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Background and Purpose: Prediction of long-term recovery of a poststroke cognitive disorder (PSCD) is currently inaccurate. We assessed whether diffusion-weighted imaging (DWI)-based measures of brain connectivity predict cognitive recovery 1 year after stroke in patients with PSCD in addition to conventional clinical, neuropsychological, and imaging variables., Methods: This prospective monocenter cohort study included 217 consecutive patients with a clinical diagnosis of ischemic stroke, aged ≥50 years, and Montreal Cognitive Assessment score below 26 during hospitalization. Five weeks after stroke, patients underwent DWI magnetic resonance imaging. Neuropsychological assessment was performed 5 weeks and 1 year after stroke and was used to classify PSCD as absent, modest, or marked. Cognitive recovery was operationalized as a shift to a better PSCD category over time. We evaluated 4 DWI-based measures of brain connectivity: global network efficiency and mean connectivity strength, both weighted for mean diffusivity and fractional anisotropy. Conventional predictors were age, sex, level of education, clinical stroke characteristics, neuropsychological variables, and magnetic resonance imaging findings (eg, infarct size). DWI-based measures of brain connectivity were added to a multivariable model to assess additive predictive value., Results: Of 135 patients (mean age, 71 years; 95 men [70%]) with PSCD 5 weeks after ischemic stroke, 41 (30%) showed cognitive recovery. Three of 4 brain connectivity measures met the predefined threshold of P <0.1 in univariable regression analysis. There was no added value of these measures to a multivariable model that included level of education and infarct size as significant predictors of cognitive recovery., Conclusions: Current DWI-based measures of brain connectivity appear to predict recovery of PSCD but at present have no added value over conventional predictors.

Objective: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments., Methods: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period., Results: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments., Conclusion: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children., (© 2020 American Academy of Neurology.)

Objectives: To investigate the independent and interaction effects of Alzheimer disease (AD) and Lewy body disease (LBD) on cognition and brain atrophy., Methods: We consecutively recruited 38 controls and 108 patients with AD-related cognitive impairment (ADCI) and/or LBD-related cognitive impairment (LBCI) from university-based dementia and movement clinics. Diagnoses of ADCI and LBCI were supported by 18 F-florbetaben PET and 18 F-N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane-PET, respectively. There were 38 controls, 26 patients with pure ADCI (18 mild cognitive impairment [MCI] and 8 dementia), 28 patients with pure LBCI (13 MCI and 15 dementia), and 54 patients with mixed ADCI and LBCI (17 MCI and 37 dementia). We performed group-wise comparisons for neuropsychological z scores and regional cortical thickness. We also evaluated the effects of ADCI and LBCI using general linear models., Results: Compared to the controls, patients in the pure ADCI group and pure LBCI group had focused cortical thinning in the bilateral entorhinal/right anterior temporal cortices and bilateral anteromedial temporal/basal frontal cortices, respectively, while the mixed disease group had additional cortical thinning in the widespread association cortices. The independent effects of ADCI and LBCI on regional cortical thinning overlapped in the widespread association cortices, especially at the bilateral temporoparietal junction and parietal cortices. ADCI and LBCI had independent detrimental effects on the copying item of the Rey-Osterrieth Complex Figure Test., Conclusions: Concomitant ADCI and LBCI are associated with the accentuation of neurodegeneration to widespread association cortices, and both diseases contribute to visuospatial dysfunction., (© 2019 American Academy of Neurology.)

Objective: We characterized the epilepsy features and contribution to cognitive regression in 47 patients with MECP2 duplication syndrome (MDS) and reviewed these characteristics in over 280 MDS published cases., Methods: The institutional review board approved this retrospective review of medical records and case histories of patients with MDS., Results: The average age at enrollment was 10 ± 7 years. Patients with epilepsy were older (13 ± 7 years vs 8 ± 5 years, p = 0.004) and followed for a longer time (11.8 ± 6.5 years vs 6.3 ± 4.2 years, p = 0.003) than patients without a seizure disorder. Epilepsy affected 22/47 (47%) patients with MDS. It was treatment-refractory and consistent with epileptic encephalopathy in 18/22 (82%) cases. Lennox-Gastaut syndrome (LGS) was present in 12/22 (55%) patients and manifested between late childhood and adulthood in 83% of cases. The emergence of neurologic regression coincided with the onset of epilepsy. The MECP2 duplication size and gene content did not correlate with epilepsy presence, type, age at onset, or treatment responsiveness., Conclusion: Epilepsy in MDS is common, often severe, and medically refractory. LGS occurs frequently and may have a late onset. Developmental regression often follows the onset of epilepsy. The MECP2 duplication extent and gene content do not discriminate between patients with or without epilepsy. Our findings inform clinical care and family counseling with respect to early epilepsy recognition, diagnosis, specialty referral, and implementation of aggressive seizure therapy to minimize detrimental effect of uncontrolled seizures on cognitive functions or preexisting neurologic deficits., (© 2018 American Academy of Neurology.)

The study aimed to compare the whole-brain gray matter volume (GMV) and white matter volume (WMV) difference between primary angle closure glaucoma (PACG) patients and health controls (HCs) using a voxel-based morphometry method. A total of 27 patients with PACG (17 males and 10 females) and 27 HCs (17 males and 10 females), closely matched for age and education, were enrolled in the study. All subjects underwent magnetic resonance imaging (MRI) scans. The MRI data were processed using SPM8 software in voxel-based morphometry 8 toolbox. The relationship between the mean GMV values of brain regions and the clinical features including psychological testing and mean retinal nerve fiber layer (RNFL) thickness in PACG groups were analyzed by using Pearson correlation. Compared with HCs, PACG patients showed significantly decreased GMV values in the left cerebellum posterior lobe (CPL), right extra-nuclear, and right superior temporal gyrus. In contrast, PACG patients showed significantly increased GMV values in the left CPL, right CPL, right superior temporal gyrus, right thalamus and right insula (P<0.01). Moreover, in the PACG group, the left mean RNFL showed a positive correlation with the mean GMV values of the left CPL (r=0.719; P<0.001) and the right mean RNFL showed a positive correlation with the mean GMV values of the left CPL (r=0.721; P<0.001). The Hamilton depression score showed a positive correlation with the mean GMV values of right insula (r=0.897; P<0.001). Our results demonstrated that PACG patients showed altered brain structure in various regions related to visuomotor function, thalamocortical pathway, and emotion function, which might provide a useful informations to understanding the anatomy neural mechanisms of deficit in vision loss and depression in PACG.

