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Dopaminergic (DA) system function is frequently disrupted after traumatic brain injury (TBI). However, published interventions that target the DA system with the hope of enhancing functional outcom...

We examined whether the efficacy of steady-state cerebral autoregulation (CA) is reduced in older adults with amnestic mild cognitive impairment (aMCI), a prodromal stage of clinical Alzheimer disease (AD). Forty-two patients with aMCI and 24 cognitively normal older adults (NC) of similar age, sex, and education underwent stepwise decreases and increases in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Changes in cerebral blood flow (CBF) were measured repeatedly in the internal carotid and vertebral artery. Linear mixed modeling, including random effects of both individual intercept and regression slope, was used to quantify the MAP-CBF relationship accounting for nonindependent, repeated CBF measures. Changes in end-tidal CO(2) (EtCO(2)) associated with changes in MAP were also included in the model to account for their effects on CBF. Marginal mean values of MAP were reduced by 13–14 mmHg during sodium nitroprusside and increased by 20–24 mmHg during phenylephrine infusion in both groups with similar doses of drug infusion. A steeper slope of changes in CBF in response to changes in MAP was observed in aMCI relative to NC, indicating reduced efficacy of CA (MAP × Group, P = 0.040). These findings suggest that cerebrovascular dysfunction may occur early in the development of AD. NEW & NOTEWORTHY Cerebral autoregulation is a fundamental regulatory mechanism to protect brain perfusion against changes in blood pressure that, if impaired, may contribute to the development of Alzheimer’s disease. Using a linear mixed model, we demonstrated that the efficacy of cerebral autoregulation, assessed during stepwise changes in arterial pressure, was reduced in individuals with amnestic mild cognitive impairment, a prodromal stage of Alzheimer’s disease. These findings support the hypothesis that cerebrovascular dysfunction may be an important underlying pathophysiological mechanism for the development of clinical Alzheimer’s disease.

Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer's disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex.

Background Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). Objective The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. Method Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset. Results Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. Conclusions Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

Objective The feasibility and reliability of neuropsychological assessment at a distance have been demonstrated, but the validity of this testing medium has not been adequately demonstrated. The purpose of this study was to determine the ability of video teleconferencing administration of neuropsychological measures (teleneuropsychology) in discriminating cognitively impaired from non-impaired groups of older adults. It was predicted that measures administered via video teleconference would distinguish groups and that the magnitude of differences between impaired and non-impaired groups would be similar to group differences achieved in traditional administration. Methods The sample consisted of 197 older subjects, separated into two groups, with and without cognitive impairment. The cognitive impairment group included 78 individuals with clinical diagnoses of mild cognitive impairment or Alzheimer’s disease. All participants completed counterbalanced neuropsychological testing using alternate test forms in both a teleneuropsychology and a traditional face-to-face (FTF) administration condition. Tests were selected based upon their common use in dementia evaluations, brevity, and assessment of multiple cognitive domains. Results from FTF and teleneuropsychology test conditions were compared using individual repeated measures ANCOVA, controlling for age, education, gender, and depression scores. Results All ANCOVA models revealed significant main effects of group and a non-significant interaction between group and administration condition. All ANCOVA models revealed non-significant main effects for administration condition, except category fluency. Conclusions Results derived from teleneuropsychologically administered tests can distinguish between cognitively impaired and non-impaired individuals similar to traditional FTF assessment. This adds to the growing teleneuropsychology literature by supporting the validity of remote assessments in aging populations.

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies. OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO(2)max) with WM fiber integrity and neurocognitive performance in older adults with MCI. METHODS: Eighty-one participants (age = 65 ± 7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO(2)max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach. RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO(2)max. VO(2)max was associated positively with DTI metrics of fractional anisotropy in ~54% WM fiber tracts, and negatively with mean and radial diffusivities in ~46% and ~56 of the WM fiber tracts. The associations of VO(2)max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO(2)max were associated with executive function performance in MCI patients. CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

Background Alzheimer's disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. Objective We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. Methods We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. Results Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. Conclusion Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.

