Faculty Bibliography

Background: There have been numerous reports of acute and delayed impairment of neurocognitive performance following surgery. Structural MRI has been used to successfully diagnose and monitor Alzheimer's disease, and is here applied to examine the impact of surgery on baseline atrophy in elderly patients. We compared changes in cortical anatomy for defined inter-visit intervals between a surgical cohort and a frequency matched non-surgical control. Methods: Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (www.loni.ucla.edu/ADNI), and included subjects either cognitively normal (NL) or diagnosed with mild cognitive impairment (MCI), and who did not progress. Ages are from 55 through 90, with minimum 6 grades of education. Putative surgical patients were selected by searching the comment fields for positive key words (e.g. surgery, thoracotomy, operative etc.) and then screening manually for confirmation. The final cohort contained 32 subjects and 79 non-surgical subjects, frequency matched by follow up time. Repeated Measures ANCOVA was used to evaluate the change in bilateral grey (GM) and white matter (WM) volume, before and after surgery, or between the last two evaluations for non-surgery group. Covariants included intracranial volume, age, and months to follow-up evaluation with diagnostic group (NL or MCI) a cofactor. Statistical significance was p < 0.05 (SPSS version 18.0; Chicago, IL). Results: Examining GM volume (left hemisphere), the 3-way interaction of evaluation, diagnosis, and surgery was significant (F1,104 =6.4, p<.05) indicating that slopes were different depending on diagnostic group; where MCI with surgery showed a significantly greater decrease inGMvolume compared toMCIwithout surgery (F1,47=7.9, p<.01); no significant difference for NL. Examining GM (right hemisphere), the 3-way interaction was not significant, but there was a significant decrease in GM volume (F1,105 =4.1, p<.05) for surgery compared to non-surgery subjects. No significant differences found for WM volume. Conclusions: In our cohort of elderly subjects, surgery resulted in amore pronounced GMvolume atrophy than seen in non-surgical subjects, with MCI subjects at higher risk. An examination of neurocognitive effects of surgery, in progress, suggests a correlation between atrophy and function

Introduction: A harmonized protocol for hippocampal MR-based segmentation is required for diagnosis and tracking of Alzheimer's disease (AD) and other disorders. A survey of segmentation protocols identified anatomical sources of heterogeneity in volume estimates. Aim: To identify differences among segmentation protocols and provide quantitative information supporting decisions for an international harmonized protocol. Methods: We selected 12 most used hippocampal tracing protocols in the AD literature for evaluation. The same rater carried out complete tracings on two MR scans (one control, one matched AD ADNI subjects) on 1.2 mm slices, using each of the 12 protocols. We arranged individual interactive web conferences with the primary author of each protocol, to check the appropriate execution of the tracing, and correct it when necessary. Landmark differences were extracted from the semantically harmonized landmarks obtained from the certified protocols (available at www.hippocampal-protocol.net). Results: The main differences between the protocols consisted in (a) inclusion/exclusion of hippocampal white matter (alveus/fimbria) (b) definition of the posterior most slice, and (c) definition of the separation between the subiculum and the parahippocampal gyrus. Heterogeneities in the definition of the boundary with the amygdala are no longer an issue due to the currently available software allowing 3D navigation. Conclusions: These results are preparatory to an international consensus for a harmonized protocol for the manual tracing of the hippocampus

Background: Midbrain atrophy is a well-known feature of progressive supranuclear palsy (PSP). Some clinical features of vascular parkinsonism (VP) such as pseudobulbar phenomena, lower body predominance and early postural instability suggest that the brainstem could be associated with VP. The aim of this study was to determine whether midbrain atrophy was present in patients with VP. Methods: We measured the midbrain (Amd) and pons area (Apn) of 20 patients with VP, 15 patients with probable PSP and 30 patients with idiopathic Parkinson's disease (IPD). The Amd and Apn were measured on mid-sagittal T(1)-weighted MRI scans using a computerized image analysis system. Results: For the Amd, the patients with VP (99.86 mm(2)) and PSP (87.30 mm(2)) had significantly smaller areas than the patients with IPD (130.52 mm(2)). For the Apn, there was a significant difference only between the VP (407.23 mm(2)) and the IPD (445.05 mm(2)) patients. The Amd/Apn ratios of the patients with VP (0.245) and PSP (0.208) were significantly smaller than in the patients with IPD (0.292). Conclusions: Our study shows that brainstem atrophy often occurs in patients with VP and the midbrain is more vulnerable than the pons to atrophic changes

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, Positron Emission Tomography (PET) imaging with amyloid-beta (Abeta) tracers and 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) is largely utilized in the early and differential diagnosis of AD. Abeta PET tracers bind to Abeta plaques in brain, and provide an in vivo estimate of AD pathology. FDG-PET is used to measure glucose metabolism, a marker of brain activity. This paper reviews brain Abeta-and FDG-PET studies in AD patients as well as in non-demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Abeta-PET to improve the early detection of AD. 2011 The authors and IOS Press. All rights reserved