Objectives: To investigate the long-term impact of postoperative delirium in children., Design: Single-center point prevalence study., Setting: Twenty-two bed PICU., Patients: Forty-seven patients 1-16 years old., Interventions: Standardized neuropsychologic follow-up investigation after a mean time of 17.7 ± 2.9 months after PICU discharge., Measurements and Main Results: Pediatric delirium did not have significant long-term impact on global cognition, executive functions, or behavior. Severity of delirium did not influence the outcome. Different predictors were identified for later cognitive functioning, executive functions, and behavioral problems. Younger age was confirmed to be a relevant risk factor for delirium as well as for the cognitive and behavioral outcome., Conclusions: Contrary to the findings in adults, there was no clear association between pediatric delirium and long-term cognition or behavior in this cohort. However, this is a first pilot study with several limitations that should promote more comprehensive prospective trials.

Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH)., Methods: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression., Results: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component., Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes., (© 2018 American Academy of Neurology.)

Objective: To investigate the association of enlarged perivascular spaces (ePVS) with cognition in elderly without dementia., Methods: We included 5 studies from the Uniform Neuro-Imaging of Virchow-Robin Space Enlargement (UNIVRSE) consortium, namely the Austrian Stroke Prevention Family Study, Study of Health in Pomerania, Rotterdam Study, Epidemiology of Dementia in Singapore study, and Risk Index for Subclinical Brain Lesions in Hong Kong study. ePVS were counted in 4 regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) with harmonized rating across studies. Mini-Mental State Examination (MMSE) and general fluid cognitive ability factor (G-factor) were used to assess cognitive function. For each study, a linear regression model was performed to estimate the effect of ePVS on MMSE and G-factor. Estimates were pooled across studies with the use of inverse variance meta-analysis with fixed- or random-effect models when appropriate., Results: The final sample size consisted of 3,575 persons (age range 63.4-73.2 years, 50.6% women). Total ePVS counts were not significantly associated with MMSE score (mean difference per ePVS score increase 0.001, 95% confidence interval [CI] -0.007 to 0.008, p = 0.885) or G-factor (mean difference per ePVS score increase 0.002, 95% CI -0.001 to 0.006, p = 0.148) in age-, sex-, and education-adjusted models. Adjustments for cardiovascular risk factors and MRI markers did not change the results. Repeating the analyses with region-specific ePVS rendered similar results., Conclusions: In this study, we found that ePVS counts were not associated with cognitive dysfunction in the general population. Future studies with longitudinal designs are warranted to examine whether ePVS contribute to cognitive decline., (© 2018 American Academy of Neurology.)

Objective: To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline., Methods: A total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir ( 18 F-AV-1451) tau PET scan, a florbetapir ( 18 F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed., Results: Results from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning., Conclusions: Together, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression., (© 2018 American Academy of Neurology.)

Objective: To investigate whether the effect of prestroke and stroke-related lesions on incident poststroke dementia (PSD) is mediated by a unique pattern of domain-specific cognitive impairment, and the relative strength of these anatomical-cognitive associations in predicting incident PSD., Methods: In this incident case-control study (n = 150), we defined incident cases as acute stroke patients who developed PSD and controls as acute stroke patients who remained free from dementia at a 6 month follow-up, matched on age, prestroke cognitive status, and number of stroke-related lesions. MRI was performed at initial clinical presentation; neuropsychological assessments and clinical diagnosis of PSD was performed 6 months poststroke. Moderated mediation analysis evaluated the interactions among PSD, anatomical lesions, cognitive domains, and individual demographic and medical characteristics., Results: Compared to stroke-related lesions, prestroke lesions were associated with the widest range of cognitive domain impairments and had stronger clinical utility in predicting incident PSD. Specifically, global cortical atrophy (GCA) and deep white matter hyperintensities (WMH) were indirectly associated with PSD by disrupting executive functions, memory, and language. Acute infarcts were indirectly associated with PSD by disrupting executive functions and language. The strongest mediator was executive dysfunction, increasing risk of PSD in patients with deep WMH, GCA, and large infarcts by more than 9 times, with sex and educational attainment moderating the magnitude of association. Periventricular WMH were directly associated with incident PSD but not mediated by deficits in cognitive domains., Conclusion: We provide an anatomical-cognitive framework that can be applied to stratify patients at highest risk of PSD and to guide personalized interventions., (© 2018 American Academy of Neurology.)

Objective: While epilepsy studies rarely examine brainstem, we sought to examine the hypothesis that temporal lobe epilepsy (TLE) leads to subcortical arousal center dysfunction, contributing to neocortical connectivity and neurocognitive disturbances., Methods: In this case-control study of 26 adult patients with TLE and 26 controls, we used MRI to measure structural and functional connectivity of the cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus, and ventral tegmental area. Ascending reticular activating system connectivity patterns were related to neuropsychological and disease measures., Results: Compared to controls, patients with TLE demonstrated reductions in ascending reticular activating system structural and functional connectivity, most prominently to neocortical regions ( p < 0.05, unpaired t tests, corrected). While reduced CSC structural connectivity was related to impaired performance IQ and visuospatial memory, diminished CSC functional connectivity was associated with impaired verbal IQ and language abilities ( p < 0.05, Spearman ρ, t tests). Finally, CSC structural connectivity decreases were quantitatively associated with consciousness-impairing seizure frequency ( p < 0.05, Spearman ρ) and the presence of generalized seizures ( p < 0.05, unpaired t test), suggesting a relationship to disease severity., Conclusions: Connectivity perturbations in brainstem arousal centers are present in TLE and may contribute to neurocognitive problems. These studies demonstrate the underappreciated role of brainstem networks in epilepsy and may lead to novel neuromodulation targets to treat or prevent deleterious brain network effects of seizures in TLE., (© 2018 American Academy of Neurology.)

Rationale: We report a 45-year-old male patient with unilateral brachial plexopathy following acute carbon monoxide (CO) intoxication., Patient Concerns: The patient suddenly developed severe left upper extremity weakness and cognitive impairment after CO intoxication., Diagnoses: He showed severe weakness in the left upper extremity and decreased cognitive function during physical examination. Whole body bone scan revealed increased radioisotope uptake in the left shoulder, suggesting rhadomyolysis. Brain magnetic resonance imaging showed high signal intensity in both globus pallidus. The electrodiagnostic finding was compatible with incomplete left total brachial plexopathy (axonopathy)., Interventions: High oxygen therapy and massive intravenous normal saline infusion were administered immediately after acute CO intoxication. Since then, intensive rehabilitation treatment has been provided., Outcome: Despite having received medical and rehabilitation treatment, the patient has not recovered severe weakness in the left upper extremity and decline in cognition., Lessons: Localized swelling in the left shoulder caused by rhabdomyolysis may be a key mechanism in developing unilateral brachial plexopathy after acute CO intoxication. The early diagnosis and treatment of rhadomyolysis might be important preventing peripheral neuropathy. An electrodiagnostic study may be helpful for diagnosis of peripheral neuropathy after CO intoxication and prediction of patient's prognosis.

Background and Purpose: Magnetic resonance imaging may be useful to assess disease severity in cerebral small vessel disease (SVD), identify those individuals who are most likely to progress to dementia, monitor disease progression, and act as surrogate markers to test new therapies. Texture analysis extracts information on the relationship between signal intensities of neighboring voxels. A potential advantage over techniques, such as diffusion tensor imaging, is that it can be used on clinically obtained magnetic resonance sequences. We determined whether texture parameters (TP) were abnormal in SVD, correlated with cognitive impairment, predicted cognitive decline, or conversion to dementia., Methods: In the prospective SCANS study (St George's Cognition and Neuroimaging in Stroke), we assessed TP in 121 individuals with symptomatic SVD at baseline, 99 of whom attended annual cognitive testing for 5 years. Conversion to dementia was recorded for all subjects during the 5-year period. Texture analysis was performed on fluid-attenuated inversion recovery and T1-weighted images. The TP obtained from the SVD cohort were cross-sectionally compared with 54 age-matched controls scanned on the same magnetic resonance imaging system., Results: There were highly significant differences in several TP between SVD cases and controls. Within the SVD population, TP were highly correlated to other magnetic resonance imaging parameters (brain volume, white matter lesion volume, lacune count). TP correlated with executive function and global function at baseline and predicted conversion to dementia, after controlling for age, sex, premorbid intelligence quotient, and magnetic resonance parameters., Conclusions: TP, which can be obtained from routine clinical images, are abnormal in SVD, and the degree of abnormality correlates with executive dysfunction and global cognition at baseline and decline during 5 years. TP may be useful to assess disease severity in clinically collected data. This needs testing in data clinically acquired across multiple sites., (© 2018 The Authors.)

Objective: To test whether symptoms of autonomic dysfunction in Parkinson disease (PD) are associated with alterations in intrinsic hypothalamic functional connectivity, given the regulatory role of the hypothalamus (HTH) in the autonomic nervous system., Methods: Resting-state fMRI scans from patients with PD were analyzed, comparing patients with the highest (n = 24) and lowest (n = 28) quartile scores in a questionnaire assessing autonomic dysfunction in PD (Scales for Outcomes in Parkinson's Disease-Autonomic [SCOPA-AUT]), obtained from a larger pool of patients (n = 93). Higher scores on the SCOPA-AUT indicate more severe symptoms. Seed-based functional connectivity maps, based on a seed region in the left and right HTH, were computed for each patient and compared by use of a general linear model, with false discovery rate correction for multiple comparisons. Partial correlation tests were additionally performed to test whether the associations between SCOPA-AUT scores and hypothalamic functional connectivity were independent of motor dysfunction, disease duration, cognitive function, and age., Results: Relative to patients with PD with lower SCOPA-AUT scores, patients with higher scores displayed significantly reduced functional connectivity between the HTH and the striatum (caudate, putamen) and thalamus. The significant association between striato-thalamo-hypothalamic functional connectivity and SCOPA-AUT scores was retained after controlling for each patient's corresponding Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, age, disease duration, and cognitive function., Conclusions: Patients with PD with symptoms of autonomic dysfunction show disrupted thalamo-striato-hypothalamic functional connectivity independently of overall motor dysfunction, disease duration, age and cognitive function. These findings suggest that symptoms of autonomic dysfunction in PD are accompanied by central deficits in the neural circuits that regulate autonomic function and their interaction with the basal ganglia., (© 2018 American Academy of Neurology.)

Objective: To investigate cortical and subcortical gray matter abnormalities underlying cognitive impairment in patients with REM sleep behavior disorder (RBD) with or without mild cognitive impairment (MCI)., Methods: Fifty-two patients with RBD, including 17 patients with MCI, were recruited and compared to 41 controls. All participants underwent extensive clinical assessments, neuropsychological examination, and 3-tesla MRI acquisition of T1 anatomical images. Vertex-based cortical analyses of volume, thickness, and surface area were performed to investigate cortical abnormalities between groups, whereas vertex-based shape analysis was performed to investigate subcortical structure surfaces. Correlations were performed to investigate associations between cortical and subcortical metrics, cognitive domains, and other markers of neurodegeneration (color discrimination, olfaction, and autonomic measures)., Results: Patients with MCI had cortical thinning in the frontal, cingulate, temporal, and occipital cortices, and abnormal surface contraction in the lenticular nucleus and thalamus. Patients without MCI had cortical thinning restricted to the frontal cortex. Lower patient performance in cognitive domains was associated with cortical and subcortical abnormalities. Moreover, impaired performance on olfaction, color discrimination, and autonomic measures was associated with thinning in the occipital lobe., Conclusions: Cortical and subcortical gray matter abnormalities are associated with cognitive status in patients with RBD, with more extensive patterns in patients with MCI. Our results highlight the importance of distinguishing between subgroups of patients with RBD according to cognitive status in order to better understand the neurodegenerative process in this population., (© 2018 American Academy of Neurology.)

Objective: To investigate differential atrophy patterns based on the presence of cortical superficial siderosis (cSS) and the role of cSS in predicting amyloid positivity in memory clinic patients fulfilling the diagnostic criteria for probable cerebral amyloid angiopathy (CAA)., Methods: We retrospectively collected data from 44 cognitively impaired patients with probable CAA who underwent 3-dimensional, T1-weighted MRIs (cSS+, n = 27; cSS-, n = 17). Amyloid-positive patients with Alzheimer disease (AD) (n = 56) and amyloid-negative cognitively normal participants (n = 34) were recruited as controls. Among the patients with CAA who underwent amyloid-PET scans (75.0%), we investigated whether amyloid-negative cases were unevenly distributed based on cSS presentation. APOE genotypes, Mini-Mental State Examination scores, and cortical atrophy pattern along with hippocampal volume were compared across groups., Results: Ten patients with probable CAA presented amyloid negativity and all of them belonged to the cSS- group (58.8%). Compared to the cSS- group, the cSS+ group presented higher APOE ε4 frequency, worse memory dysfunction, and lower hippocampal volume. Compared with cognitively normal participants, the cSS+ group exhibited atrophy in the precuneus, posterior cingulate, parietotemporal, superior frontal, and medial temporal areas, a pattern similar to AD-specific atrophy. The cSS- group exhibited atrophy in the parietotemporal, superior frontal, and precentral regions., Conclusion: Our findings imply that the current version of the Boston criteria may not be sufficient enough to remove non-CAA cases from a cognitively impaired population, especially in the absence of cSS. Patients with probable CAA presenting cSS appear to reflect a CAA phenotype that shares pathologic hallmarks with AD, providing insight into the CAA-to-AD continuum., (© 2018 American Academy of Neurology.)

