Jagan A. Pillai

Association of Crossword Puzzle Participation with Memory Decline in Persons Who Develop Dementia

Participation in cognitively stimulating leisure activities such as crossword puzzles may delay onset of the memory decline in the preclinical stages of dementia, possibly via its effect on improving cognitive reserve. We followed 488 initially cognitively intact community residing individuals with clinical and cognitive assessments every 12-18 months in the Bronx Aging Study. We assessed the influence of crossword puzzle participation on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model. Crossword puzzle participation at baseline delayed onset of accelerated memory decline by 2.54 years. Inclusion of education or participation in other cognitively stimulating activities did not significantly add to the fit of the model beyond the effect of puzzles. Our findings show that late life crossword puzzle participation, independent of education, was associated with delayed onset of memory decline in persons who developed dementia. Given the wide availability and accessibility of crossword puzzles, their role in preventing cognitive decline should be validated in future clinical trials.

Clinical Trials in Predementia Stages of Alzheimer Disease

Effective treatments of Alzheimer disease (AD) dementia are an urgent necessity. There is a growing consensus that effective disease-modifying treatment before the onset of clinical dementia and slowing the progression of mild symptoms are needed after recent setbacks in AD therapeutics. The identification of at-risk and preclinical AD populations is becoming important for targeting primary and secondary prevention clinical trials in AD. This article reviews the strategies and challenges in targeting at-risk and preclinical AD populations for a new generation of AD clinical trials. Design, outcome measures, and complexities in successfully completing a clinical trial targeting this population are reviewed.

Patients with epilepsy and psychogenic non-epileptic seizures: An inpatient video-EEG monitoring study

Seizure and EEG characteristics of patients with epilepsy and concomitant psychogenic non-epileptic seizures (PNES) were compared to age and sex matched controls with epilepsy alone in a retrospective case control study. 39 patients with clearly documented epileptic and non-epileptic events were compared to 78 age and sex matched controls, sequentially admitted for video-EEG monitoring with documentation of epilepsy alone. Frontal seizures were higher in prevalence in patients with PNES who had concomitant epilepsy (P<0.001), while temporal seizures were higher in prevalence in patients with epilepsy alone (P<0.04). On regression analysis, the odds of having a frontal seizure was found to be significantly lower in the epilepsy alone group compared to the epilepsy+PNES group (odds ratio 0.13, 95% CI, 0.033-0.51). This significant association between frontal lobe epilepsy and PNES may be related to misattribution of frontal seizures for PNES events, or may reflect frontal lobe cortical dysfunction in this subgroup.

Retinal Nerve Fiber Layer Thinning in Alzheimer’s Disease A Case–Control Study in Comparison to Normal Aging, Parkinson’s Disease, and Non-Alzheimer’s Dementia

Retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and macular volume (MV) utilizing spectral domain optical coherence tomography (SD-OCT) were compared among patients with Alzheimer’s disease (AD) dementia, non-Alzheimer’s disease (non-AD) dementia, amnestic mild cognitive impairment (aMCI), Parkinson’s disease (PD), and age- and sex-matched controls in a cross-sectional cohort study. A total of 116 participants were diagnosed and evaluated (21 AD, 20 aMCI, 20 non-AD, 20 PD, and 34 controls) after comprehensive neurological, neuropsychology, and magnetic resonance imaging (MRI) volumetric evaluations. Retinal nerve fiber layer thickness, GCL thickness, and MV were measured. Analysis of variance models were used to compare groups on MRI volumetric measures, cognitive test results, and SD-OCT measures. Associations between SD-OCT measures and other measures were performed using mixed-effect models. Spectral domain optical coherence tomography analysis of retinal markers, including RNFL thickness, GCL thickness, and MV, did not differ between amnestic MCI, AD dementia, PD, non-AD, dementia, and age- and sex-matched controls in a well-characterized patient cohort.

Higher education is not associated with greater cortical thickness in brain areas related to literacy or intelligence in normal aging or mild cognitive impairment.

Education may reduce risk of dementia through passive reserve, by increasing neural substrate. We tested the hypotheses that education is associated with thicker cortex and reduced rates of atrophy in brain regions related to literacy and intellectual ability. Healthy older adults and those with mild cognitive impairment were categorized into high (≥18 years) and low (≤13 years) education groups. Higher education was associated with thinner cortices in several areas, but one-year atrophy rates in these areas did not differ by education group. These results do not support a passive reserve model in which early-life education protects against dementia by increasing cortical thickness. Connectivity and synaptic efficiency or other lifestyle factors may more directly reflect cognitive reserve.

