Graff‐Radford, Neill R.

Object Management of idiopathic normal-pressure hydrocephalus (iNPH) is hard because the diagnosis is difficult and shunt surgery has high complication rates. An important complication is overdrainage, which often can be treated with adjustable–shunt valve manipulations but also may result in the need for subdural hematoma evacuation. The authors evaluated shunt surgery overdrainage complications in iNPH and their relationship to lumbar puncture opening pressure (LPOP). Methods The authors reviewed the charts of 164 consecutive patients with iNPH who underwent shunt surgery at their institution from 2005 to 2011. They noted age, sex, presenting symptoms, symptom duration, hypertension, body mass index (BMI), imaging findings of atrophy, white matter changes, entrapped sulci, LPOP, valve opening pressure (VOP) setting, number of valve adjustments, serious overdrainage (subdural hematoma requiring surgery), radiological overdrainage (subdural hematomas or hygroma seen on postoperative imaging), clinical overdrainage (sustained or postural headache), other complications, and improvements in gait, urine control, and memory. Results Eight patients (5%) developed subdural hematomas requiring surgery. All had an LPOP of greater than 160 mm H2O and an LPOP-VOP of greater than 40 mm H2O. Radiological overdrainage was more common in those with an LPOP of greater than 160 mm H2O than in those with an LPOP of less than 160 mm H2O (38% vs 21%, respectively; p = 0.024). The BMI was also significantly higher in those with an LPOP of greater than 160 mm H2O (median 30.2 vs 27.0, respectively; p = 0.005). Conclusions Serious overdrainage that caused subdural hematomas and also required surgery after shunting was related to LPOP and LPOP-VOP, which in turn were related to BMI. If this can be replicated, individuals with a high LPOP should have their VOP set close to the LPOP, or even higher. In doing this, perhaps overdrainage complications can be reduced.

AbstractFrontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk. image We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD‐TDP in these patients.

AbstractBackgroundGenetic variants at the CLU, CR1, and PICALM loci associate with risk for late‐onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects.MethodsWe pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale–Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E ε4 dosage.ResultsWe identified nominally significant or suggestive associations between the LOAD‐risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068–.046, β = −2.7 to −1.2). The LOAD‐protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099–.027, β = 0.31–0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed.ConclusionThese results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD‐protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Background and purposeTo evaluate the association between systolic, diastolic and pulse pressure, and increase in ventricular size (VS). Observations in laboratory animals suggest intraventricular pulse pressure (systolic–diastolic) may play a role in ventricular enlargement.MethodsInitial magnetic resonance (MR) scans and vascular risk factors evaluation were performed in 1812 Atherosclerosis Risk in Communities participants in 1994–1995. In 2004–2006, 1130 participants underwent repeat MR. VS was rated using a validated nine‐point scale. Multiple logistic regression analysis assessed association between blood pressure measures and pulse pressure, and the change between the MR scans of VS controlling for age, sex and race.ResultsAt baseline 1112 participants (385 black women, 200 black men, 304 white women and 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models pulse pressure at baseline was associated with an increase in VS [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01–1.40], as was systolic pressure (OR 1.28, 95% CI 1.03–1.58).ConclusionsSystolic pressure and pulse pressure are associated with future development of increased VS. The findings are consistent with the animal literature that increased pulse pressure predisposes to risk of future increased VS. High pulse pressure might play a role in the pathogenesis of normal pressure hydrocephalus.