Objective: To determine whether white matter changes influence progression of cognitive decline in individuals with clinically diagnosed Alzheimer disease (AD) and differing biomarker profiles., Methods: Two hundred thirty-six individuals from the Alzheimer's Disease Neuroimaging Initiative database with clinical diagnoses of cognitively normal older adult (older controls [OCs]), mild cognitive impairment, and AD were studied. Support vector machine experiments were first performed to determine the utility of various biomarkers for classifying individuals by clinical diagnosis. General linear models were implemented to assess the relationships between CSF measures of β-amyloid 1-42, phosphorylated tau 181p , and MRI-based white matter signal abnormality (WMSA) volumes and cognitive decline. Analyses were performed across all patients as well as within subgroups of individuals that were defined by clinical cutoff points for both CSF measures., Results: CSF biomarkers alone classified individuals with AD vs OCs with 82% accuracy, and the addition of WMSA did not enhance this. Both CSF biomarkers as well as WMSA volume significantly contributed to predicting cognitive decline in executive and memory domains when assessed across all 236 individuals. In individuals with pathologic levels of both CSF biomarkers, WMSA only significantly contributed to models of future executive function decline. In individuals with subpathologic CSF biomarker levels (levels similar to those in OC individuals), WMSA significantly contributed to prediction of memory decline and were the sole significant predictor of executive function decline., Conclusions: WMSA hold additional predictive power regarding cognitive progression in older individuals and are most effective as biomarkers in individuals who are cognitively impaired but do not fit the expected CSF biomarker profile of AD., (© 2018 American Academy of Neurology.)

Objective: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline., Methods: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSp MRI ], limbic predominant [LP MRI ], typical AD [tAD MRI ]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models., Results: When participants were divided categorically, the HpSp MRI group showed significantly more AD-like hypometabolism on 18 F-fluorodeoxyglucose-PET ( p < 0.05) and poorer baseline executive function ( p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSp MRI also showed faster subsequent clinical decline than participants with LP MRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog 13 ), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tAD MRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog 13 score ( p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy., Conclusions: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation., (© 2017 American Academy of Neurology.)

Objective: To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD)., Methods: In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined., Results: Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85., Conclusions: This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Repetitive transcranial magnetic stimulation (rTMS) and intensive cognitive rehabilitation (CR) were administered to two patients with cognitive dysfunction following brain injury. The first case was a 67-year-old man who presented with memory dysfunction, attention dysfunction, and decreased insight following diffuse axonal injury. High-frequency rTMS (10 Hz, 2400 pulses/day) targeting the anterior cingulate using a navigation system and CR were administered for 12 days at 1 year from the onset of injury. The patient showed improved neuropsychological performance and activities of daily living. In addition, single photon emission computer tomography with Tc-ECD showed improved perfusion in the anterior cingulate gyrus. The second case was a 68-year-old man who presented with dysfunction of memory, attention, and executive function following a cerebral infarction in the middle cerebral artery region within the right hemisphere. This patient received 12 days (except for Sundays) of low-frequency rTMS (1 Hz, 1200 pulses/day) targeting the left dorsolateral prefrontal cortex and the left posterior parietal cortex and CR. Following this intervention, the patient's neuropsychological performance and activities of daily living improved. Furthermore, single photon emission computer tomography showed changes in perfusion in the rTMS target sites and areas surrounding the targets. We have shown the safety and efficacy of rTMS therapy using a navigation system combined with intensive CR on two patients with cognitive dysfunction following brain injury. In addition, we observed changes in the areas around the rTMS target sites in brain imaging data.

The current study aimed to investigate the altered cerebellar-cerebral functional connectivity (FC) induced by radiotherapy to nasopharyngeal carcinoma (NPC) patients. Twenty-four NPC patients without treatment, and 35 NPC patients receiving radiotherapy underwent functional MRI scanning. Montreal cognitive assessment (MoCA) was performed to evaluate the cognitive status of all participants. FC between 10 predefined cerebellar seeds, which were demonstrated to be involved in different brain functional networks, and all brain voxels was obtained for each participant. Using a second-level two-sample t-test, three significantly different FCs between the two patient groups were found, including the connections between the left lobule VIII and the right medial frontal gyrus, the left lobule VIII and the right crus I, and the right lobule VIIb and the right fusiform gyrus. The altered cerebellar-cerebral FCs were also significantly correlated to the MoCA score, as well as the attention score, one of the seven subscores in MoCA. We suggested that the altered cerebellar-cerebral FCs may underlie the radiation-induced cognitive deficits in NPC patients, especially in the domain of attention. Furthermore, considering the functional networks in which the altered connections involved, the anticorrelation between the default network and dorsal attention network may be impaired, and the mediating function of the frontoparietal network to dorsal attention network may be disrupted. The significantly altered cerebellar-cerebral FC may serve as the potential biomarker in revealing the radiation-induced functional abnormalities and may help in the early intervention to the cognitive impairment.

Background and Purpose: Several markers of poststroke cognitive impairment have been reported. The role of brain cortical volume remains uncertain. The aim of this study was to evaluate the influence of brain cortical volume on cognitive outcomes using a voxel-based morphometry approach in subjects without prestroke dementia., Methods: Ischemic stroke patients were prospectively recruited 24 to 72 hours post stroke (M0). Cognition was evaluated at M0, 3 months, and 1 year (M12) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo's cancellation task. A 3-T brain magnetic resonance imaging was performed at M0. Grey matter (GM) was segmented using Statistical Parametric Mapping 12 software. Association between global GM volume and cognitive score slopes between M0 and M12 was evaluated using a linear mixed model. Correlations between focal GM volumes and changes in cognitive performance were evaluated using Statistical Parametric Mapping 12., Results: Two-hundred forty-eight patients were included (mean age 65±SD 14 years old, 66% men). Global GM volume was significantly associated with changes in Montreal Cognitive Assessment scores (β=0.01; P =0.04) and in the number of errors on the Zazzo's cancellation task (β=-0.02; P =0.04) independently of other clinical/radiological confounders. Subjects with lower GM volumes in the left fronto-temporo-insular cortex were more vulnerable to transient Montreal Cognitive Assessment and Isaacs set test impairment. Subjects with lower GM volumes in right temporo-insular cortex, together with basal ganglia, were more vulnerable to transient cognitive impairment on the Zazzo's cancellation task., Conclusions: Smaller cortical volumes in fronto-temporo-insular areas measured 24 to 72 hours post stroke are associated with cognitive vulnerability in the subacute stroke phase., (© 2017 American Heart Association, Inc.)

