Mesial Temporal Atrophy Research Articles

Using eZIS to Predict Progression from MCI to Dementia in Three Years.

(1) Background: Mild cognitive impairment (MCI) due to Alzheimer's disease (AD) progresses to dementia at a higher annual rate, while other MCIs may remain stable or even improve over time. Discriminating progressive from non-progressive cases of MCI is crucial and challenging. (2) Methods: A retrospective study of individuals with MCI was conducted at a university hospital located in southern Taiwan. The researchers collected demographic data, comorbidities, the scores of cognitive tests, three easy Z-score imaging system (eZIS) indicators (severity, extent, and ratio), Fazekas scale scores, mesial temporal atrophy (MTA) scores, clinical outcomes including deterioration of Cognitive Abilities Screening Instrument, Mini-mental State Examination, Clinical Dementia Rating Sum of Box scores, and the conversion from MCI to dementia. Those who converted to dementia in three years and non-converters were compared by the three eZIS indicators to test the predictive utility, and the clinical outcomes were evaluated by regression and ROC curve analysis. (3) Results: The three eZIS indicators were significantly higher in the group of progressive MCI than in stable MCI. eZIS severity is positively correlated with a deterioration in the scores of the Cognitive Abilities Screening Instrument and Clinical Dementia Rating Sum of Box. eZIS severity is also positively correlated with conversion from MCI to dementia. The AUC for severity is 0.719, and the optimal cutoff value of severity for predicting conversion is 1.22. (4) Conclusions: During three years of follow-up, MCI individuals with greater eZIS severity were significantly associated with worse cognitive assessment scores and a higher conversion rate to dementia.

Comparison of Continuous Intracortical and Scalp Electroencephalography in Comatose Patients with Acute Brain Injury.

Depth electroencephalography (dEEG) is a recent invasive monitoring technique used in patients with acute brain injury. This study aimed to describe in detail the clinical manifestations of nonconvulsive seizures (NCSzs) with and without a surface EEG correlate, analyze their long-standing effects, and provide data that contribute to understanding the significance of certain scalp EEG patterns observed in critically ill patients. We prospectively enrolled a cohort of 33 adults with severe acute brain injury admitted to the neurological intensive care unit. All of them underwent multimodal invasive monitoring, including dEEG. All patients were scanned on a 3T magnetic resonance imaging scanner at 6months after hospital discharge, and mesial temporal atrophy (MTA) was calculated using a visual scale. In 21 (65.6%) of 32 study participants, highly epileptiform intracortical patterns were observed. A total of 11 (34.3%) patients had electrographic or electroclinical seizures in the dEEG, of whom 8 had both spontaneous and stimulus-induced (SI) seizures, and 3 patients had only spontaneous intracortical seizures. An unequivocal ictal scalp correlate was observed in only 3 (27.2%) of the 11 study participants. SI-NCSzs occurred during nursing care, medical procedures, and family visits. Subtle clinical manifestations, such as restlessness, purposeless stereotyped movements of the upper limbs, ventilation disturbances, jerks, head movements, hyperextension posturing, chewing, and oroalimentary automatisms, occurred during intracortical electroclinical seizures. MTA was detected in 18 (81.8%) of the 22 patients. There were no statistically significant differences between patients with MTA with and without seizures or status epilepticus. Most NCSzs in critically ill comatose patients remain undetectable on scalp EEG. SI-NCSzs frequently occur during nursing care, medical procedures, and family visits. Semiology of NCSzs included ictal minor signs and subtle symptoms, such as breathing pattern changes manifested as patient-ventilator dyssynchrony.

Mesial temporal atrophy in preoperative MRI rather than steep Trendelenburg position is associated with postoperative delirium in patients undergoing a major urologic surgery.

