Resting State BOLD Variability in Alzheimer's Disease: A Marker of Cognitive Decline or Cerebrovascular Status?

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that may benefit from early diagnosis and intervention. Therefore, there is a need to identify early biomarkers of AD using non-invasive techniques such as functional magnetic resonance imaging (fMRI). Recently, novel approaches to the analysis of resting-state fMRI data have been developed that focus on the moment-to-moment variability in the blood oxygen level dependent (BOLD) signal. The objective of the current study was to investigate BOLD variability as a novel early biomarker of AD and its associated psychophysiological correlates. Method: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 2 database from 19 participants with AD and 19 similarly aged controls. For each participant, a map of BOLD signal variability (SDBOLD) was computed as the standard deviation of the BOLD timeseries at each voxel. Group comparisons were performed to examine global differences in resting state SDBOLD in AD versus healthy controls. Correlations were then examined between participant SDBOLD maps and (1) ADNI-derived composite scores of memory and executive function and (2) neuroimaging markers of cerebrovascular status. Results: Between-group comparisons revealed significant (p < 0.05) increases in SDBOLD in patients with AD relative to healthy controls in right-lateralized frontal regions. Lower memory scores and higher WMH burden were associated with greater SDBOLD in the healthy control group (p < 0.1), but not individuals with AD. Conclusion: The current study provides proof of concept of a novel resting state fMRI analysis technique that is non-invasive, easily accessible, and clinically compatible. To further explore the potential of SDBOLD as a biomarker of AD, additional studies in larger, longitudinal samples are needed to better understand the changes in SDBOLD that characterize earlier stages of disease progression and their underlying psychophysiological correlates.

Relationship Between DTI Metrics and Cognitive Function in Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder with a clinical presentation characterized by memory impairment and executive dysfunction. Our group previously demonstrated significant alterations in white matter microstructural metrics in AD compared to healthy older adults. We aimed to further investigate the relationship between white matter microstructure in AD and cognitive function, including memory and executive function. Methods: Diffusion tensor imaging (DTI) and neuropsychological data were downloaded from the AD Neuroimaging Initiative database for 49 individuals with AD and 48 matched healthy older adults. The relationship between whole-brain fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and composite scores of memory and executive function was examined. We also considered voxel-wise relationships using Tract-Based Spatial Statistics. Results: As expected, individuals with AD had lower composite scores on tests of memory and executive function, as well as disrupted white matter integrity (low FA, high MD, AxD, and RD) relative to healthy older adults in widespread regions, including the hippocampus. When the AD and healthy older adult groups were combined, we found significant relationships between DTI metrics (FA/MD/AxD/RD) and memory scores across widespread regions of the brain, including the medial temporal regions. We also found significant relationships between DTI metrics (FA/MD/AxD/RD) and executive function in widespread regions, including the frontal areas in the combined group. However, when the groups were examined separately, no significant relationships were found between DTI metrics (FA/MD/AxD/RD) and memory performance for either group. Further, we did not find any significant relationships between DTI metrics (FA/MD/AxD/RD) and executive function in the AD group, but we did observe significant relationships between FA/RD, and executive function in healthy older adults. Conclusion: White matter integrity is disrupted in AD. In a mixed sample of AD and healthy elderly persons, associations between measures of white matter microstructure and memory and executive cognitive test performance were evident. However, no significant linear relationship between the degree of white matter disruption and level of cognitive functioning (memory and executive abilities) was found in those with AD. Future longitudinal studies of the relations between DTI metrics and cognitive function in AD are required to determine whether DTI has potential to measure progression of AD and/or treatment efficacy.

Case Report: A Comprehensive Neuropsychological Assessment of a Case of Superficial Siderosis.

OBJECTIVE: Superficial siderosis (SS) is a neurodegenerative condition due to the long-term effects of hemosiderin deposition on the surface of the brain, cerebellum, brainstem, and spinal cord. SS symptoms include sensorineural hearing loss, ataxia and upper motor neuron signs. SS was diagnostically evasive until magnetic resonance imaging (MRI) became available. As the detection of SS improved, case studies have become more prevalent. To our knowledge, however, this is the first report of SS detailing a comprehensive neuropsychological assessment. METHOD: The current study presents a right-handed female in her early 60s, with a university level of education, who was diagnosed with SS. RESULTS: Her neuropsychological profile showed impairment across multiple domains, including memory and executive function, with consistent behavioral findings. The results from a comprehensive neuropsychological assessment include dementia and a cerebellar cognitive affective syndrome. CONCLUSIONS: Neuropsychological evaluation of a patient with new cognitive impairment in combination with unexplained hearing loss, gait disorder, or myelopathy should lead to a referral for MRI that includes techniques sensitive for iron deposition, in order to rule out SS.