Background and Purpose: Ultrasound markers of carotid atherosclerosis may be related to cognitive status. We hypothesized that individuals with greater carotid intima-media thickness (cIMT) and carotid plaque burden would exhibit worse cognition., Methods: One thousand one hundred sixty-six stroke-free participants from the NOMAS (Northern Manhattan Study) underwent carotid ultrasound and neuropsychological examination. Among them, 826 underwent a second neuropsychological examination an average of 5 years later. cIMT and plaque were assessed by a standardized B-mode ultrasound imaging and reading protocol. We used multivariable linear regression to examine cIMT, carotid plaque presence, and carotid plaque area as correlates of domain-specific neuropsychological Z scores cross-sectionally and over time. We also investigated possible effect modification by APOE ε4 allele, age, and race/ethnicity., Results: Participants had a mean (SD) age of 70 (9) years and were 60% women, 66% Hispanic, 15% white, and 18% black. Those with greater cIMT exhibited worse episodic memory after adjustment for demographics and vascular risk factors (β=-0.60; P =0.04). APOE ε4 carriers with greater cIMT exhibited worse episodic memory (β=-1.31; P =0.04), semantic memory (β=-1.45; P =0.01), and processing speed (β=-1.21; P =0.03). Participants with greater cIMT at baseline did not exhibit significantly greater cognitive decline after adjustment. APOE ε4 noncarriers with greater cIMT exhibited greater declines in executive function (β=-0.98; P =0.06). Carotid plaque burden was not significantly associated with cognition at baseline or over time., Conclusions: Subclinical carotid atherosclerosis was associated with worse cognition among those at higher risk for Alzheimer disease. Interventions targeting early stages of atherosclerosis may modify cognitive aging., (© 2017 The Authors.)

Objective: To examine the influence of the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship., Methods: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11 C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF -related cognitive trajectories., Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory ( p = 0.002) and speed and flexibility ( p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline ( p = 0.033)., Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics., (© 2017 American Academy of Neurology.)

Objective: To investigate atrophy of the corpus callosum on MRI in Parkinson disease (PD) and its relationship to cognitive impairment., Methods: One hundred patients with PD and 24 healthy control participants underwent clinical and neuropsychological evaluations and structural MRI brain scans. Participants with PD were classified as cognitively normal (PD-NC; n = 28), having mild cognitive impairment (PD-MCI; n = 47), or having dementia (PDD; n = 25) by Movement Disorder Society criteria. Cognitive domain (attention/working memory, executive function, memory, language, visuospatial function) z scores were calculated. With the use of FreeSurfer image processing, volumes for total corpus callosum and its subsections (anterior, midanterior, central, midposterior, posterior) were computed and normalized by total intracranial volume. Callosal volumes were compared between participants with PD and controls and among PD cognitive groups, covarying for age, sex, and PD duration and with multiple comparison corrections. Regression analyses were performed to evaluate relationships between callosal volumes and performance in cognitive domains., Results: Participants with PD had reduced corpus callosum volumes in midanterior and central regions compared to healthy controls. Participants with PDD demonstrated decreased callosal volumes involving multiple subsections spanning anterior to posterior compared to participants with PD-MCI and PD-NC. Regional callosal atrophy predicted cognitive domain performance such that central volumes were associated with the attention/working memory domain; midposterior volumes with executive function, language, and memory domains; and posterior volumes with memory and visuospatial domains., Conclusions: Notable volume loss occurs in the corpus callosum in PD, with specific neuroanatomic distributions in PDD and relationships of regional atrophy to different cognitive domains. Callosal volume loss may contribute to clinical manifestations of PD cognitive impairment., (© 2017 American Academy of Neurology.)

Objective: To investigate the effects of topiramate (TPM), zonisamide (ZNS), and levetiracetam (LEV) on cognitive network activations in patients with focal epilepsy using an fMRI language task., Methods: In a retrospective, cross-sectional study, we identified patients from our clinical database of verbal fluency fMRI studies who were treated with either TPM (n = 32) or ZNS (n = 51). We matched 62 patients for clinical measures who took LEV but not TPM or ZNS. We entered antiepileptic comedications as nuisance variables and compared out-of-scanner psychometric measures for verbal fluency and working memory between groups., Results: Out-of-scanner psychometric data showed overall poorer performance for TPM compared to ZNS and LEV and poorer working memory performance in ZNS-treated patients compared to LEV-treated patients. We found common fMRI effects in patients taking ZNS and TPM, with decreased activations in cognitive frontal and parietal lobe networks compared to those taking LEV. Impaired deactivation was seen only with TPM., Conclusions: Our findings suggest that TPM and ZNS are associated with similar dysfunctions of frontal and parietal cognitive networks, which are associated with impaired performance. TPM is also associated with impaired attenuation of language-associated deactivation. These studies imply medication-specific effects on the functional neuroanatomy of language and working memory networks., Classification of Evidence: This study provides Class III evidence that in patients with focal epilepsy, TPM and ZNS compared to LEV lead to disruption of language and working memory networks., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To investigate how changes in functional network hierarchy determine cognitive impairment in multiple sclerosis (MS)., Methods: A cohort consisting of 332 patients with MS (age 48.1 ± 11.0 years, symptom duration 14.6 ± 8.4 years) and 96 healthy controls (HCs; age 45.9 ± 10.4 years) underwent structural MRI, fMRI, and extensive neuropsychological testing. Patients were divided into 3 groups: cognitively impaired (CI; n = 87), mildly cognitively impaired (MCI; n = 65), and cognitively preserved (CP; n = 180). The functional importance of brain regions was quantified with degree centrality, the average strength of the functional connections of a brain region with the rest of the brain, and eigenvector centrality, which adds to this concept by adding additional weight to connections with brain hubs because these are known to be especially important. Centrality values were calculated for each gray matter voxel based on resting-state fMRI data, registered to standard space. Group differences were assessed with a cluster-wise permutation-based method corrected for age, sex, and education., Results: CI patients demonstrated widespread centrality increases compared to both HCs and CP patients, mainly in regions making up the default-mode network. Centrality decreases were similar in all patient groups compared to HCs, mainly in occipital and sensorimotor areas. Results were robust across centrality measures., Conclusions: Patients with MS with cognitive impairment show hallmark alterations in functional network hierarchy with increased relative importance (centrality) of the default-mode network., (© 2017 American Academy of Neurology.)

Background: Creutzfeldt-Jacob disease (CJD) is a human prion disease generally characterized by subacute changes in behavior and intellectual function, often followed by ataxia, vision changes, and myoclonus. Ten percent of cases may present atypically, both symptomatically and in respect to initial investigations., Methods: We report a case of CJD mimicking acute stroke and review all similar cases in the magnetic resonance imaging era reported in English, identified through a PubMed and SCOPUS search., Results: A 68-year-old woman presented with an acute left parietal syndrome, initially referred as a left middle cerebral artery territory stroke. Structural imaging was unremarkable and focal electroencephalogram changes suggested nonconvulsive status epilepticus. Subsequent clinical progression, with the development of cortical high signal on diffusion-weighted imaging and positive 14-3-3 protein in the cerebrospinal fluid, confirmed a diagnosis of CJD. Review of the literature identified 14 further cases mimicking both anterior and posterior stroke syndromes., Conclusions: CJD develops primarily within a population in whom stroke risk factors are common and represents a rare but important stroke mimic. Negative vascular imaging in elderly patients with apparent acute stroke syndromes should prompt diagnostic review including consideration of prion diseases.

