Clinical–Pathological Agreement in Dementing Disorders: Embracing the Complexity

This editorial was written in response to: Giorelli M, Losignore NA, Bagnoli J, et al. The progression of posterior cortical atrophy to corticobasal syndrome: Lumping or splitting neurodegenerative diseases? Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D81G0JC

What Predicts Mortality in Essential Tremor? A Prospective, Longitudinal Study of Elders

Objective: Essential tremor (ET) is among the most common neurologic diseases. Although in the past it was considered a benign condition, recent research has demonstrated increased risk of mortality. To date, however, no studies have examined predictors of mortality in ET.Methods: In a longitudinal, prospective study of 141 elders with ET, we used Cox proportional-hazards models to estimate hazard ratios (HRs) for death.Results: The mean baseline age was 81.1 ± 8.8 years. During the follow-up interval, 27 (19.1%) died. Average time from baseline to death was 12.3 ± 8.7 months (range = 0.3–31.2). In univariate Cox regression models, older age (HR = 1.16, p < 0.001), lower Montreal Cognitive Assessment score (HR = 0.88, p = 0.004), higher Clinical Dementia Rating (CDR) score (HR = 4.53, p < 0.001), higher score on the Geriatric Depression scale (GDS) (HR = 1.07, p = 0.048), less balance confidence (HR = 0.98, p = 0.006), more falls (HR = 1.11, p = 0.003), and more tandem mis-steps (HR = 1.53, p = 0.004) were associated with increased risk of mortality. In the final multivariate Cox model, older age (HR = 1.14, p = 0.005), higher CDR score (HR = 3.80, p = 0.002) and higher GDS (HR = 1.11, p = 0.01) were independently associated with increased risk of mortality.Conclusions: This study highlights several independent predictors of mortality in elderly ET; clinicians should consider screening for depressive symptoms, assessing cognition and tracking CDR scores, and assessing balance while evaluating patients with ET

Differential medial temporal lobe morphometric predictors of item- and relational-encoded memories in healthy individuals and in individuals with mild cognitive impairment and Alzheimer's disease.

INTRODUCTION:Episodic memory processes are supported by different subregions of the medial temporal lobe (MTL). In contrast to a unitary model of memory recognition supported solely by the hippocampus, a current model suggests that item encoding engages perirhinal cortex, whereas relational encoding engages parahippocampal cortex and the hippocampus. However, this model has not been examined in the context of aging, neurodegeneration, and MTL morphometrics. METHODS:Forty-four healthy subjects (HSs) and 18 cognitively impaired subjects (nine mild cognitive impairment [MCI] and nine Alzheimer's disease [AD] patients) were assessed with the relational and item-specific encoding task (RISE) and underwent 3T magnetic resonance imaging. The RISE assessed the differential contribution of relational and item-specific memory. FreeSurfer was used to obtain measures of cortical thickness of MTL regions and hippocampus volume. RESULTS:Memory accuracies for both item and relational memory were significantly better in the HS group than in the MCI/AD group. In MCI/AD group, relational memory was disproportionately impaired. In HSs, hierarchical regressions demonstrated that memory was predicted by perirhinal thickness after item encoding, and by hippocampus volume after relational encoding (both at trend level) and significantly by parahippocampal thickness at associative recognition. The same brain morphometry profiles predicted memory accuracy in MCI/AD, although more robustly perirhinal thickness for item encoding (R2 = 0.31) and hippocampal volume and parahippocampal thickness for relational encoding (R2 = 0.31). DISCUSSION:Our results supported a model of episodic memory in which item-specific encoding was associated with greater perirhinal cortical thickness, while relational encoding was associated with parahippocampal thickness and hippocampus volume. We identified these relationships not only in HSs but also in individuals with MCI and AD. In the subjects with cognitive impairment, reductions in hippocampal volume and impairments in relational memory were especially prominent

Childhood Learning Disabilities and Atypical Dementia: A Retrospective Chart Review

Objective To further our understanding of the association between self-reported childhood learning disabilities (LDs) and atypical dementia phenotypes (Atypical Dementia), including logopenic primary progressive aphasia (L-PPA), Posterior Cortical Atrophy (PCA), and Dysexecutive-type Alzheimer’s Disease (AD). Methods This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social and Developmental History of the initial neuropsychological evaluation. Results 85 subjects (Typical AD n=68, Atypical AD n=17) were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3-128.4). All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math. Conclusions In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias

A Two-Study Comparison of Clinical and MRI Markers of Transition from Mild Cognitive Impairment to Alzheimer's Disease

A published predictor model in a single-site cohort study (questionable dementia, QD) that contained episodic verbal memory (SRT total recall), informant report of function (FAQ), and MRI measures was tested using logistic regression and ROC analyses with comparable measures in a second multisite cohort study (Alzheimer's Disease Neuroimaging Initiative, ADNI). There were 126 patients in QD and 282 patients in ADNI with MCI followed for 3 years. Within each sample, the differences in AUCs between the statistical models were very similar. Adding hippocampal and entorhinal cortex volumes to the model containing AVLT/SRT, FAQ, age and MMSE increased the area under the curve (AUC) in ADNI but not QD, with sensitivity increasing by 2% in ADNI and 2% in QD for a fixed specificity of 80%. Conversely, adding episodic verbal memory (SRT/AVLT) and FAQ to the model containing age, Mini Mental State Exam (MMSE), hippocampal and entorhinal cortex volumes increased the AUC in ADNI and QD, with sensitivity increasing by 17% in ADNI and 10% in QD for 80% specificity. The predictor models showed similar differences from each other in both studies, supporting independent validation. MRI hippocampal and entorhinal cortex volumes showed limited added predictive utility to memory and function measures

The Experience of Essential Tremor Caregivers: Burden and Its Correlates

BackgroundEssential tremor (ET) is associated with physical and cognitive impairments, as well as embarrassment, avoidance of social settings, and related difficulties that negatively impact the lives of patients. In similar disease contexts, burden on friends and relatives acting as caregivers has been noted and has well-documented implications. There has been no study examining caregiver burden related to ET.MethodsData were gathered from 55 ET participants enrolled in a clinical study and their caregivers. The Zarit Burden Interview was used to assess caregiver burden. To assess clinical features that may be associated with burden, we collected several variables including the Montreal Cognitive Assessment, self-reported tremor disability, a videotaped neurological examination, questionnaires assessing ET participants’ suffering, caregivers’ perceptions of that suffering, and both caregiver and ET participant depressive symptoms. Spearman’s correlations were performed between caregiver burden and clinical features, and we created a multivariate linear regression model predicting caregiver burden.ResultsMany ET caregivers provide little to no care and experience little to no burden. However, some caregivers (11%) provide over 25 h of care/week, and 13% experience high levels of burden. Caregivers most commonly provided assistance with writing and cooking. Increased burden was associated with the ET participants’ decreased cognition, more caregiving tasks, more hours/week of caregiving activities, a longer duration of care, more ET participant falls/year, more medications taken by the ET participant, and more depressive symptoms in both the ET participant and the caregiver (all p < 0.05). ET participants’ suffering and their caregivers’ perceptions of suffering were both associated with increased burden. Neither tremor severity score nor self-reported tremor disability score was associated with increased caregiver burden. Using a multivariate linear regression model, we found that caregivers’ increased perception of their partners’ suffering was the best predictor of caregiver burden.ConclusionWhile not all relatives and friends of ET patients provide extensive care or experience high burden, there is a group reporting high levels of caregiver burden that requires the attention and counseling of clinicians. This burden is associated with primarily non-tremor symptoms of ET and with caregivers’ perception that their partners are suffering

Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome

OBJECTIVE: To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). METHODS: This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. RESULTS: Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale-2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). CONCLUSIONS: In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%)

Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis

Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes. Methods: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment

Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer’s disease

Anosognosia for memory loss is a common feature of Alzheimer’s disease (AD). Recent theories have proposed that anosognosia, a disruption in awareness at a global level, may reflect specific deficits in self-monitoring, or local awareness. Though anosognosia for memory loss has been shown to relate to memory self-monitoring, it is not clear if it relates to self-monitoring deficits in other domains (i.e., motor). The current study examined this question by analyzing the relationship between anosognosia for memory loss, memory monitoring, and motor monitoring in 35 individuals with mild to moderate AD. Anosognosia was assessed via clinical interview before participants completed a metamemory task to measure memory monitoring, and a computerized agency task to measure motor monitoring. Cognitive and psychological measures included memory, executive functions, and mood. Memory monitoring was associated with motor monitoring; however, anosognosia was associated only with memory monitoring, and not motor monitoring. Cognition and mood related differently to each measure of self-awareness. Results are interpreted within a hierarchical model of awareness in which local self-monitoring processes are associated across domain, but appear to only contribute to a global level awareness in a domain-specific fashion

1-Ethyl 2-methyl 3,4-bis(acetyloxy)pyrrolidine-1,2-dicarboxylate: crystal structure, Hirshfeld surface analysis and computational chemistry

The title compound, C13H19NO8, is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C—C bond; the Cm—Ca—Ca—Cme torsion angle is 38.26 (15)° [m = methyl­carboxyl­ate, a = acet­yloxy and me = methyl­ene]. While the N-bound ethyl­carboxyl­ate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supra­molecular double-layers are formed by weak methyl- and methyl­ene-C—H...O(carbon­yl) inter­actions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional inter­actions between them. The Hirshfeld surface is dominated by H...H (55.7%) and H...C/C...H (37.0%) contacts; H...H contacts are noted in the inter-double-layer region. The inter­action energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal