Towards validation in clinical routine: a comparative analysis of visual MTA ratings versus the automated ratio between inferior lateral ventricle and hippocampal volumes in Alzheimer's disease diagnosis.

PURPOSE: To assess the performance of the inferior lateral ventricle (ILV) to hippocampal (Hip) volume ratio on brain MRI, for Alzheimer's disease (AD) diagnostics, comparing it to individual automated ILV and hippocampal volumes, and visual medial temporal lobe atrophy (MTA) consensus ratings. METHODS: One-hundred-twelve subjects (mean age ± SD, 66.85 ± 13.64 years) with varying degrees of cognitive decline underwent MRI using a Philips Ingenia 3T. The MTA scale by Scheltens, rated on coronal 3D T1-weighted images, was determined by three experienced radiologists, blinded to diagnosis and sex. Automated volumetry was computed by icobrain dm (v. 5.10) for total, left, right hippocampal, and ILV volumes. The ILV/Hip ratio, defined as the percentage ratio between ILV and hippocampal volumes, was calculated and compared against a normative reference population (n = 1903). Inter-rater agreement, association, classification accuracy, and clinical interpretability on patient level were reported. RESULTS: Visual MTA scores showed excellent inter-rater agreement. Ordinal logistic regression and correlation analyses demonstrated robust associations between automated brain segmentations and visual MTA ratings, with the ILV/Hip ratio consistently outperforming individual hippocampal and ILV volumes. Pairwise classification accuracy showed good performance without statistically significant differences between the ILV/Hip ratio and visual MTA across disease stages, indicating potential interchangeability. Comparison to the normative population and clinical interpretability assessments showed commensurability in classifying MTA "severity" between visual MTA and ILV/Hip ratio measurements. CONCLUSION: The ILV/Hip ratio shows the highest correlation to visual MTA, in comparison to automated individual ILV and hippocampal volumes, offering standardized measures for diagnostic support in different stages of cognitive decline.

Plasma repressor element 1-silencing transcription factor levels are decreased in patients with Alzheimer's disease.

BACKGROUND: Repressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer's disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy. METHODS: Participants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis. RESULTS: The plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02). CONCLUSION: The plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

Validity and reliability of the medial temporal lobe atrophy scale in a memory clinic population.

BACKGROUND: Visual rating of medial temporal lobe atrophy (MTA) is often performed in conjunction with dementia workup. Most prior studies involved patients with known or probable Alzheimer's disease (AD). This study investigated the validity and reliability of MTA in a memory clinic population. METHODS: MTA was rated in 752 MRI examinations, of which 105 were performed in cognitively healthy participants (CH), 184 in participants with subjective cognitive impairment, 249 in subjects with mild cognitive impairment, and 214 in patients with dementia, including AD, subcortical vascular dementia and mixed dementia. Hippocampal volumes, measured manually or using FreeSurfer, were available in the majority of cases. Intra- and interrater reliability was tested using Cohen's weighted kappa. Correlation between MTA and quantitative hippocampal measurements was ascertained with Spearman's rank correlation coefficient. Moreover, diagnostic ability of MTA was assessed with receiver operating characteristic (ROC) analysis and suitable, age-dependent MTA thresholds were determined. RESULTS: Rater agreement was moderate to substantial. MTA correlation with quantitative volumetric methods ranged from -0.20 (p< 0.05) to -0.68 (p < 0.001) depending on the quantitative method used. Both MTA and FreeSurfer are able to distinguish dementia subgroups from CH. Suggested age-dependent MTA thresholds are 1 for the age group below 75 years and 1.5 for the age group 75 years and older. CONCLUSIONS: MTA can be considered a valid marker of medial temporal lobe atrophy and may thus be valuable in the assessment of patients with cognitive impairment, even in a heterogeneous patient population.

Pre-stroke cognitive impairment is associated with vascular imaging pathology: a prospective observational study.

BACKGROUND: Chronic brain pathology and pre-stroke cognitive impairment (PCI) is predictive of post-stroke dementia. The aim of the current study was to measure pre-stroke neurodegenerative and vascular disease burden found on brain MRI and to assess the association between pre-stroke imaging pathology and PCI, whilst also looking for potential sex differences. METHODS: This prospective brain MRI cohort is part of the multicentre Norwegian cognitive impairment after stroke (Nor-COAST) study. Patients hospitalized with acute ischemic or hemorrhagic stroke were included from five participating stroke units. Visual rating scales were used to categorize baseline MRIs (N = 410) as vascular, neurodegenerative, mixed, or normal, based on the presence of pathological imaging findings. Pre-stroke cognition was assessed by interviews of patients or caregivers using the Global Deterioration Scale (GDS). Stroke severity was assessed with the National Institute of Health Stroke Scale (NIHSS). Univariate and multiple logistic regression analyses were performed to investigate the association between imaging markers, PCI, and sex. RESULTS: Patients' (N = 410) mean (SD) age was 73.6 (±11) years; 182 (44%) participants were female, the mean (SD) NIHSS at admittance was 4.1 (±5). In 68% of the participants, at least one pathological imaging marker was found. Medial temporal lobe atrophy (MTA) was present in 30% of patients, white matter hyperintensities (WMH) in 38% of patients and lacunes in 35% of patients. PCI was found in 30% of the patients. PCI was associated with cerebrovascular pathology (OR 2.5; CI = 1.4 to 4.5, p = 0.001) and mixed pathology (OR 3.4; CI = 1.9 to 6.1, p = 0.001) but was not associated with neurodegeneration (OR 1.0; CI = 0.5 to 2.2; p = 0.973). Pathological MRI markers, including MTA and lacunes, were more prevalent among men, as was a history of clinical stroke prior to the index stroke. The OR of PCI for women was not significantly increased (OR 1.2; CI = 0.8 to 1.9; p = 0.3). CONCLUSIONS: Pre-stroke chronic brain pathology is common in stroke patients, with a higher prevalence in men. Vascular pathology and mixed pathology are associated with PCI. There were no significant sex differences for the risk of PCI. TRIAL REGISTRATION: NCT02650531 , date of registration: 08.01.2016.

Neuropsychological and neuroimaging assessments of early cognitive impairment in patients after mild ischemic stroke and transient ischemic attack.

This study aimed to identify markers of early cognitive impairment after acute mild ischemic cerebrovascular disease. To further explore the relationship between neuroimaging markers of vascular and neurodegenerative injuries and post-stroke cognitive impairment, 86 patients with transient ischemic attack/acute mild ischemic stroke were recruited. Demographic information, clinical data, stroke scale scores (Modified Rankin Scale, National Institutes of Health Stroke Scale), and neuroimaging parameters (medial temporal lobe atrophy, global cortical atrophy, white matter hyperintensities, location and number of acute infarcts) were collected. All participants underwent neuropsychological evaluation at the time of discharge. The neurocognitive assessment was conducted using the Montreal Cognitive Assessment-Basic and Trail-Making Test A. It was found that low Montreal Cognitive Assessment-Basic scores were associated with global cortical atrophy and lower education levels. The completion time on the Trail-Making Test A was significantly correlated with medial temporal lobe atrophy and less education. It is concluded that global cortical atrophy and lower education levels can be used as rapid indicators of early cognitive impairment in patients after a transient ischemic attack and acute mild ischemic stroke. Medial temporal lobe atrophy also appears to be associated with mental processing speed in patients after a transient ischemic attack and acute mild ischemic stroke.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Medial Temporal Lobe Atrophy is Related to Learning Strategy Changes in Amnestic Mild Cognitive Impairment.

OBJECTIVE: Deficits in the semantic learning strategy were observed in subjects with amnestic mild cognitive impairment (aMCI) in our previous study. In the present study, we explored the contributions of executive function and brain structure changes to the decline in the semantic learning strategy in aMCI. METHODS: A neuropsychological battery was used to test memory and executive function in 96 aMCI subjects and 90 age- and gender-matched healthy controls (HCs). The semantic clustering ratio on the verbal learning test was calculated to evaluate learning strategy. Medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) were measured on MRI with the MTA and Fazekas visual rating scales, respectively. RESULTS: Compared to HCs, aMCI subjects had poorer performance in terms of memory, executive function, and the semantic clustering ratio (P < .001). In aMCI subjects, no significant correlation between learning strategy and executive function was observed. aMCI subjects with obvious MTA demonstrated a lower semantic clustering ratio than those without MTA (P < .001). There was no significant difference in the learning strategies between subjects with high-grade WMH and subjects with low-grade WMH. CONCLUSION: aMCI subjects showed obvious impairment in the semantic learning strategy, which was attributable to MTA but independent of executive dysfunction and subcortical WMH. These findings need to be further validated in large cohorts with biomarkers identified using volumetric brain measurements. (JINS, 2019, 25, 706-717).