Objective: To quantitatively assess white matter injury (WMI) volume and location in very preterm neonates, and to examine the association of lesion volume and location with 18-month neurodevelopmental outcomes., Methods: Volume and location of WMI was quantified on MRI in 216 neonates (median gestational age 27.9 weeks) who had motor, cognitive, and language assessments at 18 months corrected age (CA). Neonates were scanned at 32.1 postmenstrual weeks (median) and 68 (31.5%) had WMI; of 66 survivors, 58 (87.9%) had MRI and 18-month outcomes. WMI was manually segmented and transformed into a common image space, accounting for intersubject anatomical variability. Probability maps describing the likelihood of a lesion predicting adverse 18-month outcomes were developed., Results: WMI occurs in a characteristic topology, with most lesions occurring in the periventricular central region, followed by posterior and frontal regions. Irrespective of lesion location, greater WMI volumes predicted poor motor outcomes ( p = 0.001). Lobar regional analysis revealed that greater WMI volumes in frontal, parietal, and temporal lobes have adverse motor outcomes (all, p < 0.05), but only frontal WMI volumes predicted adverse cognitive outcomes ( p = 0.002). To account for lesion location and volume, voxel-wise odds ratio (OR) maps demonstrate that frontal lobe lesions predict adverse cognitive and language development, with maximum odds ratios (ORs) of 78.9 and 17.5, respectively, while adverse motor outcomes are predicted by widespread injury, with maximum OR of 63.8., Conclusions: The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern., (© 2017 American Academy of Neurology.)

Objective: We investigated sex differences in verbal memory across different levels of neural dysfunction, measured by temporal lobe glucose metabolic rates (TLGluMR)., Methods: Three hundred ninety controls and 672 participants with amnestic mild cognitive impairment (aMCI) and 254 with Alzheimer disease (AD) dementia from the Alzheimer's Disease Neuroimaging Initiative completed the Rey Auditory Verbal Learning Test (RAVLT) and [ 18 F]-fluorodeoxyglucose-PET. Cross-sectional analyses were conducted using linear regression to examine the sex by TLGluMR interaction on RAVLT performance in the overall sample and within diagnostic groups adjusting for age, education, and APOE ε4 genotype., Results: Across groups, female sex and higher TLGluMR and their interaction were associated with better verbal memory (p values ≤ 0.005). The female advantage in verbal memory varied by TLGluMR such that the advantage was greatest among individuals with moderate to high TLGluMR and minimal or absent among individuals with lower TLGluMR. Diagnosis-stratified analyses revealed that this interaction was driven by the aMCI group (p values = 0.009). The interaction was not significant in control and AD dementia groups., Conclusions: Women show better verbal memory than men in aMCI despite similar levels of brain hypometabolism. The lifelong advantage that females show over males in verbal memory might represent a form of cognitive reserve that delays verbal memory decline until more advanced pathology, as indexed by TLGluMR. This issue is clinically important because verbal memory scores are used in diagnosing aMCI and AD dementia., (© 2016 American Academy of Neurology.)

Objective: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology., Methods: We analyzed 18 F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period., Results: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression., Conclusions: Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD., (© 2016 American Academy of Neurology.)

Objective: To evaluate if cognitive reserve (CR) contributes to interindividual differences in frontal gray matter density (GMD) and executive impairment that underlie heterogeneity in the disease course of confirmed frontotemporal lobar degeneration (FTLD) pathology., Methods: Fifty-five patients with autopsy confirmation or a pathogenic mutation consistent with underlying tau (FTLD-tau) or TDP-43 (FTLD-TDP) pathology and 90 demographically comparable healthy controls were assessed with T1 MRI and neuropsychological measures (Mini-Mental State Examination, letter fluency, forward digit span, Rey complex figure, and Boston Naming Test). CR was indexed using a composite measure of education and occupation. We used t tests to identify reduced GMD in patients with FTLD relative to controls, regression analyses to relate reduced GMD to CR index, and correlations to relate regions of GMD associated with CR to performance on neuropsychological measures., Results: Patients with FTLD demonstrated impairment on neuropsychological measures. Patients with FTLD exhibited reduced bilateral frontotemporal GMD relative to controls, consistent with the known anatomic distribution of FTLD pathology. Higher CR index was associated with superior letter fluency and with GMD in right dorsolateral prefrontal cortex, orbitofrontal cortex, rostral frontal cortex, and inferior frontal gyrus. Furthermore, we found that higher GMD in frontal regions associated with CR was associated with superior letter fluency., Conclusions: Executive control and verbal ability assessed by letter fluency in FTLD is mediated in part by CR and frontal GMD. The identification of factors influencing cognitive and anatomic heterogeneity in FTLD suggests that CR should be considered in symptom detection, prognosis, and treatment., (© 2016 American Academy of Neurology.)

Objective: We examined the risk factors of cortical cerebral microinfarcts (CMIs) on 3T MRI and their association with cognitive impairment., Methods: Participants (aged 60 years and older) from the multiethnic Epidemiology of Dementia In Singapore Study underwent detailed neuropsychological testing and 3T brain MRI. Cortical CMIs were graded using a previously validated protocol. Cognitive impairment was categorized into cognitive impairment, no dementia (CIND)-mild, CIND-moderate, and dementia. Cognitive function was summarized as composite and domain-specific z scores., Results: Among 861 participants, 54 (6.3%) had ≥1 cortical CMI. In multivariate-adjusted models, the risk factors of cortical CMIs were increasing age, Malay ethnicity, hypertension, diabetes, history of stroke, and markers of both large (cortical infarcts and intracranial stenosis) and small (lacunar infarcts, white matter hyperintensities, cerebral microbleeds) vessel disease. Presence of cortical CMIs was associated with CIND-moderate (odds ratio: 3.12; 95% confidence interval [CI]: 1.18-8.58), dementia (odds ratio: 16.92; 95% CI: 3.37-85.05), and poorer cognitive function (mean difference in composite z score: -0.42; 95% CI: -0.62 to -0.21). Additional adjustments for vascular risk factors and other MRI markers did not alter these associations., Conclusions: Cortical CMIs are a novel MRI marker of cerebrovascular disease and are independently associated with cognitive impairment and dementia. These findings provide new insights into the burden of cerebrovascular disease in cognitive impairment. Future research is needed to establish the additional etiologic and prognostic significance of cortical CMIs., (© 2016 American Academy of Neurology.)