To investigate whether steep Trendelenburg in a major urologic surgery is associated with postoperative delirium, and to examine other potential clinical and radiologic factors predictive of postoperative delirium. 182 patients who received a major urologic surgery and underwent a 3.0-T brain MRI scan within 1year prior to the date of surgery were retrospectively enrolled. Preoperative brain MRIs were used to analyze features related to small vessel disease burden and mesial temporal atrophy. Presence of a significant mesial temporal atrophy was defined as Scheltens' scale ≥ 2. Patients' clinico-demographic data and MRI features were used to identify significant predictors of postoperative delirium using the logistic regression analysis. Independent predictors found significant in the univariate analysis were further evaluated in the multivariate analysis. Incidence of postoperative delirium was 6.0%. Patients with postoperative delirium had lower body mass index (21.3 vs. 25.0kg/m2, P = 0.003), prolonged duration of anesthesia (362.7 vs. 224.7min, P < 0.001) and surgery (302.2 vs. 174.5min, P < 0.001), and had more significant mesial temporal atrophy (64% vs. 30%, P = 0.046). In the univariate analysis, female sex, type of surgery (radical prostatectomy over cystectomy), prolonged duration of anesthesia (≥ 6h), and presence of a significant mesial temporal atrophy were significant predictors (all P-values < 0.050), but only the presence of significant mesial temporal atrophy was significant in the multivariate analysis [odds ratio (OR), 3.69; 95% CI 0.99-13.75; P = 0.046]. Steep Trendelenburg was not associated with postoperative delirium. Significant mesial temporal atrophy (Scheltens' scale ≥ 2) in preoperative brain MRI was predictive of postoperative delirium. Not applicable.

Synergistic role of white matter changes and CSF biomarkers in amnestic and non‐amnestic AD phenotypes

AbstractBackgroundAlzheimer’s disease (AD) is pathologically diagnosed based on abnormal amyloid and tau pathology but is also related to additional pathologic processes. (1) The cognitive symptoms are not directly associated with AD pathology but are the consequence of a complex mechanism, showing discordance between clinical symptoms and CSF biomarkers. (2) Previous evidence suggests a range from the synergistic role of white matter signal abnormality (WMSA) and CSF biomarkers on AD to no relationship between the two. (1) We aimed to analyze the CSF biomarker profiles, and brain MRI changes in AD patients with different phenotypes.MethodCSF was collected by lumbar puncture from 40 individuals with AD. We analyzed CSF levels (Aβ‐42, Aβ‐40, t‐tau, p‐tau, tau / Aβ‐42, and Aβ‐42/40) in two different samples. The clinical characteristics included: AD phenotype (amnestic or non‐amnestic), age, gender, education, and age‐onset. We used the brain MRI scales: MTA (mesial temporal lobe atrophy), and Fazekas, for white matter signal abnormality (WMSA), considering pathological changes (≥ 2).ResultPreliminary results in 16 patients showed that most of the patients with CSF typical AD pattern presented an amnestic phenotype, revealing WMSA changes. The patients with no CSF changes showed little or no WMSA changes in both clinical presentations. The amnestic phenotype showed more MTA changes in patients with typical AD CSF pattern, and no difference was found between the phenotypes in patients with no CSF changes.ConclusionIt can be a positive relation between cerebrovascular diseases, WMSA changes, and CSF pathological changes in AD, regardless of the phenotype, supporting that Aβ pathology may lead to secondary vascular damage including white matter lesions.

Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine-Altering Variants.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. Patients with the cysteine-altering NOTCH3 variant were enrolled in a cross-sectional study, including the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B, -4.090 [95% CI, -6.708 to -1.473]; P=0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B, 2.854 [95% CI, 0.603-5.105]; P=0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively. APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment.

Poster Symposium: How Well do Western Methods Used to Assess Atypical Aging in Western Countries Generalize to Sub-Saharan African Countries?

