and increasingly recognized as important to consider when evaluating therapeutic interventions for PD. OBJECTIVE: The objective was to assess presurgical neuropsychological and clinical factors associated with PD patient- and caregiver-reported cognitive decline in two or more domains after DBS. METHOD: A single telephone survey was used to assess patient- and caregiver-reported cognitive decline in five domains at both one and four months after DBS surgery. Decline in two or more domains was considered multidomain cognitive decline (MDCD). Baseline demographic, clinical, and neuropsychological factors were compared in those with or without MDCD. Preoperative neuropsychological measures were evaluated as risk factors and regressed on the presence of MDCD, with demographic covariates, using multiple logistic regression. RESULTS: Preoperative performance in verbal recognition memory, language knowledge, and verbal processing decline were associated with postoperative, patient-reported MDCD in the first four weeks. MDCD at four months after DBS was associated with worse preoperative verbal reasoning, verbal recall, and semantic verbal fluency. Caregiver-reported MDCD one month after DBS was associated with poorer baseline verbal memory recognition accuracy/discriminability, visuospatial problem solving, and constructional praxis. CONCLUSION: Poor presurgical performance in verbal memory recognition, language processing, and visuospatial performance is associated with patient- or caregiver-reported decline following DBS surgery. Posterior cortical dysfunction seems to portend significant self-reported cognitive decline following deep brain stimulation.

Risk perception before and after presymptomatic genetic testing for Huntington's disease: Not always what one might expect.

BACKGROUND: In 1983, Huntington's disease (HD) was the first genetic disease mapped using DNA polymorphisms. Shortly thereafter, presymptomatic genetic testing for HD began in the context of two research studies. One of these trials was at the Johns Hopkins University Huntington's Disease Center. METHODS: As part of the protocol, risk perception (RP) values were collected at 16 time points before and after testing. The current study investigated changes in RP scores before and after genetic testing. Of the 186 participants with pre- and post-testing RP values, 39 also had contemporaneous research clinic notes and recent semi-structured interviews available for analysis. RESULTS: The data reveal tremendous diversity in RP. While the RP scores of most individuals change in the way one would expect, 27% of participants demonstrated unexpected changes in RP after disclosure. A significantly higher proportion of individuals who received an expanded repeat result had unexpected changes in RP, compared with those who received normal repeat results. CONCLUSIONS: The data suggest that individuals' RP is influenced by more than merely the results of genetic testing. This finding is important for genetic counselors and healthcare providers, as it suggests that even comprehensive patient education and disclosure of genetic test results may not ensure that people fully appreciate their disease risk.

Regio- and Stereoselective Hydroamination of Alkynes Using an Ammonia Surrogate: Synthesis of N-Silylenamines as Reactive Synthons.

An anti-Markovnikov selective hydroamination of alkynes with N-silylamines to afford N-silylenamines is reported. The reaction is catalyzed by a bis(amidate)bis(amido)Ti(IV) catalyst and is compatible with a variety of terminal and internal alkynes. Stoichiometric mechanistic studies were also performed. This method easily affords interesting N-silylenamine synthons in good to excellent yields and the easily removable silyl protecting group enables the catalytic synthesis of primary amines.

Neuropsychological investigation of "the amazing memory man".

OBJECTIVE: Mnemonists, memory champions, and persons with highly superior autobiographical memory (HSAM) are apparently rare breeds, with no more than a few dozen cases of each described in the neuroscientific literature. This report describes a newly discovered HSAM case who has extraordinary memory for a wider range of material than has heretofore been described. METHOD: Subject MM was interviewed about his personal life and administered standard clinical tests of cognition and personality, as well as experimental tasks assessing personal and generic episodic and semantic memory. Finally, he was studied with high resolution structural MRI of the medial temporal lobes, as well as brain connectivity analysis using resting-state functional MRI. RESULTS: MM's ability to recall general factual information, historical facts and dates, sports statistics, and popular culture, as well as personal life experiences, is exceptional, even though he performs in only the average range on tests of intellect and new learning ability. Unlike most mnemonists, he denies using any specific mnemonic strategy and, unlike many other HSAM cases, is unable to recall highly specific details of days in his adult life. Structural brain imaging in MM reveals atypical anatomy in his left temporal lobe, and functional neuroimaging suggests greater than usual connectivity of the left hippocampus with premotor, prefrontal and retrosplenial cingulate cortex. CONCLUSIONS: These observations are discussed in the context of previous studies of mnemonists and HSAM cases, some of which implicate hyperconnectivity among components of an expanded memory network in extraordinary memory retrieval. (PsycINFO Database Record

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.

Brief Report: Using the Internet to Identify Persons with Cognitive Impairment for Participation in Clinical Trials.

Identifying, recruiting, and enrolling persons in clinical trials of dementia treatments is extremely difficult. One approach to first-wave screening of potential participants is the use of online assessment tools. Initial studies using the Dementia Risk Assessment (DRA)-which includes a previously validated recognition memory test-support the use of this self-administered assessment to identify individuals with "suspected MCI" or "suspected dementia." In this study, we identified between 71 and 622 persons with suspected dementia and between 128 and 1653 persons with suspected mild cognitive impairment (depending on specific criteria) over the course of 22 months. Assessment tools that can inexpensively and easily identify individuals with higher than average risk for cognitive impairment can facilitate recruitment for large-scale clinical trials for dementia treatments.

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.