OBJECTIVE: Medical history information regarding prior traumatic brain injury (TBI) usually relies on self-report, although little is known about the reliability of this information with regard to injuries sustained years or decades earlier. Even less is known about the reliability of self-reported medical history information in older individuals with cognitive impairment. To this end, we assessed the test-retest reliability of self-reported TBI history in a large, national sample. METHODS: Participants (n = 4309) were older adults with intact cognition, mild cognitive impairment (MCI) and Alzheimer’s disease (AD) from the National Alzheimer’s Coordinating Center. Subjects provided TBI history information at baseline and one annual follow-up visit. Consistency of self-reported history of TBI with

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

This study examined whether peripheral vision reaction time (PVRT) in patients with mild traumatic brain injury (mTBI) correlated with white matter abnormalities in centroaxial structures and impairments in neuropsychological testing. Within 24 h after mTBI, crossed reaction times (CRT), uncrossed reaction times (URT), and crossed–uncrossed difference (CUD) were measured in 23 patients using a laptop computer that displayed visual stimuli predominantly to either the left or the right visual field of the retina. The CUD is a surrogate marker of the interhemispheric transfer time (ITT). Within 7 days after the injury, patients received a diffusion tensor-MRI (DTI) scan and a battery of neuropsychological tests. Nine uninjured control subjects received similar testing. Patients 18–50 years of age were included if they had a post-resuscitation Glasgow Coma Scale >13 and an injury mechanism compatible with mTBI. Healthy controls were either age- and gender-matched family members of the TBI patients or healthy volunteers. CUD deficits >2 standard deviations (SD) were seen in 40.9% of patients. The CUD of injured patients correlated with mean diffusivity (MD) (p

Aerobic exercise (AE) has recently received increasing attention in the prevention of Alzheimer's disease (AD). There is some evidence that it can improve neurocognitive function in elderly individuals. However, the mechanism of these improvements is not completely understood. In this prospective clinical trial, thirty amnestic mild cognitive impairment participants were enrolled into two groups and underwent 12 months of intervention. One group (n = 15) performed AE training (8M/7F, age = 66.4 years), whereas the other (n = 15) performed stretch training (8M/7F, age = 66.1 years) as a control intervention. Both groups performed 25-30 minutes training, 3 times per week. Frequency and duration were gradually increased over time. Twelve-month AE training improved cardiorespiratory fitness (p = 0.04) and memory function (p = 0.004). Cerebral blood flow (CBF) was measured at pre- and post-training using pseudo-continuous-arterial-spin-labeling MRI. Relative to the stretch group, the AE group displayed a training-related increase in CBF in the anterior cingulate cortex (p = 0.016). Furthermore, across individuals, the extent of memory improvement was associated with CBF increases in anterior cingulate cortex and adjacent prefrontal cortex (voxel-wise p < 0.05). In contrast, AE resulted in a decrease in CBF of the posterior cingulate cortex, when compared to the stretch group (p = 0.01). These results suggest that salutary effects of AE in AD may be mediated by redistribution of blood flow and neural activity in AD-sensitive regions of brain.

BACKGROUND The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). OBJECTIVE To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients. METHODS This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition. RESULTS Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. CONCLUSION The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

Alzheimer’s disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01–0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p < 0.03, α = 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO(2). We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.

Objective We retrospectively examined whether a history of traumatic brain injury (TBI) is associated with an earlier age of symptom onset and diagnosis in a large sample of patients with behavioural variant frontotemporal dementia (bvFTD). Methods Data on patients with bvFTD (n=678) were obtained from the National Alzheimer9s Coordinating Center Uniform Data Set. TBI was categorised based on reported lifetime history of TBI with loss of consciousness (LOC) but no chronic deficits occurring more than 1 year prior to diagnosis of bvFTD. Analysis of covariance (ANCOVA) was used to determine if clinician-estimated age of symptom onset and age at diagnosis of bvFTD differed between those who reported a history of TBI with LOC (TBI+) and those who did not (TBI−). Results Controlling for sex, the TBI+ bvFTD group had an age of symptom onset and age of diagnosis that was on average 2.8 and 3.2 years earlier (p Conclusions TBI history with LOC occurring more than 1 year prior to diagnosis is associated with an earlier age of symptom onset and diagnosis in patients with bvFTD. TBI may be related to the underlying neurodegenerative processes in bvFTD, but the implications of age at time of injury, severity and repetitive injuries remain unclear.