Summary Abstract:Risk factors associated with development of neurodegenerative disease has been well-studied in Western and European populations. However, there has been considerably less research in the assessment of such risk factors in developing countries, notably sub-Saharan Africa. There is a paucity of data at the micro level (e.g. neuroimaging and biomarker data) and macro level (e.g. cognitive assessment and psychosocial/environmental risk factors) for development of neurodegenerative conditions in these populations.This symposium examines Western methods of assessment of risk factors and cognitive profiles of older adults at risk for neurodegenerative disorder to determine if they are relevant to sub-Saharan African populations, specifically older Congolese adults. This symposium utilizes an older adult sample that has been comprehensively assessed both at the cellular level (via blood biomarkers and neuroimaging typically used for assessment of dementia in Western populations), to the individual functional level (via cognitive assessment), to finally, psychosocial and environmental risk factors for dementia seen at a community level. First, Dr. Ikanga will present on the association between performance on the African Neuropsychological Battery (ANB) with biomarkers specific to Alzhemer's disease and more general vascular risk factors for cognitive decline. Second, Dr. Hickle will present on structural neuroimaging data of mesial temporal lobe atrophy in comparison with performance on the ANB. Dr. Reyes will then discuss the utility of a cognitive screener developed for use in Sub-Saharan Africa on older adults from the Democratic Republic of Congo, with specific emphasis on educational corrections. Finally, Dr. De Wit will discuss health and psychosocial predictors of depressive symptoms as well as the relation between depressive symptoms and neuropsychological functioning in Congolese older adults, to determine if neurocognitive profiles are similar in Sub-Saharan Africa relative to Western populations. This "micro to macro" approach is unique in providing a comprehensive overview of risks associated with dementia in Congolese adults. This is the first study of its kind to utilize a multi-method approach for older adults at risk for dementia in Sub-Saharan Africa, and results suggest that some approaches are more valid in this population than others. Future areas of research will be discussed, as well as feasibility and validity of Western approaches in assessment of dementia to non-Western populations.

Prediction of post-stroke cognitive impairment after acute ischemic stroke using machine learning

Background and objectivesPost-stroke cognitive impairment (PSCI) occurs in up to 50% of patients with acute ischemic stroke (AIS). Thus, the prediction of cognitive outcomes in AIS may be useful for treatment decisions. This PSCI cohort study aimed to determine the applicability of a machine learning approach for predicting PSCI after stroke.MethodsThis retrospective study used a prospective PSCI cohort of patients with AIS. Demographic features, clinical characteristics, and brain imaging variables previously known to be associated with PSCI were included in the analysis. The primary outcome was PSCI at 3–6 months, defined as an adjusted z-score of less than − 2.0 standard deviation in at least one of the four cognitive domains (memory, executive/frontal, visuospatial, and language), using the Korean version of the Vascular Cognitive Impairment Harmonization Standards-Neuropsychological Protocol (VCIHS-NP). We developed four machine learning models (logistic regression, support vector machine, extreme gradient boost, and artificial neural network) and compared their accuracies for outcome variables.ResultsA total of 951 patients (mean age 65.7 ± 11.9; male 61.5%) with AIS were included in this study. The area under the curve for the extreme gradient boost and the artificial neural network was the highest (0.7919 and 0.7365, respectively) among the four models for predicting PSCI according to the VCIHS-NP definition. The most important features for predicting PSCI include the presence of cortical infarcts, mesial temporal lobe atrophy, initial stroke severity, stroke history, and strategic lesion infarcts.ConclusionOur findings indicate that machine-learning algorithms, particularly the extreme gradient boost and the artificial neural network models, can best predict cognitive outcomes after ischemic stroke.

Episodic Memory in Amnestic Behavioral Frontotemporal Dementia and Alzheimer's Disease.

Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer's disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

69-Year-Old Female with Progressive Supranuclear Palsy, Frontotemporal Dementia, Focal Hyperkinesia and one variant in the GCH1 gene and in the CSF1R gene

How insignificant is the detection of gene variants in a novel clinical presentation of an atypical Parkinson’s syndrome with positive family history? We present the case of a 69-year-old woman with Progressive Vertical Supranuclear Palsy (PSP), focal hyperkinesia, non-L-dopa-responsive asymmetrical Parkinsonism, postural instability as well as apraxia, cognitive, speech and frontal disorder, with a positive family history, MRI evidence of mesial temporal atrophy and tau-PET evidence of tau pathology as well as identification of one variant in the GCH1 gene and one variant in the CSF1R gene. The fact that the clinical presentation and radiological finding of our patients are not compatible with a known and well described genetic disorder caused by pathogenic mutations of these genes, supports the notion that the detected gene variants have an uncertain significance in the pathogenesis of our patient’s disease. Nevertheless, the novel description of the phenotype of our case of PSP with frontal lobe features, focal hyperkinesia and a positive family history, points to an in-vivo tauopathy, in which a genetic burden may play a role. The follow-up of the patient und her family may offer further insights into the pathophysiology of complex neurodegenerative diseases in the spectrum of tauopathies, offering possible new therapeutic targets.