Clinical severity of Huntington's disease does not always correlate with neuropathologic stage

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by a triplet‐repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in HD. The brains of 24 patients with a clinical and genetic diagnosis of HD were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (stage 1–2; n = 7) or severe (stage 3–4; n = 17). Clinical severity was assessed on the basis of the Mini–Mental State Examination (MMSE; 0–30) and two Unified Huntingtons Disease Rating Scale (UHDRS) functional components: the Independence Scale (10–100) and the Total Functional Capacity (0–13). Mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death and less well educated. Despite obvious clinical and pathological differences between mild‐moderate and severe HD subjects at autopsy, mean MMSE scores of the two groups before death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores before death were low and not statistically significant. Our results suggest that the extent of striatal changes in HD may not always correlate with clinical disease severity as measured by UHDRS functional scales.

Treatment of Vascular Cognitive Impairment.

Opinion statementCerebrovascular disease (CVD) is an important cause of cognitive dysfunction and dementia. The term vascular cognitive impairment (VCI) is used to describe the entire spectrum of cognitive dysfunction—ranging from mild impairment to dementia—attributable to all forms of cerebrovascular disease. Accurate assessment and management of vascular risk factors are a top priority in the treatment of VCI, particularly early in the disease when prevention strategies may prove to be more effective. There are limited treatment options to improve cognition and function in VCI. Several acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine have been studied in large, well-designed trials. These agents are safe and provide modest cognitive benefits in vascular dementia (VaD) but have demonstrated inconsistent efficacy on functional measures. Other therapies, such as aspirin, calcium channel blockers, and vitamin supplementation, have less evidence to support their use in improving cognition in VCI. Although primary prevention trials suggest that treatment of hypertension, adherence to a Mediterranean diet, physical activity, and smoking cessation may reduce the risk of cognitive decline, there is limited evidence regarding these interventions in helping improve cognition in VCI. The pathophysiology and treatment of cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), cerebral amyloid angiopathy (CAA), and subcortical white matter disease (SWMD) deserves special consideration.

Sleep and Neurodegeneration: A Critical Appraisal

Sleep abnormalities are clearly recognized as a distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep-related symptoms has a positive impact on quality of life in patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes seen in common neurodegenerative diseases, with a focus on Alzheimer disease and synucleinopathies (ie, Parkinson disease, dementia with Lewy bodies, multiple system atrophy), that have been better studied. Sleep changes may also serve as markers to identify patients in the preclinical stage of some neurodegenerative disorders. A hypothetical model is postulated founded on the conjecture that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, could be a surrogate marker reflecting pathophysiological processes related to neurodegenerative disorders. This provides a clinical strategy for screening patients in the preclinical stages of neurodegenerative disorders to enable therapeutic trials to establish the efficacy of neuroprotective agents to prevent or delay the development of symptoms and functional decline. It is unclear if sleep disturbance directly impacts neurodegenerative processes or is a secondary outcome of neurodegeneration; this is an active area of research. The clinical importance of recognizing and managing sleep changes in neurodegenerative disorders is beyond doubt.

Impact of Alzheimer's Disease, Lewy Body and Vascular Co-Pathologies on Clinical Transition to Dementia in a National Autopsy Cohort.

Aims: We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimers disease (AD) on the rate of cognitive and functional decline and transition to dementia. Methods: In an autopsy sample of prospectively characterized subjects from the National Alzheimers Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups. Results: The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects. Conclusions: The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort.

Orbitofrontal cortex dysfunction in psychogenic non-epileptic seizures. A proposal for a two-factor model

Psychogenic nonepileptic seizures (PNES) often mimic epileptic seizures and occur in both people with and without epilepsy. Pathophysiology of conversion disorders such as PNES remains unclear though significant psychological, psychiatric and environmental factors have been correlated with a diagnosis of PNES. Many clinical signs that have been considered typical for PNES can also be found in frontal epileptic seizures. Given the resemblance of seizures and affective changes from Orbitofrontal cortical dysfunction to PNES like events and correlation of psychological and environmental stress to conversion disorders such as PNES, we propose a two-factor model for the pathogenesis of PNES. We hypothesize that patients with PNES could have a higher likelihood of having both Orbitofrontal cortical dysfunction and a history of psychological stressors rather than a higher likelihood of having either one or the other. We further explore the implications of this two-factor model, including possible therapies.