Background and Purpose: We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time., Methods: Thirty-three patients with probable CAA underwent multimodal brain magnetic resonance imaging at 2 time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies of posterior-posterior, frontal-frontal, and posterior-frontal network connections were calculated. Patients with moderate versus severe CAA were defined based on microbleed count, dichotomized at the median (median=35)., Results: Global efficiency of the intracerebral hemorrhage-free hemispheric network declined from baseline to follow-up (-0.008±0.003; P=0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group×time interaction P=0.03). The decline in global network efficiency was associated with worse executive functioning (β=0.46; P=0.03). Examination of subgroups of network connections revealed a decline in fractional anisotropies of posterior-posterior connections at both levels of CAA severity (-0.006±0.002; P=0.017; group×time interaction P=0.16). The fractional anisotropies of posterior-frontal and frontal-frontal connections declined in patients with severe but not moderate CAA (group×time interaction P=0.007 and P=0.005). Associations were independent of change in white matter hyperintensity volume., Conclusions: Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and seem to progress from posterior to frontal connections with increasing disease severity., (© 2016 American Heart Association, Inc.)

Background and Purpose: Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function., Methods: We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity)., Results: About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71)., Conclusions: These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment., (© 2016 American Heart Association, Inc.)

Background: Cobalamin (Cbl) is an essential vitamin for human health. While an increasing body of evidence supports the negative impact of Cbl deficiency on cognition, the causality has yet to be determined, and the reported therapeutic responses after Cbl supplement therapy have been inconsistent. Besides, few reports have described neuroimaging characteristics associated with the therapeutic response., Methods: To describe and compare technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (Tc-99m-ECD SPECT) findings in 2 patients with Cbl deficiency with distinct therapeutic responses., Results: Case 1 scored 12/30 in the mini-mental state examination (MMSE) and 34/100 in the cognitive abilities screening instrument (CASI). Profound deficits in mental manipulation, drawing, short-term/long-term memory, and verbal fluency were noted. Case 2 scored 24/30 in the MMSE and 78/100 in the CASI, mainly due to impaired mental manipulation, abstract thinking, and borderline performance in short-term memory and verbal fluency. While both cases showed widespread hypoperfusion within bilateral frontotemporal regions and thalamus on Tc-99m-ECD SPECT, Case 2 demonstrated relatively preserved radio-uptake in the frontal regions, especially the anterior cingulate cortex (ACC) and prefrontal cortex (PFC), consistent with the better therapeutic response (Case 1: 12/30 to 11/30 in the MMSE; Case 2: 24/30 to 28/30 in the MMSE)., Conclusion: Given that the ACC integrates the limbic system and frontosubcortical circuits and the PFC governs executive function, the extent and severity of hypofrontality may be responsible for the worse prognosis. Our Tc-99m-ECD SPECT observations revealed that the negative impact on cerebral metabolic tone is relevant to the severity of Cbl deficiency, and the functional integrity of the ACC and PFC is highly associated with the preservation of global cognitive function in our cases with Cbl deficiency., Competing Interests: The authors report no conflicts of interest.

Maladaptive responses to pain-related distress, such as pain catastrophizing, amplify the impairments associated with chronic pain. Many of these aspects of chronic pain are similar to affective distress in clinical anxiety disorders. In light of the role of the amygdala in pain and affective distress, disruption of amygdalar functional connectivity in anxiety states, and its implication in the response to noxious stimuli, we investigated amygdala functional connectivity in 17 patients with chronic low back pain and 17 healthy comparison subjects, with respect to normal targets of amygdala subregions (basolateral vs centromedial nuclei), and connectivity to large-scale cognitive-emotional networks, including the default mode network, central executive network, and salience network. We found that patients with chronic pain had exaggerated and abnormal amygdala connectivity with central executive network, which was most exaggerated in patients with the greatest pain catastrophizing. We also found that the normally basolateral-predominant amygdala connectivity to the default mode network was blunted in patients with chronic pain. Our results therefore highlight the importance of the amygdala and its network-level interaction with large-scale cognitive/affective cortical networks in chronic pain, and help link the neurobiological mechanisms of cognitive theories for pain with other clinical states of affective distress.

The risk of Alzheimer's disease can be predicted by volumetric analyses of MRI data in the medial temporal lobe. The present study compared a volumetric measurement of the hippocampus with a novel measure of hippocampal integrity (HI) derived from the ratio of parenchyma volume over total volume. Participants were cognitively intact and aged 60 years or older at baseline, and were tested twice, roughly 3 years apart. Participants had been recruited for a study on late-life major depression (LLMD) and were evenly split between depressed patients and controls. Linear regression models were applied to the data with a cognitive composite score as the outcome, and HI and volume, together or separately, as predictors. Subsequent cognitive performance was predicted well by models that included an interaction between HI and LLMD status, such that lower HI scores predicted more cognitive decline in depressed patients. More research is needed, but tentative results from this study appear to suggest that the newly introduced measure HI is an effective tool for the purpose of predicting future changes in general cognitive ability, and especially so in individuals with LLMD.

Background and Purpose: The National Institutes of Health Stroke Scale (NIHSS) includes minimal assessment of cognitive function, particularly in right hemisphere (RH) stroke. Descriptions of the Cookie Theft picture from the NIHSS allow analyses that (1) correlate with aphasia severity and (2) identify communication deficits in RH stroke. We hypothesized that analysis of the picture description contributes valuable information about volume and location of acute stroke., Methods: We evaluated 67 patients with acute ischemic stroke (34 left hemisphere [LH]; 33 RH) with the NIHSS, analysis of the Cookie Theft picture, and magnetic resonance imaging, compared with 35 sex- and age-matched controls. We evaluated descriptions for total content units (CU), syllables, ratio of left:right CU, CU/minute, and percent interpretive CU, based on previous studies. Lesion volume and percent damage to regions of interest were measured on diffusion-weighted imaging. Multivariable linear regression identified variables associated with infarct volume, independently of NIHSS score, age and sex., Results: Patients with RH and LH stroke differed from controls, but not from each other, on CU, syllables/CU, and CU/minute. Left:right CU was lower in RH compared with LH stroke. CU, syllables/CU, and NIHSS each correlated with lesion volume in LH and RH stroke. Lesion volume was best accounted by a model that included CU, syllables/CU, NIHSS, left:right CU, percent interpretive CU, and age, in LH and RH stroke. Each discourse variable and NIHSS score were associated with percent damage to different regions of interest, independently of lesion volume and age., Conclusions: Brief picture description analysis complements NIHSS scores in predicting stroke volume and location., (© 2016 The Authors.)

Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity., Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE., Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology., Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology., (© 2016 American Academy of Neurology.)