Multidisciplinary Management of Pediatric Sports-Related Concussion.

OBJECTIVES: To summarize the clinical characteristics and outcomes of pediatric sports-related concussion (SRC) patients who were evaluated and managed at a multidisciplinary pediatric concussion program and examine the healthcare resources and personnel required to meet the needs of this patient population. METHODS: We conducted a retrospective review of all pediatric SRC patients referred to the Pan Am Concussion Program from September 1st, 2013 to May 25th, 2015. Initial assessments and diagnoses were carried out by a single neurosurgeon. Return-to-Play decision-making was carried out by the multidisciplinary team. RESULTS: 604 patients, including 423 pediatric SRC patients were evaluated at the Pan Am Concussion Program during the study period. The mean age of study patients was 14.30 years (SD: 2.32, range 7-19 years); 252 (59.57%) were males. Hockey (182; 43.03%) and soccer (60; 14.18%) were the most commonly played sports at the time of injury. Overall, 294 (69.50%) of SRC patients met the clinical criteria for concussion recovery, while 75 (17.73%) were lost to follow-up, and 53 (12.53%) remained in active treatment at the end of the study period. The median duration of symptoms among the 261 acute SRC patients with complete follow-up was 23 days (IQR: 15, 36). Overall, 25.30% of pediatric SRC patients underwent at least one diagnostic imaging test and 32.62% received referral to another member of our multidisciplinary clinical team. CONCLUSION: Comprehensive care of pediatric SRC patients requires access to appropriate diagnostic resources and the multidisciplinary collaboration of experts with national and provincially-recognized training in TBI.

Psychiatric outcomes after pediatric sports-related concussion.

OBJECT: The objectives of this study were twofold: (1) to examine the prevalence of emotional symptoms among children and adolescents with a sports-related concussion (SRC) who were referred to a multidisciplinary pediatric concussion program and (2) to examine the prevalence, clinical features, risk factors, and management of postinjury psychiatric outcomes among those in this clinical population. METHODS: The authors conducted a retrospective chart review of all patients with SRC referred to a multidisciplinary pediatric concussion program between September 2013 and October 2014. Clinical assessments carried out by a single neurosurgeon included clinical history, physical examination, and Post-Concussion Symptom Scale (PCSS) scoring. Postinjury psychiatric outcomes were defined as a subjective worsening of symptoms of a preinjury psychiatric disorder or new and isolated suicidal ideation or diagnosis of a novel psychiatric disorder (NPD). An NPD was defined as a newly diagnosed psychiatric disorder that occurred in a patient with or without a lifetime preinjury psychiatric disorder after a concussion. Clinical resources, therapeutic interventions, and clinical and return-to-play outcomes are summarized. RESULTS: One hundred seventy-four patients (mean age 14.2 years, 61.5% male) were included in the study. At least 1 emotional symptom was reported in 49.4% of the patients, and the median emotional PCSS subscore was 4 (interquartile range 1-8) among those who reported at least 1 emotional symptom. Overall, 20 (11.5%) of the patients met the study criteria for a postinjury psychiatric outcome, including 14 patients with an NPD, 2 patients with isolated suicidal ideation, and 4 patients with worsening symptoms of a preinjury psychiatric disorder. Female sex, a higher initial PCSS score, a higher emotional PCSS subscore, presence of a preinjury psychiatric history, and presence of a family history of psychiatric illness were significantly associated with postinjury psychiatric outcomes. Interventions for patients with postinjury psychiatric outcomes included pharmacological therapy alone in 2 patients (10%), cognitive behavioral therapy alone in 4 (20%), multimodal therapy in 9 (45%), and no treatment in 5 (25%). Overall, 5 (25%) of the patients with postinjury psychiatric disorders were medically cleared to return to full sports participation, whereas 5 (25%) were lost to follow-up and 9 (45%) remained in treatment by the multidisciplinary concussion program at the end of the study period. One patient who was asymptomatic at the time of initial consultation committed suicide. CONCLUSIONS: Emotional symptoms were commonly reported among pediatric patients with SRC referred to a multidisciplinary pediatric concussion program. In some cases, these symptoms contributed to the development of an NPD, isolated suicidal ideation, and worsening symptoms of a preexisting psychiatric disorder. Future research is needed to clarify the prevalence, pathophysiology, risk factors, and evidence-based management of postinjury psychiatric outcomes after pediatric SRC. Successful management of these patients requires prompt recognition and multidisciplinary care by experts with clinical training and experience in concussion and psychiatry.

Clinical decision trees for predicting conversion from cognitive impairment no dementia (CIND) to dementia in a longitudinal population-based study.

The lack of gold standard diagnostic criteria for cognitive impairment in the absence of dementia has resulted in variable nomenclature, case definitions, outcomes, risk factors, and prognostic utilities. Our objective was to elucidate the clinical correlates of conversion to dementia in a longitudinal population-based sample. Using data from the Canadian Study of Health and Aging, a machine learning algorithm was used to identify symptoms that best differentiated converting from nonconverting cognitively impaired not demented participants. Poor retrieval was the sole predictor of conversion to dementia over 5 years. This finding suggests that patients with impaired retrieval are at greater risk for progression to dementia at follow-up. Employing significant predictors as markers for ongoing monitoring and assessment, rather than as clinical markers of conversion, is recommended given the less than optimal specificity of the predictive algorithms.

Patterns of cognitive decline, conversion rates, and predictive validity for 3 models of MCI.

Our objective was to compare the predictive ability of different models of mild cognitive impairment (MCI) as a marker of incipient dementia in a longitudinal population-based Canadian sample. We examined the use of existing, well-documented MCI criteria using data from persons who underwent a clinical examination in the second wave of the Canadian Study of Health and Aging (CSHA). Demographic characteristics, average neuropsychological test performance, and sample frequencies and conversion rates were calculated for each classification. Receiver operating characteristic (ROC) analyses were employed to assess the predictive power of each cognitive classification. The highest sample frequencies and conversion rates were associated with case definitions of multiple-domain MCI. The only diagnostic criteria to significantly predict dementia 5 years later was the cognitive impairment no dementia (CIND)-2 case definition. More restrictive MCI case definitions fail to address the varying temporal increases in decline across different cognitive domains in the progression from normal cognitive functioning and dementia.

Neuropsychiatric impairments as predictors of mild cognitive impairment, dementia, and Alzheimer's disease.

In this study, the relations between cognitive status and neuropsychiatric impairments in nondemented older adults in cross section and over time is examined. Using data from the Canadian Study of Health and Aging (CSHA), a longitudinal, nation-wide study in which data were collected 3 times (ie, CSHA-1, CSHA-2, CSHA-3) at 5-year intervals, individuals were classified with (n = 240) and without (n = 386) cognitive impairment at CSHA-2. Loss of interest, changes in personality and mood, and depression were reported by a knowledgeable informant (ie, family or friends) more frequently for those with cognitive impairment than for those without cognitive impairment. After controlling for initial cognitive status, loss of interest and depression contributed significantly to the prediction of mild cognitive impairment, dementia, and Alzheimer's disease over time. These findings suggest that these neuropsychiatric impairments play significant roles throughout the course of cognitive decline and should be taken into consideration even before cognitive impairment is evident.

Chronic mild stress exacerbates the effects of permanent bilateral common carotid artery occlusion on CA1 neurons.

The effect of chronic mild stress (CMStress) was examined in an animal model of chronic cerebral hypoperfusion. Eight-month-old male Sprague-Dawley rats underwent permanent bilateral occlusion of the carotid arteries (2VO) or sham surgery. At 7 days postsurgery, animals from these groups were randomly assigned to undergo CMStress consisting of relatively mild stressor exposure 6 days a week for 6 weeks or a no-stress regimen. They were perfused 24 h thereafter and stereology was used to estimate the total number of hippocampal CA1 and CA3 pyramidal cells. Glial fibrillary acid protein (GFAP) immunoreactivity in the hippocampus was also measured. Degenerating neurons were quantified with the Fluoro-Jade B staining technique. CMStress significantly potentiated CA1 cell loss in 2VO rats (17% loss), compared to a 7% loss of CA1 cells in nonstressed 2VO rats. CMStress had no effect on CA3 cell number. CMStress also caused a significant reduction in GFAP-immunoreactive astrocyte density in CA1, CA3, and the hilus of both sham and 2VO rats. Fluoro-Jade staining was absent, indicating that cell loss probably occurred in the early stage of combined 2VO and CMStress. It was concluded that CMStress exacerbates the consequences of chronic cerebral hypoperfusion on CA1 probably by reducing astrocytes, thereby increasing extracellular glutamate and/or diminishing free radical defense systems. These findings have particular relevance to understanding the contribution of chronic stress to Alzheimer's disease, which, in its premorbid stage, is characterized by cerebral hypoperfusion, and, in its clinical stage, is characterized by CA1 cell loss.