Preexisting Cerebral Abnormalities and Functional Outcomes After Acute Ischemic Stroke.

PURPOSE: The aim of this study was to investigate the association between preexisting cerebral abnormalities in patients with acute ischemic stroke upon their functional outcomes. METHODS: We recruited 272 patients with first-ever acute ischemic stroke. Cerebral abnormalities on magnetic resonance imaging included infarction, silent brain infarcts (SBI), enlarged perivascular spaces, white matter lesions (WMLs), global brain atrophy, and medial temporal lobe atrophy (MTLA). Functional outcomes were assessed using the instrumental activities of daily living (IADL) scale and basic activities of daily living (BADL) scale, at 3 and 6 months after the index stroke. RESULTS: Two hundred and fifty patients completed the 3-month follow-up and 246 patients completed the 6-month follow-up. Univariate analyses showed that patients with poor IADL and BADL were older, more likely to be men, had higher National Institutes of Health Stroke Scale (NIHSS) score on admission, more frequent atrial fibrillation, and large artery atherosclerosis subtypes. They also had more frequent cortical infarcts, subcortical infarcts, infratentorial infarcts, larger infarct volume, more frequent presence of SBI, severe WMLs, and MTLA. In multiple regression analyses, NIHSS on admission, subcortical region infarct and MTLA were significant predictors of poor IADL at 3 months. National Institutes of Health Stroke Scale on admission, SBI and MTLA were significant predictors of poor IADL at 6 months. National Institutes of Health Stroke Scale on admission and MTLA were significant predictors of poor BADL at 3 months. National Institutes of Health Stroke Scale on admission and SBI were significant predictors of poor BADL at 6 months. CONCLUSIONS: In patients with acute ischemic stroke, the presence of SBI, and severe MTLA represent significant predictors of poorer functional outcomes, thus highlighting the importance of preexisting cerebral abnormalities.

Modified Visual Magnetic Resonance Rating Scale for Evaluation of Patients with Forgetfulness.

BACKGROUND: As cognitive impairment increases with age, sulcal atrophy (SA) and the enlargement of the ventricles also increase. Considering the measurements on the previously proposed visual scales, a new scale is proposed in this study that allows us to evaluate the atrophy, white matter hyperintensities (WMHs), basal ganglia infarct (BGI), and infratentorial infarct (ITI) together. Our aim of this study is to propose a practical and standardized MRI for the clinicians to be used in daily practice. METHODS: A total of 97 patients older than 60 years and diagnosed with depression or Alzheimer's disease (AD) are included. Cranial MRI, Mini Mental State Examination (MMSE), detailed neuropsychometric tests, and depression scales are applied to all patients. The SA, ventricular atrophy (VA), medial temporal lobe atrophy (MTA), periventricular WMH (PWMH), subcortical WMH (SCWMH), BGI, and ITI are scored according to the scale. The total score is also recorded. RESULTS: The average age of the patients was 74.53, and the mean MMSE score was 22.7 in the degenerative group and 27.8 in the non-degenerative group. Among the patients, 50 were diagnosed with AD. All parameters significantly increased with age. In the degenerative group, SA, VA, MTA, PWMH, SCWMH, and total scores were found to be significantly higher. Sensitivities of VA, PWMH, SCWMH, and total scores, as well as both sensitivity and specificities of MTA score, were observed to be high. When they were combined, sensitivities and specificities were found to be high. CONCLUSION: The scale is observed to be predictive in discriminating degenerative and non-degenerative processes. This discrimination is important, particularly in depressive patients complaining of forgetfulness.