Transient epileptic amnesia: a retrospective cohort study of 127 cases, including CSF amyloid and tau features.

Transient epileptic amnesia (TEA) is a late-onset epilepsy syndrome encompassing transient iterative amnesias and interictal cognitive impairment, two features that overlap with incipient neurodegenerative dementias. We, therefore, examined the yield of CSF amyloid and tau biomarkers in TEA. In this retrospective study, 127 TEA patients with unremarkable imaging findings were divided into 2 groups, namely, CSF (n = 71) and no-CSF (n = 56). Both were compared for demographics; medical history; baseline neurological, cognitive, and behavioral features; baseline mesial temporal lobe atrophy; and cognitive follow-up at a median of 13months. CSF samples were examined for amyloid β-42 peptide as well as phospho-tau and total-tau levels. At baseline, the CSF-TEA group had significantly (p < 0.01) more frequent mild parkinsonism (42.9% vs. 20%) and cognitive concerns (31% vs. 10.7%), a more blunted sense of smell (34.3% vs. 9.4%), a lower baseline MMSE score (27 vs. 28.9), a more frequent amnestic mild cognitive impairment profile (69% vs. 42.6%), and more atrophic hippocampal changes. At follow-up, the CSF-TEA group had significantly (p < 0.01) lower MMSE scores (27.8 vs. 28.9). CSF analyses revealed amyloid and/or tau changes in 27 patients (38%), including an Alzheimer's disease (AD) profile in 17 (24%). This study shows a good diagnostic value of CSF sampling in a specific population of TEA with characteristics suggestive of incipient degenerative diseases (i.e., red flags). It argues for TEA being the inaugurating feature in some cases of AD. More broadly, our results suggest an etiological heterogeneity in TEA.

Frailty, MRI, and FDG-PET Measures in an Australian Memory Clinic Cohort

Given that the global population is aging, the number of age-related syndromes, such as frailty, is expected to rise in conjunction. Frailty is characterized by the loss of homeostatic reserve, rendering the individual vulnerable to poor health outcomes. Many biological mechanisms have been proposed to contribute to frailty. However, few studies have assessed the associations between frailty and brain diseases or neuroimaging biomarkers.Aims: The aims of this study were to measure the prevalence of frailty in a memory clinic and to examine associations between frailty and brain changes found on magnetic resonance imaging (MRI) and 18-F deoxyglucose (FDG) positron emission tomography (PET) in memory clinic attendees.Methods: A 54-items Frailty Index was retrospectively assessed for all clinic attendees from 2014. Frailty was defined as FI > 0.25. MR images were analyzed for stroke, cerebral small vessel disease [CSVD, including cerebral microbleeds (CMBs), cortical superficial siderosis (CSS), and white matter hyperintensity (WMH)], and neurodegenerative changes [MRI: mesial temporal atrophy (MTA), FDG-PET: regional hypometabolism], blind to clinical findings.Results: There were 209 clinic attendees in 2014, of whom 121 had MRI performed. The prevalence of frailty (using FI) in the memory clinic in 2014 was 38.3% overall (patients without MRI: 43.2%, patients with MRI 34.7%, p = 0.25). Frailty was associated with presence of deep WMH, increased severity of periventricular WMH, and presence of CSS, but not neurodegeneration markers (MTA atrophy/FDG-PET hypometabolism).Conclusion: The findings support the idea that previously reported associations between frailty and imaging evidence of CSVD in other cohorts are also relevant to the Australian clinic setting. Given that a large proportion of memory clinic attendees are frail, there may be opportunities for interventions to reduce preventable adverse health outcomes, such as falls and fractures, and reduce the prevalence and impact of frailty in this cohort.

