Tammie L.S. Benzinger

APOE4 Allele Disrupts Resting State fMRI Connectivity in the Absence of Amyloid Plaques or Decreased CSF Aβ42

Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimers disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.

Loss of Intranetwork and Internetwork Resting State Functional Connections with Alzheimer's Disease Progression

Alzheimers disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brains functional organization.

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords.

OBJECTIVE Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. BACKGROUND In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. METHODS DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. RESULTS Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). CONCLUSIONS Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.

Absence of Pittsburgh Compound B Detection of Cerebral Amyloid β in a Patient With Clinical, Cognitive, and Cerebrospinal Fluid Markers of Alzheimer Disease: A Case Report

BACKGROUND To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained. OBJECTIVE To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD. DESIGN Case report. SETTING Alzheimer disease research center. PARTICIPANT Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments. MAIN OUTCOME MEASURES Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy. RESULTS Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 88(1/2) years, but at age 89(1/2) years there was reduced amyloid beta 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid beta plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection. CONCLUSION Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid beta using amyloid imaging agents such as PiB that primarily label fibrillar amyloid beta plaques.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies. Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease

PET imaging of pathological tau correlates more closely with Alzheimer’s disease–related cognitive impairment than does imaging of β-amyloid. A window into Alzheimer’s disease Alzheimer’s disease is pathologically defined by the accumulation of β-amyloid (Aβ) plaques and tau tangles. The cognitive and pathological correlates of Aβ deposition have been well studied owing to the availability of PET imaging ligands. Using newly available tau imaging agents, Brier et al. now explore relationships among tau pathology and Aβ with PET imaging, cerebrospinal fluid measures of disease, and cognition. Overall, tau imaging provided a more robust predictor of disease status than did Aβ imaging. Thus, whereas Aβ imaging provides a good marker for early disease state, tau imaging is a more robust predictor of disease progression. Alzheimer’s disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimers disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Longitudinal cerebrospinal fluid biomarker analyses reveal decreases in neuronal injury markers in later stages of autosomal-dominant Alzheimer’s disease. Biphasic Changes in CSF Biomarkers in AD Data from clinicopathological and biomarker studies of Alzheimer’s disease (AD) have converged to support the existence of a long “preclinical” (asymptomatic) stage during which pathologies develop before the appearance of cognitive symptoms. Substantiating the longitudinal change in biomarkers over time will advance our basic understanding of the disease and provide information critical for the design and interpretation of disease-modifying clinical trials that use biomarkers for subject enrollment, for proof of target engagement, or as outcome measures. Biomarkers are required to identify individuals in the preclinical stage to target them for secondary prevention trials designed to preserve normal cognitive function. Study of families with autosomal-dominant AD (ADAD) mutations permits characterization of biomarker changes during the full range of the disease process because of the certainty of eventual dementia in mutation carriers and the relatively predictable ages at symptom onset within families. Analysis of cerebrospinal fluid (CSF) collected longitudinally in research participants in the Dominantly Inherited Alzheimer Network (DIAN), a multicenter, international biomarker study of ADAD, revealed reductions in amyloid-β1–42 (indicating the presence of amyloid plaques) and increases in markers of neuronal injury (tau, ptau181, and VILIP-1) in mutation carriers during the early presymptomatic stage. However, concentrations of injury-related markers in carriers at later stages of the disease decreased over time, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. If corroborated, this longitudinal pattern of neurodegeneration-related biomarker change will likely influence the definition and interpretation of a positive versus negative effect of a therapy on disease progression. Clinicopathological evidence suggests that the pathology of Alzheimer’s disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“preclinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1–42 (Aβ1–42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Functional connectivity and graph theory in preclinical Alzheimer’s disease

Alzheimers disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.

Diffuse Microstructural Abnormalities of Normal-Appearing White Matter in Late Life Depression: A Diffusion Tensor Imaging Study

BACKGROUND Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter hyperintensities on T2-weighted imaging (WMH) and changes in the diffusion tensor properties of water. However, no study of LLD to date has examined the integrity of white matter outside of WMH (i.e., in normal-appearing white matter). METHODS We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects (n = 73) and nondepressed control subjects (n = 23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid, and WMH. The DTI parameters were calculated in white matter regions of interest after excluding the WMH. RESULTS Compared with control subjects, in the LLD group there were widespread abnormalities in DTI parameters, particularly in prefrontal regions. From a comprehensive neuropsychological battery, the strongest correlations were observed between cognitive processing speed and DTI abnormalities. CONCLUSIONS These results suggest that further investigation is warranted to determine potential reversibility and/or prognosis in LLD.