CONTEXTE: Dans la mesure où les manifestations de déficience cognitive ont tendance à augmenter avec le vieillissement, on constate aussi une augmentation de l'atrophie des sillons du cortex cérébral et de l'élargissement des ventricules cérébraux. En tenant compte des mesures propres à des échelles visuelles utilisées antérieurement, cette étude entend proposer une nouvelle échelle nous permettant d'évaluer en même temps des cas d'atrophie ainsi que la présence d'hyperdensités de la substance blanche, d'anomalies des ganglions de la base et d'infarctus affectant l'étage sus-tentoriel (infratentorial infarcts). L'objectif de cette étude est donc de proposer un examen d'IRM pratique et standardisé pouvant être utilisé quotidiennement par les cliniciens. MÉTHODES: Nous avons inclus dans cette étude 97 patients âgés de plus de 60 ans qui étaient soit atteints de dépression, soit de la maladie d'Alzheimer. Tous les patients recrutés ont été soumis à des examens d'IRM crâniens, au test de Folstein (ou MMSE), à un ensemble de tests neuro-psychométriques approfondis et à des échelles diagnostiques permettant d'évaluer la dépression. L'incidence de l'atrophie des sillons du cortex cérébral, de la région ventriculaire, du lobe temporal médian, des régions péri-ventriculaire et sous-corticale et de la substance blanche qu'elles contiennent, d'anomalies affectant les ganglions de base et d'infarctus à l'étage sus-tentoriel a été ainsi mesurée selon notre échelle. Le score total obtenu a aussi été enregistré. RÉSULTATS: L'âge moyen des patients était de 74,53 ans. Leur score moyen au test de Folstein était de 22,7 dans le cas du groupe de patients atteints d'une maladie dégénérative et de 27,8 dans le cas du groupe de patients n'étant pas atteints par ce type de maladie. Fait à noter, cinquante patients avaient reçu un diagnostic de maladie d'Alzheimer. Tous les paramètres évalués ont augmenté de façon notable avec l'âge. Ainsi, tant les scores obtenus dans le cas de l'atrophie des sillons du cortex cérébral, de celle affectant le lobe temporal médian, la région ventriculaire, la région péri-ventriculaire, la région sous-corticale que les scores totaux se sont révélés nettement plus élevés au sein du groupe de patients atteints d'une maladie dégénérative. La sensibilité des scores totaux et des scores évaluant l'atrophie des régions vasculaire, péri-vasculaire et sous-corticale, de même que la sensibilité et la spécificité des scores évaluant l'atrophie du lobe temporal médian, se sont révélées élevées. Lorsque combinées, la sensibilité et la spécificité sont apparues élevées. CONCLUSIONS: Notre échelle possède un caractère prédictif en ce qu'elle permet d'établir une distinction entre les processus dégénératifs et les processus non-dégénératifs. Cette capacité est particulièrement importante dans le cas de patients dépressifs qui se plaignent de perte de mémoire.

A new age-related cutoff of medial temporal atrophy scale on MRI improving the diagnostic accuracy of neurodegeneration due to Alzheimer's disease in a Chinese population.

BACKGROUND: Visual rating scales are still the most popular tools in assessing atrophy degrees of whole brain and lobes. However, the false negative rate of the previous cutoff score of visual rating scales was relatively high for detecting dementia of Alzheimer's type (DAT). This study aimed to evaluate the diagnostic value of new cutoffs of visual rating scales on magnetic resonance imaging for discriminating DAT in a Chinese population. METHODS: Out of 585 enrolled subjects, 296 participants were included and diagnosed as normal cognition (NC)(n = 87), 138 diagnosed as amnestic mild cognitive impairment (aMCI), and 71 as dementia of Alzheimer's type (DAT). Receiver operating characteristic (ROC) curve analyses were used to calculate the diagnostic value of visual rating sales (including medial temporal atrophy (MTA), posterior atrophy rating scale (PA),global cortical atrophy scale (GCA) and medial temporal-lobe atrophy index (MTAi))for detecting NC from DAT . RESULTS: Scores of MTA correlated to age and Mini-mental state examination score. When used to detect DAT from NC, the MTA showed highest diagnostic value than other scales, and when the cutoff score of 1.5 of MTA scale, it obtained an optimal sensitivity (84.5%) and specificity (79.1%) respectively, with a 15.5% of false negative rate. Cutoff scores and diagnostic values were calculated stratified by age. For the age ranges 50-64, 65-74, 75-84 years, the following cut-offs of MTA should be used, ≥1.0(sensitivity and specificity were 92.3 and 68.4%), ≥1.5(sensitivity and specificity were 90.4 and 85.2%), ≥ 2.0(sensitivity and specificity were 70.8 and 82.3%) respectively. All of the scales showed relatively lower diagnostic values for discriminating aMCI from NC. CONCLUSIONS: The new age-based MTA cutoff showed better diagnostic accuracy for detecting DAT than previous standard, the list of practical cut-offs proposed here might be useful in clinical practice.

Validation of an Magnetic Resonance Imaging Acquisition and Review Protocol for Alzheimer's Disease and Related Disorders.