The neurophysiology and seizure outcomes of late onset unexplained epilepsy

ObjectiveTo investigate neurophysiologic and neuroimaging characteristics of patients with late onset unexplained epilepsy (LOUE). MethodsWe performed a retrospective chart review of elderly patients with ICD9 diagnosis codes consistent with epilepsy/seizures. Inclusion criteria included unprovoked seizures, and absence of cortical lesions on magnetic resonance imaging (MRI). Electroencephalograms (EEGs) findings were also analyzed. MRI images were scored for degree of white matter hyperintensities (Fazekas Scale) and mesial temporal atrophy (MTA). Vascular risk factors, and Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores were compared to controls from the Harvard Aging Brain study (HABS). ResultsWe identified 224 LOUE patients and 8% were drug resistant. Epileptiform abnormalities were captured on EEG in 35%. The location was temporal with left sided predominance in 49%. Fazekas scale consisted of 25% beginning of confluent lesions, and 10% large confluent lesions. MTA scores consisted of 21% moderate-severe hippocampal atrophy. LOUE patients had on average a 2.3% (adjusted), 7.4% (unadjusted) increased FHS-CVD score. ConclusionsOur findings highlight LOUE as pharmacosensitive and left temporal predominant. Given the higher prevalence of vascular risk factors, investigations are needed to study their role in pathophysiology. SignificancePhysicians caring for patients with LOUE should evaluate for vascular risk factors and investigate the presence of hippocampal atrophy.

Long term sequelae of amygdala enlargement in temporal lobe epilepsy

PurposeAmygdala enlargement (AE) has been reported in drug resistant lesional and non-lesional temporal lobe epilepsy (TLE). Its contribution to development of intractability of epilepsy is at best uncertain. Our aim was to study the natural course of AE in a heterogenous group of TLE patients with follow-up imaging and clinical outcomes. MethodsA prospective observational study in patients with TLE with imaging features of AE recruited from epilepsy clinics between 1994 and 2018. Demographic data, details of epilepsy syndrome, outcomes and follow up neuroimaging were extracted. ResultsForty-two patients were recruited including 19 males (45 %). Mean age at onset of epilepsy was 30.6 years and mean duration of epilepsy was 19.9 years. On MRI, 33 patients had isolated unilateral AE and eleven had AE with hippocampal enlargement (HE). Twenty (48 %) underwent temporal resections with most common histopathology being amygdalar gliosis (40 %). Engel Class IA outcome at last follow up (mean, 10 years) was 60 %.Thirty-four patients had neuroimaging follow up of at least 1 year (mean, 5 years). AE resolved in 6, persisted in 25, evolved into bilateral HS in 1, bilateral mesial temporal atrophy in 1 and ipsilateral mesial temporal atrophy in 1. Resolution of AE was associated with better seizure free outcomes (p = 0.013). ConclusionsTLE with AE is associated with favourable prognosis yet not benign. Over 50 % were drug resistant and surgical outcomes were similar to mTLE. Resolution of AE on follow up neuroimaging was associated with better seizure free outcomes.

Trajectories of brain remodeling in temporal lobe epilepsy.

Temporal lobe epilepsy has been usually associated with progressive brain atrophy due to neuronal cell loss. However, recent animal models demonstrated a dual effect of epileptic seizures with initial enhancement of hippocampal neurogenesis followed by abnormal astrocyte proliferation and neurogenesis depletion in the chronic stage. Our aim was to test for the hypothesized bidirectional pattern of epilepsy-associated brain remodeling in the context of the presence and absence of mesial temporal lobe sclerosis. We acquired MRIs from a large cohort of mesial temporal lobe epilepsy patients with or without hippocampus sclerosis on radiological examination. The statistical analysis tested explicitly for common and differential brain patterns between the two patients' cohorts and healthy controls within the computational anatomy framework of voxel-based morphometry. The main effect of disease was associated with continuous hippocampus volume loss ipsilateral to the seizure onset zone in both temporal lobe epilepsy cohorts. The post hoc simple effects tests demonstrated bilateral hippocampus volume increase in the early epilepsy stages in patients without hippocampus sclerosis. Early age of onset and longer disease duration correlated with volume decrease in the ipsilateral hippocampus. Our findings of seizure-induced hippocampal remodeling are associated with specific patterns of mesial temporal lobe atrophy that are modulated by individual clinical phenotype features. Directionality of hippocampus volume changes strongly depends on the chronicity of disease. Specific anatomy differences represent a snapshot within a progressive continuum of seizure-induced structural remodeling.