Objective: To identify the metabolic signature of the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET)., Methods: A total of 170 ALS cases consecutively enrolled at the ALS Center of Turin underwent brain 18F-FDG-PET and were classified as displaying normal cognition (ALS-Cn; n = 94), full-blown frontotemporal dementia (ALS-FTD; n = 20), executive or nonexecutive cognitive impairment not fulfilling FTD criteria (ALS-Ci; n = 37), prevalent behavioral changes (n = 9), or nonclassifiable impairment (n = 10) according to neuropsychological testing. Group comparisons of 18F-FDG-PET pattern were carried out among the cognitive subgroups., Results: We found a significantly reduced frontal and prefrontal metabolism in ALS-FTD as compared to ALS-Cn, while ALS-Ci showed an intermediate metabolic behavior in frontal cortex, being hypometabolic as compared to ALS-Cn, and relatively hypermetabolic as compared to ALS-FTD. Hypometabolism in frontal regions was associated in all comparisons to hypermetabolism in cerebellum, midbrain, and corticospinal tracts: the more severe the cognitive decline, the larger the size of the cluster and the statistical significance of 18F-FDG uptake differences., Conclusions: This study demonstrated in a large cohort of patients with ALS a continuum of frontal lobe metabolic impairment reflecting the clinical and anatomic continuum ranging from pure ALS, through ALS with intermediate cognitive deficits, to ALS-FTD, and showing that patients with intermediate cognitive impairment display a characteristic metabolic pattern. Since 18F-FDG-PET allows us to estimate the cerebral lesion load in vivo in neurodegenerative diseases, it might be helpful to investigate in ALS its association with neuropsychological testing along the disease course to disclose the early metabolic signature of possible cognitive impairment., (© 2015 American Academy of Neurology.)

Background and Purpose: We hypothesized that comorbid amyloid-beta (Aβ) deposition played a key role in long-term cognitive decline in subjects with stroke/transient ischemic attack., Methods: We recruited 72 subjects with cognitive impairment after stroke/transient ischemic attack to receive Carbon-11-labeled Pittsburgh compound B positron emission tomography. We excluded subjects with known clinical Alzheimer's disease. Those with and without Alzheimer's disease-like Aβ deposition were classified as mixed vascular cognitive impairment (mVCI, n=14) and pure VCI (pVCI, n=58), respectively. We performed Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment to evaluate global cognition and cognitive domains (memory, visuospatial function, language, attention, and executive function) at 3 to 6 months (baseline) and annually for 3 years after the index event. We compared cognitive changes between mVCI and pVCI using linear mixed models and analysis of covariance adjusted for age and education., Results: Over 3 years, there were significant differences between mVCI and pVCI on change of MMSE score over time (group×time interaction, P=0.007). We observed a significant decline on MMSE score (P=0.020) in the mVCI group but not in the pVCI group (P=0.208). The annual rates of decline on MMSE (P=0.023) and Montreal Cognitive Assessment score (P=0.003) were greater in the mVCI group than in the pVCI group. Memory, visuospatial, and executive function domain scores on the Montreal Cognitive Assessment were related to Aβ deposition., Conclusions: Compared with subjects without Alzheimer's disease-like Aβ deposition, those with Aβ deposition experienced a more severe and rapid cognitive decline over 3 years after stroke/transient ischemic attack. Aβ was associated with changes in multiple cognitive domains., (© 2015 American Heart Association, Inc.)

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD)., Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education., Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination., Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials., (© 2015 American Academy of Neurology.)

Background and Purpose: The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants., Methods: At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance., Results: Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory., Conclusions: We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging., (© 2015 American Heart Association, Inc.)

Background and Purpose: By definition, the symptoms of a transient ischemic attack (TIA) subside completely within 24 hours. Imaging studies show signs of persistent ischemic tissue damage in a substantial amount of patients with TIA. Cerebral infarction can cause permanent cognitive impairment. Whether permanent cognitive impairment occurs after TIA is unclear, as is its profile., Methods: Patients with TIA aged 45 to 65 years without prior stroke or dementia underwent comprehensive neuropsychological testing within 3 months. Z scores per cognitive domain were obtained, based on the mean of a control group within the same age range. Cognitive impairment was defined as a domain z score <-1.65. Patients underwent either computed tomography or MRI brain imaging., Results: One hundred seven patients with TIA (63% women, mean age, 56.6 years) were included and compared with 81 controls (56% women, mean age, 52.9 years). Patients performed worse on all cognitive domains except episodic memory. Working memory (25%), attention (22%), and information processing speed (16%) were most frequently impaired and more often than in the control group (age- and sex-adjusted odds ratios, respectively, 22.5 [95% confidence interval, 2.9-174.3], 6.8 [1.9-24.3], 7.1 [1.5-32.5]). More than 35% of patients with TIA had impairment of ≥1 cognitive domain. Presence of silent brain infarcts was related to worse executive functioning but did not explain the whole relationship between TIA and cognitive impairment., Conclusions: More than a third of patients with TIA have impairment of ≥1 cognitive domain within 3 months after their TIA. The affected domains fit in the vascular cognitive impairment profile., (© 2014 American Heart Association, Inc.)

Purpose of Review: To give an update on recent biomarker imaging studies using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) on cognitive impairment in Lewy-body diseases (LBD)., Recent Findings: Imaging studies of regional cerebral glucose metabolism with [F]fluorodeoxyglucose(FDG)-PET support the concept that Parkinson's disease (PD) with mild cognitive impairment represents a prodromal stage of PD with dementia (PDD). Furthermore, [F]FDG-PET may be suited for risk stratification for dementia in PD. In line with neuropathological studies, preliminary amyloid-beta (Aβ) PET studies suggest that Aβ acts synergistically with Lewy pathology in LBD, leading to an earlier manifestation of cognitive impairment in dementia with Lewy-bodies compared with PDD and a more rapid cognitive decline in PD patients with concomitant Aβ pathology., Summary: Molecular neuroimaging with SPECT and PET provides unique in-vivo insights into neuropathological and pathophysiological changes underlying cognitive impairment in LBD. Future prospective studies are needed to confirm the prognostic value of [F]FDG-PET and to define the value of amyloid PET and upcoming techniques, such as tau imaging, for diagnosis and prognosis in LBD.

HIV-associated neurocognitive disorders (HAND) remain among the most common clinical disorders encountered in people infected with HIV despite widespread use of antiretroviral therapy. There is an enormous need for further evaluation and early diagnosis of HAND. The variety of PET agents such as FDG, C-PiB and [C]-R-PK11195 as well as SPECT agents Tc-HMPAO, I-FP-CIT and I-IBZM have been investigated for the diagnosis of HAND, for distinguishing between demented and nondemented HIV patients, for differentiation between HAND and nonHIV related dementia, as well as for assessing the influence of coinfection with the other viral pathogens on the brain functionality. In spite of some interesting results, none of these tracers have been specifically created for HAND and none can be recommended for HAND diagnosis. Specialized tracers need to be developed for better diagnosis and management of HAND. The potential role of therapeutic nuclear medicine as part of the curative strategies for HIV is also discussed.