Charlene Hoffman-Snyder

Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes

Objective: To characterize the effects of cerebrovascular (CV) risk factors on preclinical memory decline in cognitively normal individuals at 3 levels of genetic risk for Alzheimer disease (AD) based on APOE genotype. Methods: We performed longitudinal neuropsychological testing on an APOE ε4 enriched cohort, ages 21–97. The long-term memory (LTM) score of the Auditory Verbal Learning Test (AVLT) was the primary outcome measure. Any of 4 CV risk factors (CVany), including hypercholesterolemia (CHOL), prior cigarette use (CIG), diabetes mellitus (DM), and hypertension (HTN), was treated as a dichotomized variable. We estimated the longitudinal effect of age using statistical models that simultaneously modeled the cross-sectional and longitudinal effects of age on AVLT LTM by APOE genotype, CVany, and the interaction between the two. Results: A total of 74 APOE ε4 homozygotes (HMZ), 239 ε4 heterozygotes (HTZ), and 494 ε4 noncarriers were included. APOE ε4 carrier status showed a significant quadratic effect with age-related LTM decline in all models as previously reported. CVany was associated with further longitudinal AVLT LTM decline in APOE ε4 carriers (p = 0.02), but had no effect in noncarriers. When ε4 HTZ and HMZ were considered separately, there was a striking effect in HMZ (p < 0.001) but not in HTZ. In exploratory analyses, significant deleterious effects were found for CIG (p = 0.001), DM (p = 0.03), and HTN (p = 0.05) in APOE ε4 carriers only that remained significant only for CIG after correction for multiple comparisons. Conclusion: CV risk factors influence age-related memory decline in APOE ε4 HMZ.

Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers

Background: Fibrillar amyloid deposition preferentially affects the frontal lobes, temporal pole/neocortex, and posterior cingulate by age 65 years in APOE ε4 carriers prior to the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), but is it impairing frontally mediated neuropsychological performance? Methods: A total of 71 ε4 homozygotes (HMZ), 194 ε4 heterozygotes (HTZ), and 356 ε4 noncarriers (NC) who did not differ significantly in mean age (56.6 years), years of education (15.6), gender (70% women), or follow-up duration (6.3 years) had neuropsychological testing every 2 years including the Auditory Verbal Learning Test (AVLT) and frontal/executive tasks sensitive to psychomotor speed, working memory, problem solving, and activity. A subset also received the Iowa Gambling Task (IGT). Findings were then tested in a clinical sample of 27 patients with incident MCI and AD. Results: APOE ε4 carriers had greater acceleration of decline (quadratic effect) than NC on the AVLT (p = 0.04) but not on any frontal test. APOE ε4 HMZ had greater velocity of decline (linear effects) than NC on all mental arithmetic tests: paced auditory serial attention task (PASAT) 3 second (p = 0.01) and 2 second (p = 0.004) versions; and Wechsler Adult Intelligence Scale–Revised arithmetic (p = 0.048). IGT performance did not differ between 12 ε4 HMZ, 27 ε4 HTZ, and 44 NC. Among 27 patients with incident MCI and AD, the PASAT showed progressive decline preceding diagnosis in 50%. Conclusions: No frontal cognitive effects were as robust as memory decline. APOE ε4 HMZ declined more quickly than NC on mental arithmetic tests related to frontal lobe–mediated working memory ability.

Clinical and Electrodiagnostic Findings in Copper Deficiency Myeloneuropathy

Introduction: Copper deficiency is an increasingly recognised cause of neurological impairment. This retrospective review highlights clinical and electrodiagnostic findings in patients diagnosed at our institution with copper deficiency. Methods: Clinical, radiographic and electrodiagnostic findings were reviewed in patients with evidence of copper deficiency. Patients with other potential causes of myelopathy or neuropathy were excluded. Results: The predominant clinical feature in all six patients was a sensory ataxia, resulting in marked gait unsteadiness. Nerve conduction studies and needle EMG were performed in all patients and revealed a mild to moderate distal, axonal, sensorimotor peripheral neuropathy. Median and tibial somatosensory evoked potentials were abnormal in all five patients in which it was performed, showing impaired conduction in central or proximal peripheral somatosensory pathways. Conclusions: This pattern of electrodiagnostic findings suggests that impairment in somatosensory pathways demonstrated by somatosensory evoked potential testing is the main cause of the sensory ataxia in patients with copper deficiency.

The neuropsychology of normal aging and preclinical Alzheimer's disease.

A National Institute on Aging–sponsored work group on preclinical Alzheimers disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.

Skin biopsy for diagnosis of small fiber neuropathy: a critically appraised topic.