Ambulatory blood pressure (ABP) reflects the end-organ vascular stress in daily life; however, its influence on brain neuronal fiber integrity and cerebral blood flow (CBF) remains unclear. The objective of this study was to determine the associations among ABP, white matter (WM) neuronal fiber integrity, and CBF in older adults. We tested 144 participants via ABP monitoring and diffusion tensor imaging. The total level and pulsatile indices of CBF were measured by phase-contrast MRI and transcranial Doppler, respectively. Neuropsychological assessment was conducted in 72 participants. Among ambulatory and office BP measures, elevated 24-h pulse pressure (PP) was associated with the greatest number of WM skeleton voxels with decreased fractional anisotropy (FA) and increased mean diffusivity (MD). Furthermore, these associations remained significant after adjusting for age, antihypertensive use, aortic stiffness, WM lesion volume, and office PP. Radial diffusivity (RD) was elevated in the regions with decreased FA, while axial diffusivity was unaltered. The reduction in diastolic index explained a significant proportion of the individual variability in FA, MD, and RD. Executive function performance was correlated with WM fiber integrity. These findings suggest that elevated ambulatory PP may deteriorate brain neuronal fiber integrity via reduction in diastolic index.

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

We propose that pre-supplementary motor area (pre-SMA)–thalamic interactions govern processes fundamental to semantic retrieval of an integrated object memory. At the onset of semantic retrieval, pre-SMA initiates electrical interactions between multiple cortical regions associated with semantic memory subsystems encodings as indexed by an increase in theta-band EEG power. This starts between 100–150 ms after stimulus presentation and is sustained throughout the task. We posit that this activity represents initiation of the object memory search, which continues in searching for an object memory. When the correct memory is retrieved, there is a high beta-band EEG power increase, which reflects communication between pre-SMA and thalamus, designates the end of the search process and resultant in object retrieval from multiple semantic memory subsystems. This high beta signal is also detected in cortical regions. This circuit is modulated by the caudate nuclei to facilitate correct and suppress incorrect target memories.

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

This study examined whether a history of traumatic brain injury (TBI) is associated with earlier onset of Alzheimer disease (AD), independent of apolipoprotein ε4 status (Apoe4) and gender.Participants with a clinical diagnosis of AD (n = 7625) were obtained from the National Alzheimer's Coordinating Center Uniform Data Set, and categorized based on self-reported lifetime TBI with loss of consciousness (LOC) (TBI+ vs. TBI-) and presence of Apoe4. ANCOVAs, controlling for gender, race, and education were used to examine the association between history of TBI, presence of Apoe4, and an interaction of both risk factors on estimated age of AD onset.Estimated AD onset differed by TBI history and Apoe4 independently (p's .001). The TBI+ group had a mean age of onset 2.5 years earlier than the TBI- group. Likewise, Apoe4 carriers had a mean age of onset 2.3 years earlier than non-carriers. While the interaction was non-significant (p = .34), participants having both a history of TBI and Apoe4 had the earliest mean age of onset compared to those with a TBI history or Apoe4 alone (MHistory of self-reported TBI can be associated with an earlier onset of AD-related cognitive decline, regardless of Apoe4 status and gender. TBI may be related to an underlying neurodegenerative process in AD, but the implications of age at time of injury, severity, and repetitive injuries remain unclear.

Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT(2A) receptor inverse agonist pimavanserin was recently approved by the US FDA for the treatment of PDP and may prove to be a more targeted therapy without the downsides of atypical antipsychotics.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Amnestic mild cognitive impairment represents an early stage of Alzheimer’s disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O2/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO2-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.

Using diffusion tensor imaging (DTI), we assessed the relationship of white matter integrity and performance on the Boston Naming Test (BNT) in a group of retired professional football players and a control group. We examined correlations between fractional anisotropy (FA) and mean diffusivity (MD) with BNT T-scores in an unbiased voxelwise analysis processed with tract-based spatial statistics (TBSS). We also analyzed the DTI data by grouping voxels together as white matter tracts and testing each tract's association with BNT T-scores. Significant voxelwise correlations between FA and BNT performance were only seen in the retired football players (p

OBJECTIVE To determine the feasibility and reliability of a brief battery of standard neuropsychological tests administered via video teleconference (VTC) to a sample of rural American Indians compared with traditional face-to-face administration. METHODS The sample consisted of 84 participants from the Choctaw Nation in Oklahoma, including 53 females and 31 males [M age = 64.89 (SD = 9.73), M education = 12.58 (SD = 2.35)]. Of these, 29 had a diagnosis of mild cognitive impairment or dementia, and 55 were cognitively normal. Tests included the MMSE, Clock Drawing, Digit Span Forward and Backward, Oral Trails, Hopkins Verbal Learning Test-Revised, Letter and Category Fluency, and a short form Boston Naming Test. Alternative forms of tests were administered in counterbalanced fashion in both face-to-face and VTC conditions. Intraclass correlation coefficients (ICCs) were used to compare test scores between test conditions across the entire sample. RESULTS All ICCs were significant (p< .0001) and ranged from 0.65 (Clock Drawing) to 0.93 (Boston Naming Test), with a mean ICC of 0.82. CONCLUSION Results add to the expanding literature supporting the feasibility and reliability of remote videoconference-based neuropsychological test administration and extend findings to American Indians.