PURPOSE: Magnetic resonance imaging (MRI) of the brain allows for the identification of structural lesions typical of Alzheimer's disease (AD), the main cause of dementia. However, to have a clinical impact, it is imperative that acquisition and reporting of this MRI-based evidence be standardized, ensuring the highest possible reliability and reproducibility. Our objective was to validate a systematic radiological MRI acquisition and review process in the context of AD. METHODS: We included 100 individuals with a suspicion of dementia due to AD for whom MRI were acquired using our proposed protocol of clinically achievable acquisitions and used a unified reading grid to gather semi-quantitative evidence guiding diagnostic. MRIs were read by 3 raters with different experience levels. Interrater reliability was measured using Cohen's kappa statistic. RESULTS: Interrater reliability average for lesions occupying space, hemorrhage, or ischemia, was respectively 0.754, 0.715, and 0.501. Average reliability of white matter hyperintensity burden (Fazekas), global cortical atrophy, and temporal lobe atrophy (Scheltens) scales was 0.687, 0.473, and 0.621 (right)/0.599 (left), respectively. The kappas for regional cortical atrophy (frontal, parietal, occipital, temporal, and posterior cingulum) varied from 0.281-0.678. The average MRI reading time varied between 1.43-5.22 minutes. CONCLUSIONS: The presence of space occupying lesions, hemorrhagic or ischemic phenomena, and radiological scales have a good interrater reproducibility in MRI. Coupled with standardized acquisitions, such a protocol should be used when evaluating possible dementias, especially those due to probable AD.

Medial temporal lobe atrophy is independently associated with behavioural and psychological symptoms in Alzheimer's disease.

AIM: Evidence describing the contribution of cerebral white matter disease and medial temporal atrophy (MTA) to behavioural and psychological symptoms of dementia (BPSD) has been conflicting. The aim of this study was to assess the relationship of white matter hyperintensities (WMH) and MTA observed on magnetic resonance imaging with BPSD among patients with Alzheimer's disease. METHODS: In a cross-sectional study of a prospective cohort of patients attending a memory clinic, 46 patients with probable Alzheimer's disease (mean age: 72.38 ± 7.05 years) were studied. Sociodemographic, cognitive, and BPSD data were collected. BPSD were assessed using the Neuropsychiatric Inventory. Magnetic resonance imaging, WMH, and MTA were rated using the Scheltens scales for the assessment of signal hyperintensities and atrophy of medial temporal lobes. For multivariate analysis, two binary logistic regression analyses were carried out, with presence or absence of each BPSD as the dependent variable and with WMH or MTA as the predictor variable. Results of the logistic regression were analyzed to see if the significance of the WMH or MTA score was maintained in a model that factored in other possible confounding variables identified in univariate analysis. RESULTS: The results of binary logistic regression analysis showed that in models that accounted for confounding variables, increased total MTA was significantly associated with apathy (odds ratio = 1.605, adjusted P = 0.042) and disinhibition (odds ratio = 0.607, adjusted P = 0.042). WMH measures did not significantly predict any BPSD item. CONCLUSIONS: These findings indicate that MTA potentially contributes to the aetiology of BPSD, and they provide evidence to support the hypothesis that Alzheimer's disease pathology itself can contribute to BPSD.

Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort: gender-corrected and education-corrected normative data.

OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort. METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile. RESULTS: Most 75-year-old individuals had MTA score ≤2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline. CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of ≥2 is abnormal for low-educated women and a score of ≥2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later. KEY POINTS: • Gender and education are confounders for MTA grading. • We suggest cut-off values for 75-year-olds, taking gender and education into account. • Males have higher MTA scores than women. • Higher MTA scores are associated with worse cognitive performance.

Exploring the Spectrum of Subcortical Hyperintensities and Cognitive Decline.

