Faculty Bibliography

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (beta-amyloid [Abeta] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Abeta deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Abeta deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with 18F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with 18F-THK5117. 10 subjects additionally received 11C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of 18F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

Increase in human life expectancy has resulted in the rapid growth of the elderly population with minimal or no intellectual deterioration. The aim of this stereological study of 10 structures and 5 subdivisions with and without neurofibrillary degeneration in the brains of 28 individuals 25-102-years-old was to establish the pattern of age-associated neurodegeneration and neuronal loss in the brains of nondemented adults and elderly. The study revealed the absence of significant neuronal loss in 7 regions and topographically selective reduction of neuronal reserve over 77 years in 8 brain structures including the entorhinal cortex (EC) (-33.3%), the second layer of the EC (-54%), cornu Ammonis sector 1 (CA1) (-28.5%), amygdala, (-45.8%), thalamus (-40.5%), caudate nucleus (-35%), Purkinje cells (-48.3%), and neurons in the dentate nucleus (40.1%). A similar rate of neuronal loss in adults and elderly, without signs of accelerating neuronal loss in agers or super-agers, appears to indicate age-associated brain remodeling with significant reduction of neuronal reserve in 8 brain regions. Multivariate analysis demonstrates the absence of a significant association between neuronal loss and the severity of neurofibrillary degeneration and beta-amyloidosis, and a similar rate of age-associated neuronal loss in structures with and without neurofibrillary degeneration.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS), a motor neuron disease, is associated with various cortical symptoms including mild cognitive decline with behavior changes, suggesting the involvement of extra-motor areas in ALS. Our aim was to investigate the specific patterns of brain atrophy in sporadic, impaired ALS patients without commonly known genetic mutations using voxel-based morphometry. MATERIALS AND METHODS: Forty-seven patients with sporadic ALS and 28 age-matched healthy controls were recruited. ALS participants were divided into three groups according to comprehensive neuropsychological testing: pure (ALS-pure), cognitive impairment (ALSci) and behavioral impairment (ALSbi). Quantitative comparison of brain atrophy patterns was performed amongst these three groups using voxel-based analysis. All analyses were adjusted for total intracranial volume, age, sex, disease duration and functional disability score. RESULTS: The ALSci group exhibited decreased volume in the left cerebellum, fusiform gyrus, optic radiations and corticospinal tracts compared to healthy controls. ALSci patient imaging showed decreased brain volume in the bilateral cerebellum, right putamen gray matter and bilateral superior longitudinal fasciculi white matter compared to pure ALS patients (P < 0.001 uncorrected, corrected for the entire volume). Compared to healthy controls, ALS-pure and ALSbi groups did not show any significant volume changes in gray and white matter. CONCLUSIONS: These findings also support the hypothesis that ALS pathogenesis has a dual focality of onset (cortex and anterior horn) with contiguous spread outwards. Additionally, neuropsychological features may be an important predictor of progression and survival rates in ALS.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, phenotypically heterogeneous neurodegenerative disease affecting mainly the motor neuron system. The present voxel-based morphometry (VBM) study investigated whether patterns of brain atrophy differ among sporadic ALS subtypes. MATERIAL AND METHODS: Sporadic ALS patients (n = 62) with normal cognition and age-matched healthy controls (n = 57) were included in the study. ALS patients were divided into limb- and bulbar-onset groups according to clinical manifestations at symptom onset (n = 48 and 14, respectively). Clinical measures were ALS Functional Rating Scale-Revised (ALSFRS-R) score, disease duration, and forced vital capacity (FVC). Patterns of brain atrophy between ALS subgroups were compared by VBM. RESULTS: In limb-onset ALS patients, atrophy was largely confined to the motor cortex and adjacent pre- and postcentral regions. However, in the bulbar-onset group, affected regions were more widespread and included these same areas but also extended to the bilateral frontotemporal and left superior temporal and supramarginal gyri, and multiple regression analysis revealed that their ALSFRS-R scores were associated with extensive loss of gray matter while FVC was related to atrophy in subcortical regions of the left superior temporal gyrus. In limb-onset ALS patients, disease duration was related to the degree of atrophy in the motor and adjacent areas. CONCLUSION: Sporadic ALS subtypes show different patterns of brain atrophy. Neural networks related to limb and bulbar motor functions in each ALS subtype may underlie their distinct patterns of cerebral atrophy. That is, more extensive cortical and subcortical atrophy is correlated with greater ALSFRS-R severity and shorter disease duration in the bulbar-onset subtype and may explain the poor prognosis of these patients.

After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26