This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer's Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ɛ4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI-) a history of TBI. TBI history was a significant predictor (p < 0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05-1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10-1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94-1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p < 0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.

Objectives To test the hypothesis that cardiovascular risk factors (CRFs) influence predisposition to and the clinical course of Alzheimer disease (AD), the authors compared Choctaw Indians, a group with known high CRF with white persons with AD. In addition to CRF history, the authors investigated the frequency of apolipoprotein E4 (apoE4) genotype andplasma homocysteine (HC) levels. Method The authors compared 39 Choctaw Indians with AD and 39 Choctaw Indians without AD to 39 white persons with AD with all groups similar in age. CRF history included diabetes, hypertension, high cholesterol or hypolipidemic agent use, or myocardial infarction. The authors also compared plasma HC concentration and apoE4 allele frequency. Results Choctaw persons with AD differed significantly from white persons with AD in history of hypertension, diabetes, and in HC values but not from Indians without AD. There was a significantly lower apoE4 allele frequency in Choctaw Indian AD than white persons with AD, and both AD groups had an affected first degree relative significantly more often than Indian controls. There was no relationship between the number of CRF and age at onset among Indians or whites, whereas HC concentration was associated with significantly earlier age of onset for Choctaw Indians but not for whites. Conclusions This small study suggests that in Choctaw Indians modifiable risk factors may play more of a role in disease pathogenesis than in whites and that nonmodifiable risk factors such as apoE4 may play less of a role.

Objective—Compare subjective reports of both memory and word-finding deficits to clinical diagnosis and objective neuropsychological testing. Background—With the increasing number of aging individuals with cognitive impairments, effective screening measures would improve the likelihood of detection. Subjective reports of symptoms are typically obtained in clinical settings, yet the validity of these reports is relatively unknown. Methods—Clinical screening for dementia was carried out at an Alzheimer’s disease center. Dichotomous ratings for memory and word-finding/language problems were given by subjects and neurologists. These ratings were compared with 13 neuropsychological measures of word finding/ language and episodic memory. Results—Ratings of memory by both subjects and neurologists correlated well with standard neuropsychological measures of memory. However, both the patients’ and physicians’ ratings of word finding/language impairments had notably less of a correlation with the relevant neuropsychological measures of word finding/language. Conclusion—Compared to ratings of memory, similar assessments of word-finding/language difficulties were relatively inaccurate and thus poor predictors of impairment. It is imperative to develop effective screening methods that will help reveal cognitive impairments, as this issue will almost certainly become more pressing given the projected increase in the number of aging individuals and those with dementia.

There are currently no Food and Drug Administration-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition, and function. Forty-three individuals who met clinical criteria for FTLD [21 with frontotemporal dementia (FTD), 13 with semantic dementia (SD), and 9 with progressive nonfluent aphasia (PA)] received 26 weeks of open-label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the Mini Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), clinical dementia rating-sum of boxes, Neuropsychiatric Inventory (NPI), Frontal Behavior Inventory, Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale, and Unified Parkinson's Disease Rating Scale-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, Frontal Behavior Inventory, NPI, TFLS, and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and TFLS, but declined on the UPDRS. Memantine was well-tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.

Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.