White matter hyperintensities (WMHs) include periventricular WMH (pvWMH) and deep WMH. When hyperintensities in the basal ganglia or brainstem are included, the collective term is subcortical hyperintensities. Both WMH and medial temporal lobe atrophy (MTA) are risk factors for cognitive decline. This prospective study enrolled participants aged 50-85 years and followed their neuropsychological assessments annually for 2 years to explore the interactive effects of WMH and MTA on longitudinal clinical decline. Brain MRI was performed at the beginning of enrollment. Of the 200 participants, 57 were "normal" individuals, 40 had dysexecutive mild cognitive impairment, 53 had amnestic mild cognitive impairment, and 50 had Alzheimer's disease (AD). Overall, MTA significantly correlated with pvWMH (p=0.0004) but not with deep WMH, as defined by criteria using the Scheltens' Scale. Total Scheltens' score was specifically associated with the domain of semantic fluency (beta=-0.4, 95% CI=-0.7 to -0.2, p=0.002), which remained significant when adjusting for MTA (beta=-0.3, 95% CI=-0.5 to -0.1, p=0.017). The pvWMH was significantly higher in AD subjects than in normal control subjects (beta=0.3, 95% CI=0.1 to 0.4, p=0.001), especially the periventricular occipital caps (beta=0.2, 95% CI=0.1 to 0.3, p=0.0003). Cox proportional hazards model showed that the periventricular bands (PVB) predicted 1-year clinical decline (hazard ratio [HR]=5.3, 95% CI=1.8 to 15.7, p=0.002), which remained significant when further adjusting for MTA (HR=4.0, 95% CI=1.3 to 12.1, p=0.013). In summary, pvWMH, especially the occipital caps, was correlated with MTA and the AD subgroup. Assessment of semantic fluency may be useful for the clinical evaluation of the degree of subcortical hyperintensity burden. Visual rating of PVB could be an independent predictor for 1-year clinical decline.

Cerebral small vessel disease, medial temporal lobe atrophy and cognitive status in patients with ischaemic stroke and transient ischaemic attack.

BACKGROUND AND PURPOSE: Small vessel disease (SVD) and Alzheimer's disease (AD) are two common causes of cognitive impairment and dementia, traditionally considered as distinct processes. The relationship between radiological features suggestive of AD and SVD was explored, and the association of each of these features with cognitive status at 1 year was investigated in patients with stroke or transient ischaemic attack. METHODS: Anonymized data were accessed from the Virtual International Stroke Trials Archive (VISTA). Medial temporal lobe atrophy (MTA; a marker of AD) and markers of SVD were rated using validated ordinal visual scales. Cognitive status was evaluated with the Mini Mental State Examination (MMSE) 1 year after the index stroke. Logistic regression models were used to investigate independent associations between (i) baseline SVD features and MTA and (ii) all baseline neuroimaging features and cognitive status 1 year post-stroke. RESULTS: In all, 234 patients were included, mean (±SD) age 65.7 ± 13.1 years, 145 (62%) male. Moderate to severe MTA was present in 104 (44%) patients. SVD features were independently associated with MTA (P < 0.001). After adjusting for age, sex, disability after stroke, hypertension and diabetes mellitus, MTA was the only radiological feature independently associated with cognitive impairment, defined using thresholds of MMSE ≤ 26 (odds ratio 1.94; 95% confidence interval 1.28-2.94) and MMSE ≤ 23 (odds ratio 2.31; 95% confidence interval 1.48-3.62). CONCLUSION: In patients with ischaemic cerebrovascular disease, SVD features are associated with MTA, which is a common finding in stroke survivors. SVD and AD type neurodegeneration coexist, but the AD marker MTA, rather than SVD markers, is associated with post-stroke cognitive impairment.

Visual Evaluation of Medial Temporal Lobe Atrophy as a Clinical Marker of Conversion from Mild Cognitive Impairment to Dementia and for Predicting Progression in Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease.

BACKGROUND/AIMS: To evaluate whether visual assessment of medial temporal lobe atrophy (vaMTA) can predict 2-year conversion from mild cognitive impairment (MCI) to dementia and progression of MCI and Alzheimer's disease dementia as measured by the Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB). METHODS: vaMTA was performed in 94 patients with MCI according to the Winblad criteria and in 124 patients with AD according to ICD-10 and NINCDS-ADRDA criteria. Demographic data, the Consortium to Establish a Registry for Alzheimer's Disease 10-word delayed recall, APOE ɛ4 status, Cornell Scale for Depression in Dementia, and comorbid hypertension were used as covariates. RESULTS: vaMTA was associated with MCI conversion in an unadjusted model but not in an adjusted model (p = 0.075), where delayed recall and APOE ɛ4 status were significant predictors. With CDR-SB change as the outcome, an interaction between vaMTA and diagnosis was found, but in the adjusted model only delayed recall and age were significant predictors. For vaMTA below 2, the association between vaMTA and CDR-SB change differed between diagnostic groups. Similar results were found based on a trajectory analysis. CONCLUSION: In adjusted models, memory function, APOE ɛ4 status and age were significant predictors of disease progression, not vaMTA. The association between vaMTA and CDR-SB change was different in patients with MCI and Alzheimer's disease dementia.