Background: Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor among cognitively normal (NL) individuals. This study examines whether NL with LOAD-parents show preclinical evidence of brain AD, as reflected in increased fibrillar amyloid- beta (As) deposition on C-Pittsburgh Compound B (PiB)-PET, a major hallmark of AD pathology, and reduced glucose metabolism on 18F-fluorodeoxyglucose (FDG)-PET, a proxy for neuronal dysfunction. Methods: Forty-five 40-80 year-old NL with 8F-FDG and 11C-PIB PETexaminations were examined, including 15 NL with a maternal history (MH), 15 NL with a paternal history (PH), and 15 NL with negative family history of LOAD (NH). For all cases, the parents' AD diagnosis was clinician certified. Automated regions-of-interest, statistical parametric mapping, voxelwise inter-modality correlations and logistic regression were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. Results: Groups were comparable for clinical and demographical measures. The MH group showed higher PiB retention and lower metabolism in AD-regions compared to NH and PH, while the PH group showed milder PiB increases and no metabolic reductions compared to NH. Results remained significant controlling for age, gender, education and ApoE. Metabolism and PiB retention were negatively correlated locally in PCC, frontal and parieto-temporal regions in MHPY, whereas no correlations were observed in NH and PH. The combination of As deposition and metabolism improved group separation over either measure alone, yielding 65% accuracy for MH vs NH and PH (P < 0.05). Conclusions: Among NL with LOAD-parents, only MH show co-occurring As increases and hypometabolism in AD-vulnerable regions, suggesting that these subjects may be at a MHPYincreased risk for AD than PH. Present findings may motivate further research on familial transmission and parent-of-origin effects in LOAD, and indicate a great need for early intervention trials targeting adult children of LOAD-parents. (Figure presented)

Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-beta deposition in adult offspring of mothers, but not fathers, affected by late-onset Alzheimer's disease (LOAD). The underlying genetic mechanisms are unknown. We investigated whether cognitively normal (NL) individuals with a maternal history of LOAD (MH) have reduced platelet mitochondrial cytochrome oxidase activity (COX, electron transport chain complex IV) compared to those with paternal (PH) or negative family history (NH). Thirty-six consecutive NL individuals (age 55 +/- 15 y, range 27-71 y, 56% female, CDR = 0, MMSE >/=28, 28% APOE-4 carriers), including 12 NH, 12 PH, and 12 MH, received a blood draw to measure platelet mitochondrial COX activity. Citrate synthase activity (CS) was measured as a reference. Groups were comparable for clinical and neuropsychological measures. We found that after correcting for CS, COX activity was reduced by 29% in MH compared to NH, and by 30% in MH compared to PH (p </= 0.006). Results remained significant controlling for age, gender, education, and APOE. No differences were found between PH and NH. COX measures discriminated MH from the other groups with accuracy >/=75%, and relative risk >/=3 (p </= 0.005). Among NL with LOAD-parents, only those with MH showed reduced COX activity in platelet mitochondria compared to PH and NH. The association between maternal history of LOAD and systemic COX reductions suggests transmission via mitochondrial DNA, which is exclusively maternally inherited in humans

Background: Having a parent affected with late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. Among individuals with affected parents, those with a maternal history of AD (MH) show reductions of brain glucose metabolism on FDG-PET compared to those with a paternal history (PH) and those with negative family history (NH). This FDG-PET study investigates whether these metabolic deficits are associated with advancing maternal age at birth. Methods: Ninety-six NL individuals (age 60+10 yrs, 64% female) were examined with FDGPET, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with maternal or paternal age across groups using automated regions-of-interest and statistical parametric mapping. Results: Groups were comparable for clinical and neuropsychological measures, maternal and paternal age at birth. After controlling for subjects' age, significant negative correlations between maternal age at birth and metabolism were found in AD-vulnerable regions only for NL MH. Results remained significant after including paternal age, gender, education, and ApoE genotype in the model. There were no associations between paternal age and metabolism in any group. Conclusions: Advanced maternal age at birth negatively affects brain metabolism in the offspring of mothers, but not of fathers affected by late-onset AD. These data indicate a maternally inherited, maternal age-related mechanism that may increase risk for AD and provides further insight on risk factors and genetic transmission in late-onset AD

BACKGROUND: Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH. METHODS: Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Abeta(40), Abeta(42), Abeta(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F-isoprostanes (IsoP) (a marker of oxidative stress). RESULTS: Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Abeta(42/40) CSF levels compared with NH and with PH (p values </= .05), whereas no differences were found between NH and PH. No group differences were found for P-Tau(231) and T-Tau. The IsoP and Abeta(42/40) levels were correlated only within the MH group (R(2) = .32, p = .005) and discriminated MH from the other subjects with 70% accuracy (relative risk = 3.7%, 95% confidence interval = 1.6-9.7, p < .001). Results remained significant controlling for age, gender, education, and apolipoprotein E genotype. CONCLUSIONS: Adult children of LOAD-affected mothers express a pathobiological phenotype characterized by Abeta-associated oxidative stress consistent with AD, which might reflect increased risk for developing the disease

Atrophic changes of the hippocampus are typically regarded as an early sign of Alzheimer's dementia (AD). Using the radial distance atrophy mapping approach, we compared the longitudinal MRI data of 10 cognitively normal elderly subjects who remained normal at 3-year and 6-year follow-up (NL-NL) and 7 cognitively normal elderly subjects who were diagnosed with mild cognitive impairment (MCI) 2.8 (range 2.0-3.9) and with AD 6.8 years (range 6.1-8.2) after baseline (NL-MCI(AD)). 3D statistical maps revealed greater hippocampal atrophy in the NL-MCI(AD) relative to the NL-NL group at baseline (left p=0.05; right p=0.06) corresponding to 10-15% CA1, and 10-25% subicular atrophy, and bilateral differences at 3-year follow-up (left p=0.001, right p<0.02) corresponding to 10-30% subicular, 10-20% CA1, and 10-20% newly developed CA2-3 atrophy. This preliminary study suggests that excess CA1 and subicular atrophy is present in cognitively normal individuals predestined to decline to amnestic MCI, while progressive involvement of the CA1 and subiculum, and atrophy spreading to the CA2-3 subfield in amnestic MCI, suggests future diagnosis of AD