IMPORTANCE: To our knowledge, this is the first study to show an association between concussion, cognition, and anatomical structural brain changes across the age spectrum in former National Football League athletes. OBJECTIVE: To assess the relationship of hippocampal volume, memory performance, and the influence of concussion history in retired National Football League athletes with and without mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study assessed differences between groups, mean hippocampal volumes, and memory performance by computing age quintiles based on group-specific linear regression models corrected for multiple comparisons for both athletes and control participants. The study was conducted starting in November 2010 and is ongoing at a research center in the northern region of Texas. This current analysis was conducted from October 9, 2013, to August 21, 2014. Participants included 28 retired National Football League athletes, 8 of whom had MCI and a history of concussion, 21 cognitively healthy control participants, and 6 control participants with MCI without concussion. MAIN OUTCOMES AND MEASURES: Hippocampal volume, age, California Verbal Learning Test scores, and the number of grade 3 (G3) concussions. In addition, the number of games played was examined as an objective variable pertaining to football history. RESULTS: The mean (SD) age was 58.1 (13) years for the 28 former athletes and 59.0 (12) years for the 27 control participants. Retired athletes with concussion history but without cognitive impairment had normal but significantly lower California Verbal Learning Test scores compared with control participants (mean [SD], 52.5 [8] vs 60.24 [7]; P = .002); those with a concussion history and MCI performed worse (mean [SD], 37 [8.62]) compared with both control participants (P < .001) and athletes without memory impairment (P < .001). Among the athletes, 17 had a G3 concussion and 11 did not. Older retired athletes with at least 1 G3 concussion had significantly smaller bilateral hippocampal volumes compared with control participants at the 40th age percentile (left, P = .04; right, P = .03), 60th percentile (left, P = .009; right, P = .01), and 80th percentile (left, P = .001; right, P = .002) and a smaller right hippocampal volume compared with athletes without a G3 concussion at the 40th percentile (P = .03), 60th percentile (P = .02), and 80th percentile (P = .02). Athletes with a history of G3 concussion were more likely to have MCI (7 of 7) compared with retired athletes without a history of G3 concussion (1 of 5) older than 63 years (P = .01). In addition, the left hippocampal volume in retired athletes with MCI and concussion was significantly smaller compared with control participants with MCI (P = .03). CONCLUSION AND RELEVANCE: Prior concussion that results in loss of consciousness is a risk factor for increased hippocampal atrophy and the development of MCI. In individuals with MCI, hippocampal volume loss appears greater among those with a history of concussion.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Deficits in semantic memory in individuals with amnestic mild cognitive impairment (aMCI) have been previously reported, but the underlying neurobiological mechanisms remain to be clarified. We examined event-related potentials (ERPs) associated with semantic memory retrieval in 16 individuals with aMCI as compared to 17 normal controls using the Semantic Object Retrieval Task (EEG SORT). In this task, subjects judged whether pairs of words (object features) elicited retrieval of an object (retrieval trials) or not (non-retrieval trials). Behavioral findings revealed that aMCI subjects had lower accuracy scores and marginally longer reaction time compared to controls. We used a multivariate analytical technique (STAT-PCA) to investigate similarities and differences in ERPs between aMCI and control groups. STAT-PCA revealed a left fronto-temporal component starting at around 750 ms post-stimulus in both groups. However, unlike controls, aMCI subjects showed an increase in the frontal-parietal scalp potential that distinguished retrieval from non-retrieval trials between 950 and 1050 ms post-stimulus negatively correlated with the performance on the logical memory subtest of the Wechsler Memory Scale-III. Thus, individuals with aMCI were not only impaired in their behavioral performance on SORT relative to controls, but also displayed alteration in the corresponding ERPs. The altered neural activity in aMCI compared to controls suggests a more sustained and effortful search during object memory retrieval, which may be a potential marker indicating disease processes at the pre-dementia stage.

To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI).Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver.Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate.Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.

Objective: This study compared medical history and findings on initial clinical examination in Native Americans diagnosed with possible or probable Alzheimer's disease (AD) at Native American satellite clinics of the University of Texas (UT) Southwestern Medical Center's Alzheimer's Disease Center with those of Whites diagnosed with probable AD at the UT Southwestern Medical Center's Alzheimer's Disease Clinic. Methods: The information reviewed was contained in the database of the UT Southwestern Alzheimer's Disease Center. Results: In relation to Whites, Native Americans had slightly but significantly greater age at onset of symptoms (71.7 vs. 69.6 years, t = −2.08, p = .04) and equivalent cognitive scores at evaluation (Mini-Mental State Exam score = 17.4 vs. 18.5, t = 0.98, p = .33), despite significantly lower educational level (11.4 vs. 13.4 years, t = 5.63, p < .001). Native Americans were more frequently depressed on examination (22.8% vs. 9.5%, χ2 = 12, p = .001) and reported diabetes, hypertension, and heart disease significantly more often than did Whites (p < .01 for all), but their survival time after AD diagnosis was similar to that of Whites despite these comorbidities. Conclusions: With the exception of a greater prevalence of depression and cardiovascular risk factors in Native Americans than in Whites, Native Americans had a course of illness similar to that of Whites.

Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65 ± 6 years) with normal cognitive function or mild cognitive impairment (MCI) were tested. The neuronal fiber integrity of brain WM was assessed from diffusion metrics acquired by diffusion tensor imaging. BRS was measured in response to acute changes in blood pressure induced by bolus injections of vasoactive drugs. Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). The WM diffusion metrics including fractional anisotropy (FA) and radial (RD) and axial (AD) diffusivities, BRS, and cfPWV were not different between the control and MCI groups. Thus, the data from both groups were combined for subsequent analyses. Across WM, fiber tracts with decreased FA and increased RD were associated with lower BRS and higher cfPWV, with many of the areas presenting spatial overlap. In particular, the BRS assessed during hypotension was strongly correlated with FA and RD when compared with hypertension. Executive function performance was associated with FA and RD in the areas that correlated with cfPWV and BRS. These findings suggest that baroreflex-mediated control of systemic arterial perfusion, especially during hypotension, may play a crucial role in maintaining neuronal fiber integrity of brain WM in older adults.

Diffusion tensor imaging (DTI) has been useful in showing compromise after traumatic axonal injury (TAI) at the chronic stage; however, white matter (WM) compromise from acute stage of TAI to chronic stage is not yet well understood. This study aims to examine changes in WM integrity following TAI by obtaining DTI, on average, 1 d post injury and again approximately seven months post-injury. Sixteen patients with complicated mild to severe brain injuries consistent with TAI were recruited in the intensive care unit of a Level I trauma center. Thirteen of these patients were studied longitudinally over the course of the first seven months post-injury. The first scan occurred, on average, 1 d after injury and the second an average of seven months post-injury. Ten healthy individuals, similar to the cohort of patients, were recruited as controls. Whole brain WM and voxel-based analyses of DTI data were conducted. DTI metrics of interest included: fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity (RD). tract-based spatial statistics were used to examine DTI metrics spatially. Acutely, AD and RD increased and RD positively correlated with injury severity. Longitudinal analysis showed reduction in FA and AD (p

Researchers at the University of Texas (UT) Southwestern Medical Center’s Alzheimer’s Disease Center (ADC) have been diagnosing, treating, and studying Alzheimer’s disease in American Indians (AIs) for the past 15 years. In 1991, we were awarded a minority satellite by the National Institutes on Aging (NIA) to provide clinical care to underserved persons and to database clinical information for future research. We first served the Cherokee Nation in northeastern Oklahoma: our satellite was established with the permission of Cherokee Chief Wilma Mankiller and her council. We asked patients and families to allow us to store de-identified clinical data for research. Most agreed. Patients or their caregivers signed and kept a copy of informed consent documents approved by the UT Southwestern IRB and by the appropriate tribal body. Patients were seen by a neurologist and his staff in Tulsa, Oklahoma, and in the Hastings Indian Hospital in Tahlequah, Oklahoma, 70 miles from Tulsa. We were not able to engage Hastings Hospital staff, and ultimately, all patients were seen in Tulsa. When we later tried to develop an epidemiologic study of dementia in the Cherokee Nation, we were unable to obtain the tribe’s permission because we had published a study suggesting that Cherokees might have partial protection against AD [1]; therefore, this disease was not perceived as a problem by the Cherokee Nation. In 1998, we contacted the Dallas Urban Inter-Tribal Center of Texas (UITC), approached their outreach director, and presented our goals. The UITC staff asked what immediate benefit we could be to them and asked for assurance that we would not exploit their clients as researchers had done elsewhere. We agreed that all research would be done as part of good clinical care and pledged to do no research without the explicit permission of subjects and to maintain the confidentiality of all patient material. After consultation with a council of elders, we established the Honoring our Elders Memory Clinic. We transferred our satellite from Oklahoma, hired an AI nurse, and arranged a quarterly clinic at the UITC where individuals could be evaluated by ADC staff. Unfortunately, we were able to recruit only a few elderly patients. We were told that AIs came from Oklahoma to Texas for employment, but when they reached retirement age, they returned to Oklahoma to use tribal resources such as free medical care. In 1998, with the help of a new UITC administrator, we met the administrator of the Choctaw Nation Healthcare Center in Talihina, Oklahoma. He was enthusiastic, and