Background:Patients with lower extremity sensory symptoms and pain but without clinical or standard neurophysiological examination abnormalities may have a small fiber neuropathy. Skin biopsy with intraepidermal nerve fiber density (IENFD) assessment has been promoted as a diagnostic tool for such patients. Objectives:To evaluate the diagnostic utility of skin biopsy with IENFD in patients with suspected small fiber neuropathy. Methods:The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neuromuscular neurology. Results:One primary article was selected for review. A retrospective study using skin biopsy with IENFD detected abnormalities in 88.1% of 67 patients who had symptoms suggestive of sensory neuropathy but normal nerve conduction studies compared with 10% of healthy controls. Skin biopsy was more often abnormal in this setting than either the clinical examination (signs of small fiber impairment) or quantitative sensory testing but formal evaluation of sensitivity and specificity are compromised by inclusion of the diagnostic tests within the definition of the reference standard. Skin biopsy with IENFD was abnormal in 81% of patients clinically diagnosed with mixed large and small fiber neuropathy, 0/22 patients with large fiber neuropathy and 0/16 patients with nonperipheral neuropathic disorders. Conclusion:Detection of reduced IENFD using skin biopsy may be sensitive and specific for clinically-defined syndromes consistent with small fiber neuropathy. Skin biopsy appears to have greater diagnostic utility than the neurologic examination and quantitative sensory testing, both of which rely heavily on subjective patient perception. Prospective studies that evaluate quantitative methodology (rather than modalities that rely on patient report) and do not include the diagnostic tests in the reference standard are needed. Consensus is needed regarding a reference standard definition for small fiber neuropathy.

Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation? A critically appraised topic.

Background:Warfarin has provided protection against cardioembolic stroke in the setting of nonvalvular atrial fibrillation (NVAF) for the past 60 years. Dabigatran, the first oral direct thrombin inhibitor to be approved in the United States, promises to provide the same or better stroke protection with reduced risk of intracranial hemorrhage. However, it remains to be seen whether grand-scale adoption of dabigatran will be cost effective. Objective:To critically assess current evidence regarding the cost effectiveness of dabigatran for preventing stroke in patients with NVAF compared with warfarin. Methods:The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular neurology. Results:A cost-effectiveness analysis (CEA) that followed a hypothetical cohort of NVAF patients 65 years of age or older and CHADS2≥1 over their lifetime comparing dabigatran with adjusted-dose warfarin was reviewed. Assuming a willingness to pay a threshold of

Disrupted daytime activity and altered sleep-wake patterns may predict transition to mild cognitive impairment or dementia: a critically appraised topic.

50,000 per quality-adjusted life year (QALY), base case results favored high-dose (150 mg bid) dabigatran as a cost-effective alternative to warfarin. Sensitivity analysis asserted that the cost effectiveness of dabigatran improved if it could be obtained for ⩽

Physical activity level and future risk of mild cognitive impairment or dementia: a critically appraised topic.

13/d or if it was used in populations with high risk of stroke or intracranial hemorrhage. Conclusions:Dabigatran 150 mg bid (

Risk of development of medication overuse headache with nonsteroidal anti-inflammatory drug therapy for migraine: a critically appraised topic.

12,286 per QALY) is a cost-effective alternative to International Normalized Ratio-adjusted warfarin for the prevention of ischemic stroke in patients 65 years of age or older with NVAF.

Therapeutic hypothermia for severe traumatic brain injury: a critically appraised topic.

Background:There is a well-known relationship between neurodegenerative disease, disrupted sleep, and cognition. Pathologic and imaging studies have shown that regions in the brain shown to regulate sleep and circadian rhythm are abnormal in Alzheimer disease. Most of these studies have been cross-sectional, and often look at patients already with dementia. This leaves uncertainty with regard to the temporal relationship of circadian disruption and cognitive decline. Objective:To determine whether disrupted daytime activity and altered sleep patterns predict development of mild cognitive impairment (MCI) or dementia. Methods:The objective was addressed through the development of a structured, critically-appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, and behavioral neurology and sleep medicine content experts. Results:A prospective cohort study of 1282 cognitively normal women demonstrated that when peak circadian activity, as measured by wrist actigraphy, occurred later than average, there was an increased risk of MCI or dementia [odds ratio (OR), 1.83; 95% confidence interval (CI), 1.29-2.61]. Increased odds for dementia or MCI also existed for those with decreased circadian rhythm amplitude (OR, 1.57; 95% CI, 1.09-2.25) and robustness (OR, 1.57; 95% CI, 1.29-2.61). Conclusions:Disrupted circadian rhythm measures, including lower amplitude, a less robust rhythm, and delayed timing of peak activity on wrist actigraphy, were predictive of future development of MCI or dementia in cognitively normal women.