Evidence based management of normal pressure hydrocephalus: Lessons and future directions

Objective: To present the methodology and management tree of patients referred to the Henry Ford NPH conference for an evaluation from 2003 to 2017. Background: The diagnosis of idiopathic NPH may prove to be more challenging. Currently, a clinical triad of cognitive impairment, (Figure presented) gait disability and urinary incontinence, along with a radiological evidence of ventriculomegaly is widely accepted to be sufficient to consider a work up for NPH. Given the prevalence of comorbidities that may confound the clinical picture, an accurate diagnosis is essential for an effective patient centric management plan. (1, 2) To the appropriately selected patient population, timely surgical intervention may provide good clinical benefit. Methods: All patients presented in the multi-disciplinary NPH conference at Henry Ford Health System are prospectively registered in Research Electronic Data Capture (REDCap). The REDCap database was queried for all patients without a previous diagnosis of NPH from 2003-2017. Patients with at least radiographic evidence of ventriculomegly or clinical features of ataxia were discussed in the NPH conference. Our management algorithm with results can be seen in Figure 1-3. An Anticholinergic Cognitive Burden (ACB) score was calculated for each patient. Results: Out of the 316 patients without obstructive hydrocephalus, 149 patients (47%) were identified with alternative diagnoses not necessitating a LP. We further identified 87 patients (28%) with treatable causes, out of which 52% improved with treatment. Of the 142 patients who underwent LP, 40 patients did not improve clinically. Finally, 102 patients were referred for a surgical shunt. ACB score calculated between the non-operative and shunted cohorts did not statistically significantly differ (0.75 vs 0.84, respectively, p=0.672). Conclusions: Our methodology offers a systematic process to assess patients with suspected NPH for appropriate clinical management. Recognition of treatable causes in this patient population is imperative. In our cohort, cervical stenosis, Parkinson\u27s disease and sleep disorders constituted 64% of this subsection. Our data suggests that the prevalence of sleep apnea in patients presenting with a presentation suggestive of NPH is underappreciated. A key confounder to the clinical picture in the elderly is polypharmacy. Our study is unique in that a mean ACB score was taken into account

Differences in peripheral immune system gene expression in frontotemporal degeneration.

AbstractThe peripheral immune system has a key pathophysiologic role in Frontotemporal degeneration (FTD). We sought a comprehensive transcriptome-wide evaluation of gene expression alterations unique to the peripheral immune system in FTD compared to healthy controls and amyotrophic lateral sclerosis.Nineteen subjects with FTD with 19 matched healthy controls and 9 subjects with amyotrophic lateral sclerosis underwent isolation of peripheral blood mononuclear cells (PBMCs) which then underwent bulk ribonucleic acid sequencing.There was increased expression in genes associated with CD19+ B-cells, CD4+ T-cells, and CD8+ T-cells in FTD participants compared to healthy controls. In contrast, there was decreased expression in CD33+ myeloid cells, CD14+ monocytes, BDCA4+ dendritic cells, and CD56+ natural killer cells in FTD and healthy controls. Additionally, there was decreased expression is seen in associated with 2 molecular processes: autophagy with phagosomes and lysosomes, and protein processing/export. Significantly downregulated in PBMCs of FTD subjects were genes involved in antigen processing and presentation as well as lysosomal lumen formation compared to healthy control PBMCs.Our findings that the immune signature based on gene expression in PBMCs of FTD participants favors adaptive immune cells compared to innate immune cells. And decreased expression in genes associated with phagosomes and lysosomes in PBMCs of FTD participants compared to healthy controls

Prevalence of Alternative Diagnoses and Implications for Management in Idiopathic Normal Pressure Hydrocephalus Patients

BACKGROUND: Following Bayes theorem, ventriculomegaly and ataxia confer only a 30% chance of idiopathic Normal Pressure Hydrocephalus (NPH). When coupled with positive responses to best diagnostic testing (extended lumbar drainage), 70% of patients recommended for shunting will not actually have NPH. This is inadequate clinical care. OBJECTIVE: To determine the proportion of alternative and treatable diagnoses in patients referred to a multidisciplinary NPH clinic. METHODS: Patients without previously diagnosed NPH were queried from prospectively collected data. At least 1 neurosurgeon, cognitive neurologist, and neuropsychologist jointly formulated best treatment plans. RESULTS: Of 328 total patients, 45% had an alternative diagnosis; 11% of all patients improved with treatment of an alternative diagnosis. Of 87 patients with treatable conditions, the highest frequency of pathologies included sleep disorders, and cervical stenosis, followed by Parkinson disease. Anti-cholinergic burden was a contributor for multiple patients. Of 142 patients undergoing lumbar puncture, 71% had positive responses and referred to surgery. Compared to NPH patients, mimickers were statistically significantly older with lower Montreal Cognitive Assessment (MoCA) score and worse gait parameters. Overall, 26% of the original patients underwent shunting. Pre-post testing revealed a statistically significant improved MoCA score and gait parameters in those patients who underwent surgery with follow-up. CONCLUSION: Because the Multidisciplinary NPH Clinic selected only 26% for surgery (corroborating 30% in Bayes theorem), an overwhelming majority of patients with suspected NPH will harbor alternative diagnoses. Identification of contributing/confounding conditions will support the meticulous work-up necessary to appropriately manage patients without NPH while optimizing clinical responses to shunting in correctly diagnosed patients

A comprehensive genetic association study of Alzheimer disease in African Americans.

OBJECTIVES: To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites. DESIGN: We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population. SUBJECTS: Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects. SETTING: Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study. RESULTS: Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P = .0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes. CONCLUSIONS: Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific