Arousiak Varpetian

Biochemical markers in persons with preclinical familial Alzheimer disease.

Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease. Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Aβ40, Aβ42, F2-isoprostanes) and CSF (F2-isoprostanes, t-tau, p-tau181, Aβ40, Aβ42, and Aβ42/Aβ40 ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). Results: Plasma Aβ42 levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Aβ42/Aβ40 (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Aβ42 levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Aβ42 to Aβ40 was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau181 levels were elevated in presymptomatic FAD MCs. CSF levels of F2-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031). Conclusions: Our data indicate that Aβ42 is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Aβ42 to Aβ40 was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau181 are sensitive indicators of presymptomatic disease. Our finding of elevated F2-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

The A431E mutation in PSEN1 causing Familial Alzheimer's Disease originating in Jalisco State, Mexico: An additional fifteen families

Nine families with autosomal dominant Alzheimer’s disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.

Neuropsychological function in nondemented carriers of presenilin-1 mutations

Background: Prospective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD). Objective: To investigate these observations by the study of persons at risk for autosomal dominant forms of AD. Methods: Neuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE ε4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs. Results: MCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE ε4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores. Conclusions: This study is consistent with findings in sporadic Alzheimer disease of early problems with memory, visuospatial function, and particularly with executive function in PS1 mutation carriers. Depression, gender, and presence of an APOE ε4 allele did not demonstrate large influences on neuropsychological performance.

A multiancestral genome-wide exome array study of Alzheimer Disease, frontotemporal dementia, and progressive supranuclear palsy

IMPORTANCE Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. OBJECTIVE To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. DESIGN, SETTING, AND PARTICIPANTS We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimers Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. MAIN OUTCOMES AND MEASURES Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. RESULTS Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. CONCLUSIONS AND RELEVANCE Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

Increased prevalence of significant recurrent headache in preclinical familial Alzheimer's disease mutation carriers.

Background/Aims: A previous study found a high prevalence of headaches in persons with familial Alzheimer’s disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). Methods: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by χ2 or Fisher’s exact tests. Results: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. Conclusions: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.

Urinary retention in a patient with West Nile virus.

West Nile Virus (WNV) has received much recent attention due to multiple outbreaks in North America, its insidious onset in many patients, and a wide variety of neurologic manifestations. A 45-year-old man who exhibited urinary retention as a presenting symptom of WNV infection is presented herein. We believe this to be the first reported case of a urologic sequela secondary to WNV infection.

Alzheimer's disease neuropathologic changes in semantic dementia

Neuropathologic change underlying primary progressive aphasia (PPA) most commonly includes one of the frontotemporal lobar degenerations, such as FTLD-tau or FTLD-ubiquitin. The next most frequent etiology of PPA is Alzheimers disease (AD). We describe 5 subjects with clinical diagnoses of semantic dementia, who underwent longitudinal clinical evaluation and postmortem neuropathology examination of the central nervous system. This case series examines retrospectively which clinical parameters might have pointed to the neuropathological diagnosis of AD. Conclusion: family history of late onset dementia, APOEε4 status, combined features of semantic dementia and progressive non-fluent aphasia present early in illness, or generalized seizures, may indicate AD as the underlying pathology of semantic dementia.

Effects of ApoE genotype but not of FAD mutation status in BOLD activation during a novelty encoding task

(4.1.0). VBM (SPM5 and DARTEL) and Freesurfer were used to assess effects within grey matter at each voxel and vertex respectively (FDR corrected, q<0.05). Linear regression was used to assess the individual and independent effects of gender, age and TIV. Results: Age, gender, and TIV were individually associated with all ROI volumes (see table) except age and caudate, age and amygdala and gender and hippocampus. Age and TIV had independent associations with all ROIs. Gender had an independent effect only on whole brain (p<0.001). The 95% CIs of the slope of TIV and ROIs never contained 1 indicating that dividing by TIV is not appropriate head-size adjustment. Age had a widespread negative association with thickness and volume throughout the cortex which survived gender and TIV adjustment (see figure). TIV was associated with increased thickness in the right-sided occipital lobe but not after age and gender adjustment. TIV had a large positive association with grey matter volume, which remained following age and gender adjustment. Gender had some effect on thickness in the left hemisphere (women>men) and a large effect on volume (men>women) but these were lost following TIV and age adjustment. Conclusions: Age has a large effect on results generated by all analysis techniques. Head-size adjustment is unnecessary for thickness analysis should gender and age be used, but is required for volume analyses. Gender-adjustment may be necessary for thickness studies and some ROI analysis but not for VBM should TIV and age be used.

IC-P3-207: Decreased activation in the left medial parietal lobe in presymptomatic FAD mutation carriers in fMRI during an unrelated word pair memory task

2 and Lesion Explorer 3 WMH segmentation was performed, with VichowRobin perivascular spaces excluded. To appreciate the 3-dimensional anatomy of WMH, PV-WMH was defined as any hyperintensity touching the ventricles in 3D, the remaining discrete WMSH were defined as DWWMH. Hypointense components within PV-WMH and DW-WMH of cerebrospinal fluid intensity on T1-based segmentation were considered to represent cystic necrosis. Volumetrics were obtained. Hypointense lesion volumes were expressed as percentage of WMH. Results: Mean percentage of hypointensities were as follows: periventricular (AD 2.2%, NC 0.37%); deep white (AD 2.16%, NC 1.6%), with the PV between group difference approaching significance (p .07). Total PV-WMH and DW-WMH volumes was significantly correlated in NC (r .62, p .019) but not in AD (r .32, p .24). However, DW and PV hypointensities did not show correlation (NC: r -.05, p .87; AD: r .24, p .39). Conclusions: The higher percentage of implied cystic necrosis in the PV distribution, and the differences in DW and PV correlations in AD and NC, suggests a different underlying pathology occurring in the periventricular regions of AD patients. It is recommended that future studies examining WMH should include PV and DW delineations as well as an additional T1-based hypointense segmentation to account for these lesions.