Citations

Key PointsRadiation is appropriate primary therapy in approximately 25% of cases. Radiation provides long-term remissions in more than 50% of patients.

Objective Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. Methods Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow‐up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. Results No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. Conclusions Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. Copyright © 2013 John Wiley & Sons, Ltd.

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.

Amyloidosis affecting lymph nodes (LN) may occur in the setting of systemic amyloidosis or as an entity localized to the site of production (peritumoral). Why some LN amyloid remains peritumoral is unknown. We speculated that the composition of amyloid in these two presentations differs. We analyzed the amyloid proteome in LN amyloid samples to identify differences between the systemic and peritumoral subtypes. In immunoglobulin‐derived LN amyloidosis (N = 26), 70% had heavy chain amyloid (AH or mixed AH/AL). True localized LN amyloidosis was rare, with only 2 patients without a monoclonal protein component. Nineteen patients (73%) had typical amyloid syndromes (100% of AL vs 67% of AH/AL, P = 0.02). A trend to improved survival for the AH/AL group in comparison to AL (median 5‐year survival 48 vs. 19 months, P = 0.06) was seen. Mass spectrometric amyloid analysis is a powerful tool for characterizing amyloid and may provide additional prognostic information. Am. J. Hematol. 88:577–580, 2013. © 2013 Wiley Periodicals, Inc.

Abstract Accumulation of eosinophils in the lung with concomitant tissue damage are defining histopathologic features of human asthma. Through degranulation and the release of proinflammatory proteins such as major basic protein (MBP), eosinophils may perpetuate this inflammatory response. We investigated the extent of eosinophil degranulation in a murine model of allergic pulmonary inflammation. In this paradigm, the mice develop pulmonary eosinophilia, mucus hypersecretion, tissue damage, and airway edema and hyperreactivity. To evaluate the degree of eosinophil degranulation, we used a polyclonal antibody to murine MBP (mMBP) to perform dot blot analysis of bronchoalveolar lavage (BAL) cells and fluids, and immunohistochemical fluorescent analysis of lung tissue sections. After ovalbumin antigen challenge, we were unable to detect immunoreactive mMBP in the BAL fluids from either nonsensitized or sensitized mice. However, after lysis of the recoverable BAL cells, we were able to detect mMBP by immunoblot analysis, with the levels of immunoreactive mMBP directly related to the number of recoverable eosinophils. We also examined paraffin-embedded, lung tissue sections for patterns of mMBP deposition. Whereas lung sections from allergic mice revealed prominent peribronchial eosinophilia after antigen challenge, tissue sections from nonsensitized animals rarely displayed eosinophils. Despite the presence of numerous eosinophils, no immunohistologic evidence of extracellular mMBP could be found in antigen-challenged allergic mice. Furthermore, rechallenged allergic mice displayed a significant increase in the number of recruited pulmonary eosinophils but all immunoreactive mMBP was still intracellular. We conclude that the recruited pulmonary eosinophils have not substantially degranulated. These results suggest that, in this murine model of allergic inflammation, eosinophil degranulation and release of mMBP does not contribute to the observed pulmonary inflammation and airway hyperreactivity.

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.

ICD in Cardiac AmyloidosisBackgroundCardiac amyloidosis (CA) is associated with increased risk of sudden cardiac arrest. Although ICD therapy improves survival in patients with cardiomyopathy due to other etiologies, the benefit of ICD therapy in patients with CA is unclear in large part due to limited data on the precise mechanism of sudden cardiac arrest and selection of patients with cardiac amyloidosis for ICD therapy.ObjectiveThe objective was to determine the benefit of ICD therapy in cardiac amyloidosis.MethodsWe reviewed all ICD implant indications, procedures, and therapies, of CA patients evaluated at Mayo Clinic between 2000 and 2009.ResultsA total of 53 patients with CA (33 AL, 10 senile, 9 familial, and 1 AA) who underwent ICD implantation were included. Indication for ICD implantation was for primary prevention of sudden cardiac arrest in 41 (77%) patients and secondary prevention in 12 (23%) patients. The rate of appropriate ICD shocks was 32% in the first year and was observed almost exclusively in AL amyloidosis patients, occurring in 15 patients (12 AL amyloidosis, 2 senile, 1 AA). Appropriate ICD shocks were more frequent in patients with prior sudden cardiac arrest or sustained ventricular arrhythmias (secondary prevention indication), and less frequent in patients who presented with decreased ejection fraction or syncope.ConclusionsA high rate of appropriate ICD shocks was observed especially in patients with AL‐type amyloidosis. However, appropriate ICD therapy did not translate into overall survival benefit, suggesting that selection of patients with CA who might be candidates for ICD is imprecise.

To clarify the presentation and course of patients with chronic lymphocytic leukemia (CLL) and amyloidosis. Mayo databases were interrogated for patients who carried a diagnosis of amyloidosis and CLL evaluated at Mayo Clinic, Rochester from January 1974 to October 2012. Charts were abstracted and data analyzed. Of the 33 patients identified, 20 (61%) were diagnosed with AL and 13 (39%) with non‐AL. Only four patients had immunoglobulin light chain amyloidosis (AL) that could be solely attributed to the CLL clone; another six had both a plasma cell clone and a CLL clone that shared the same light chain. Median overall survival was 15.6 months for patients with AL and 58.1 months for patients with non‐AL. For patients with AL management involved chemotherapy targeted toward monoclonal plasma cells, lymphocytes or both, and for patients with non‐AL no specific amyloid treatment was administered. AL is a rare complication of CLL, but in this elderly population of patients non‐AL is nearly as common. Distinguishing between these two groups is essential since patients with non‐AL amyloidosis have better outcomes and they do not require cytotoxic chemotherapy to treat their amyloidosis. Am. J. Hematol. 88:375–378, 2013. © 2013 Wiley Periodicals, Inc.

Genomewide association studies (GWAS) and candidate‐gene studies have implicated single‐nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case‐control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate‐gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate‐gene studies was associated in the full case‐control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate‐gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.