BIPHASIC MODEL IN PRECLINICAL ALZHEIMER’S DISEASE: AV45 PET, CSF TAU AND CORTICAL THICKNESS

A biphasic model for brain structural changes in preclinical AD has been recently proposed (Fortea et al., 2014) using CSF biomarkers. Pathologic cortical thickening in relation to decreasing CSF ß-amyloid levels would be followed by cortical thinning once tau biomarkers in CSF become abnormal. Thus, different longitudinal trajectories for brain structural changes in the NIA-AA preclinical AD stages have been also described (Pegueroles et al., 2016). However, CSF biomarkers do not assess the specific stage in each region. Our objective was to replicate these findings using AV45-PET as amyloid biomarker as well as to study the local relationship between amyloid deposition and cortical thickness. We included all healthy controls in ADNI that had a baseline 3T MRI, AV45-PET acquisition and CSF total-tau levels (N=127). Eighty-eight subjects also had a 2y follow-up MRI. Using published cutoffs all subjects were classified in Stage 0 (AV45 SUVR <1.11 and total-tau <93 pg/mL), Stage 1 (AV45 SUVR >=1.11 and total-tau <93 pg/mL) and Stage 2 (AV45 SUVR >=1.11 and total-tau >=93 pg/mL). 8 subjects did not meet any staging criteria and were excluded. We performed group analysis between Stage 0 and the other groups cross-sectionally and longitudinally. Finally we studied the correlation between local (point-to point) and global (mean SUVR) AV45 retention and both cortical thickness and longitudinal structural changes. Stage 1 subjects presented increased cortical thickness at baseline and less longitudinal cortical thinning than Stage 0 subjects, whereas Stage 2 subjects presented accelerated mesial temporal atrophy longitudinally. In the local analysis, we found a widespread correlation between AV45 retention and increased cortical thickness in Stage 1 subjects (FIG1). The results were similar when correlating the mean SUVR with cortical thickness. The Stage 2 group also presented a cluster of increased cortical thickness in the AV45-CTh correlation analyses.

Biomarkers for the Early Detection and Progression of Alzheimer's Disease.

The recent failures of potential disease-modifying drugs for Alzheimer's disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.

White matter abnormalities in patients with temporal lobe epilepsy and amygdala enlargement: Comparison with hippocampal sclerosis and healthy subjects

PurposeCases of temporal lobe epilepsy (TLE) with ipsilateral amygdala enlargement (AE) have increasingly been reported. However, the white matter (WM) abnormalities of TLE patients with AE remain poorly investigated. Here we explored macrostructural and microstructural WM abnormalities in TLE patients with AE compared to normal controls and TLE patients with hippocampal sclerosis (HS). Material and methodsWe selected 17 patients with unilateral TLE with AE (TLE-AE) based on automated amygdala volumetry using FreeSurfer software, and 34 healthy controls and 35 patients with unilateral TLE with HS (TLE-HS) were also recruited. Subsequently, differences in gray matter (GM) and WM volumes and fractional anisotropy (FA) among the three groups were analyzed using SPM8 software. ResultsThe volume analysis of GM obtained results that are consistent with the structural characteristics of TLE with AE and with HS (i.e. amygdala increase in the TLE-AE, and mesial temporal atrophy in the TLE-HS). In the volume of WM, only the TLE-HS patients had WM reductions mainly in the ipsilateral temporal lobe. Compared to the controls, the TLE-AE group showed a significant FA decrease in the ipsilateral anterior cingulum and the corpus callosum, whereas an extended FA decrease in the whole cerebrum was observed in the TLE-HS group. ConclusionOur findings regarding the WM of TLE patients with AE may reflect characteristic pathophysiology such as the anatomical and functional connection between the amygdala and medial prefrontal cortex, and our results may thus provide insights into TLE with AE.

Gender, apolipoprotein E genotype, and mesial temporal atrophy: 2-year follow-up in patients with stable mild cognitive impairment and with progression from mild cognitive impairment to Alzheimer's disease.

This study aimed to examine the relationship between gender, apolipoprotein E (APOE) genotype, and mesial temporal atrophy in mild cognitive impairment (MCI) with and without progression to Alzheimer's disease (AD). We evaluated 236 MCI patients with (n = 121) and without (n = 115) AD progression. Longitudinal MRI-based hippocampal volumes (HV) and entorhinal cortex (ERC) thickness were obtained. The Clinical Dementia Rating Sum of Boxes (CDR-SB) score was used to assess disease severity. We found a significant effect of APOE, gender, and clinical course (stable MCI versus MCI-AD progression) on HV. There was a significant effect of clinical course and APOE, but not gender, on ERC. Baseline HV and APOE4 status predicted MCI-AD progression in women. Baseline ERC and APOE4 status predicted MCI-AD progression in men. There were significant differences in CDR-SB scores between patients with and without MCI-AD progression, but not between males and females, or APOE4 carriers and non-carriers. HV, but not ERC, is strongly influenced by gender in MCI. The effects of gender and APOE4 on neuroimaging biomarkers have potentially important implications in the prediction of MCI-AD progression and should be taken into account in clinical trials.

Feasibility and acceptance of simultaneous amyloid PET/MRI.

Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. 100 subjects (age 70 ± 10yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [18F]florbetaben or [11C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31%, 45%, and 24% of the MCI subjects being categorized as "MCI-unlikely due to AD", "MCI due to AD-intermediate likelihood", and "MCI due to AD-high likelihood", respectively. 50% of the probable AD dementia patients were categorized as "High level of evidence of AD pathophysiological process", and 56% of the possible AD dementia patients as "Possible AD dementia - with evidence of AD pathophysiological process". With regard to the International Working Group 2 classification, 36 subjects had both positive diagnostic and progression biomarkers. The patient/caregiver survey revealed a gain of convenience in 88% of responders as compared to a theoretically separate PET and MR imaging. In the referrer survey, an influence of the combined amyloid-beta PET/MRI on the final diagnosis was reported by 82% of responders, with a referrer acceptance score of 3.7 ± 1.0 on a 5-point scale. Simultaneous amyloid PET/MRI is feasible and provides imaging biomarkers of all categories which are able to supplement the clinical diagnosis of MCI due to AD and that of AD dementia. Further, patient and referrer convenience is improved by this one-stop-shop imaging approach.

Reappraisal of epileptic pain as a rare symptom of seizures.

To draw attention to epileptic pain which is a rare seizure symptom mostly causing wrong diagnosis and delayed treatment. We present nine patients in whom pain was a prominent initial or early ictal symptom. We reviewed the records of 4736 patients, and found nine patients who had pain as an aura or an early prominent symptom of their seizures. Seizure semiology, EEG, and cranial imaging features were evaluated retrospectively. Age at seizure onset ranged from 6 months to 50 years, and the mean age during the study was 37.7±11.9 years. Pain was predominantly peripherally localized in four patients, whereas cephalic pain was detected in three patients, and abdominal pain was detected in two patients. Electroencephalography (EEG) revealed epileptic abnormalities on the temporoparietal and frontotemporal regions in three patients each. Photosensitive generalized epileptic discharges were detected in one and diffuse background slowing in the remaining two other patients. Electroencephalography abnormalities were lateralized to the contralateral site of the pain in four patients with strictly localized pain. Three patients revealed no abnormality on the cranial MR imaging, whereas others showed different types of abnormality such as heterotopias (n:1), mesial temporal lobe atrophy (n:1), white and gray matter sequela lesions (n:1), diffuse white matter lesion (n:1), chronic encephalomalacia and gliosis (n:1), and perivascular space dilatation (n:1). Epileptic pain is a neglected, but important, semiologic symptom with localization and lateralization value in the patients with somatosensorial seizures of parietal as well as temporal lobe origin. It occurs mainly as peripherally localized, cephalic, or abdominal pain and is usually associated with a symptomatic etiology. Awareness of epileptic pain is important to avoid misdiagnosis and delayed treatment.