The impact of automated hippocampal volumetry on diagnostic confidence in patients with suspected Alzheimer's disease: A European Alzheimer's Disease Consortium study.

INTRODUCTION: Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear. METHODS: Three hundred fifty-six patients, under clinical evaluation for cognitive impairment, with suspected AD and Mini-Mental State Examination ≥20, were recruited across 17 European memory clinics. After the traditional diagnostic workup, diagnostic confidence of AD pathology (DCAD) was estimated by the physicians in charge. The latter were provided with the results of automated hippocampal volumetry in standardized format and DCAD was reassessed. RESULTS: An increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of -8.0% (95% credible interval: [-11.5, -5.0]). Automated hippocampal volumetry showed a statistically significant impact on DCAD beyond the contributions of neuropsychology, 18F-fluorodeoxyglucose positron emission tomography/single-photon emission computed tomography, and cerebrospinal fluid markers (-8.5, CrI: [-11.5, -5.6]; -14.1, CrI: [-19.3, -8.8]; -10.6, CrI: [-14.6, -6.1], respectively). DISCUSSION: There is a measurable effect of hippocampal volume on DCAD even when used on top of the traditional diagnostic workup.

Dementia after Three Months and One Year from Stroke: New Onset or Previous Cognitive Impairment?

OBJECTIVE: Stroke is an important risk factor for dementia, but the exact mechanism involved in cognitive decline remains unclear. METHODS: Patients were divided into 2 groups: poststroke dementia group (PSD) and poststroke nondementia group (PSND). Variables and neuroradiological hallmarks were compared between 2 groups at 3 months (114 subjects) and 1 year (105 subjects) after stroke. RESULTS: Older age (OR 1.11, 95% CI 1.0-1.2; P < .05), education (OR .6, 95% CI .4-.8; P < .05), prestroke IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly; OR .78, 95% CI .1-5.9; P < .05), premorbid apathy (OR 2.03, 95% CI 1.1-3.7; P < .05), and medial temporal lobe atrophy (MTLA) (OR 6.14, 95% CI 1.4-26.2; P < .05) were independently associated with PSD at 3 months after a cerebrovascular event, whereas at 1-year follow-up older age (OR 1.1, 95% CI 1.0-1.2; P < .05), prestroke IQCODE (OR .05, 95% CI .0-.9; P < .05), MTLA (OR 1.3, 95% CI 1.0-1.6; P < .05), and APACHE II (Acute Physiology and Chronic Health Evaluation; OR .6, 95% CI .4-.9; P < .05) were independently associated with PSD. CONCLUSIONS: Acute cerebrovascular disease could not be the only one mechanism explaining PSD. Neurodegenerative pathology must be taken into account.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.

White matter hyperintensities and cognitive impairment during electroconvulsive therapy in severely depressed elderly patients.

OBJECTIVE: Transient cognitive impairment during electroconvulsive therapy (ECT) can be a reason to discontinue ECT in depressed elderly patients. We hypothesized that both white matter hyperintensities and medial temporal lobe atrophy contribute to transient cognitive impairment during ECT. METHODS: In 81 elderly patients with depression, magnetic resonance images (MRI) were recorded before ECT. We rated white matter hyperintensities (WMH) with the Age-Related White Matter Changes scale (ARWMC). Cognitive impairment during ECT was measured weekly with the Mini Mental State Examination (MMSE), 2 days after each session. RESULTS: The mean MMSE score at baseline for all patients was 25.5 points, the lowest MMSE score during ECT was 23.3 points, and the mean MMSE score after ECT was 26.3 points. Stratification for the ECT method showed no significant difference in the lowest MMSE scores of patients with or without WMH, receiving unilateral ECT (22.5 points versus 23.9 points). There was a difference in the lowest MMSE scores in patients who switched from unilateral ECT to bilateral ECT (18.7 points in patients with WMH versus 22.0 points in patients without WMH). CONCLUSION: Depressed elderly patients with WMH who receive bilateral ECT are at increased risk of transient cognitive impairment. Our findings show, however, that cognitive impairment improves when ECT is continued. This implies that ECT does not have to be discontinued when patients experience transient cognitive impairment during ECT.