The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology.
Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions.
Subjects ≥12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS, and 10 healthy controls were included.
Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared to healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared to controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and FA within white matter regions upstream and downstream of T2 lesions were different from controls in each disease.
Higher radial diffusivity, within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared to MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions, and may be a surrogate of anterograde and retrograde degeneration.
diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI
Traditional T2 weighted MR imaging results are non-specific for the extent of underlying white matter structural abnormalities present in late life depression (LLD). Diffusion tensor imaging provides a unique opportunity to investigate the extent and nature of structural injury, but has been limited by examining only a subset of regions of interest (ROI) and by confounds common to the study of an elderly population, including comorbid vascular pathology. Furthermore, comprehensive correlation of diffusion tensor imaging (DTI) measurements, including axial and radial diffusivity measurements, has not been demonstrated in the late life depression population.
51 depressed and 16 non-depressed, age- and cerebrovascular risk factor- matched elderly subjects underwent traditional anatomic T1 and T2 weight imaging, as well as DTI. The DTI data were skeletonized using tract based spatial statistics (TBSS), and both regional and global analyses were performed.
Widespread structural abnormalities within white matter were detected in the LLD group, accounting for age, gender and education and matched for cerebrovascular risk factors and global T2 white matter hyperintensities (T2WMH). Regional differences were most prominent in uncinate and cingulate white matter and were generally characterized by an increase in radial diffusivity. Age-related changes particularly in the cingulate bundle were more advanced in individuals with LLD relative to controls. Regression analysis demonstrated significant correlations of regional fractional anisotropy and radial diffusivity with five different neuropsychological factor scores. TBSS analysis demonstrated a greater extent of white matter abnormalities in LLD not responsive to treatment, as compared to controls.
White matter integrity is compromised in late life depression, largely manifested by increased radial diffusivity in specific regions, suggesting underlying myelin injury. A possible mechanism for underlying myelin injury is chronic white matter ischemia related to intrinsic cerebrovascular disease. In some regions such as the cingulate bundle, the white matter injury related to late-life depression appears to be independent of and compounded by age-related changes. The correlations with neuropsychological testing indicate the essential effects of white matter injury on functional status. Lastly, response to treatment may depend on the extent of white matter injury, suggesting a need for intact functional networks.
Diffusion tensor imaging; Tract based spatial statistics; Anisotropy; Radial diffusivity
The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.
11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.
ADRC and HIV clinic
16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).
Main Outcome Measure(s)
Mean and regional 11C-PiB binding potentials
Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).
Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.
HIV; Pittsburgh compound B (PIB); amyloid; HIV associated neurocognitive disorders; Alzheimer’s disease
Alzheimer’s 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 AD (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 intra- and inter-network correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain’s functional organization.
Alzheimer’s disease; fMRI; resting state functional connectivity; BOLD; default mode network; salience network
Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.
preclinical Alzheimer disease; amyloid-beta accumulation; apolipoprotein E; positron emission tomography; [11C]PIB
To determine the utility of post contrast susceptibility-weighted magnetic resonance imaging (PCSWI) in the evaluation of vascular malformations of the brain (BVM).
Materials and Methods
We retrospectively evaluated PCSWI and digital subtraction angiography (DSA) data from 16 consecutive patients with known or suspected BVM, which had been entered into a prospectively maintained database during a 1-year period. There had been no intervening treatment or change in patients’ symptoms between the PCSWI and DSA studies. The utility of PCSWI in the detection of AVS was compared to that of routine non-contrast susceptibility weighted imaging (SWI), time of flight Magnetic Resonance angiography (TOFMRA) and contrast enhanced Magnetic Resonance angiography (CEMRA) using DSA results as the reference standard. The presence of AVS in PCSWI or SWI sequences was defined by the presence of abnormal signal hyperintensity in the venous structures adjacent to the BVM.
A total of 17 BVMs were identified by DSA (9 newly diagnosed arteriovenous malformations, 3 dural arteriovenous fistulas, 4 treated arteriovenous malformations with residual AVS and 1 complex developmental venous anomaly). PCSWI was 100% sensitive and 100% specific with 100% positive predictive value (PPV) and 100% negative predictive value (NPV) for the detection of AVS in these BVMs. The PCSWI/SWI signal intensity ratio in the most prominent early draining venous structure was 1.2 ± 0.32.
PCSWI appears to be superior to SWI, TOFMRA and CEMRA in detecting AVS in BVMs and may be useful in the initial diagnosis and follow-up of patients with BVMs.
Susceptibility-weighted imaging (SWI); Arteriovenous shunting; Arteriovenous malformation (AVM); Developmental venous anomalies (DVA)
To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.
Longitudinal cohort study.
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.
Main outcome measure
Time to cognitive impairment (CDR ≥ 0.5).
Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.
Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are two rare types of acute post-infectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetrical lesions in the thalami, putamen, cerebral and cerebellar white matter and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating CNS disorder, which predominantly affects the white matter. Diffusion MRI is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by an analytical approach to directional diffusivity derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the CNS white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis and control cases correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsied brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy and decreased axial and radial diffusivity. Whereas in acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity and markedly increased radial diffusivity compatible with active inflammatory demyelination, were noted consistent with tissue biopsy neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional MRI in post-infectious encephalopathy in children.
To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.
Adult Children Study (ACS).
Washington University's Knight Alzheimer's Disease Research Center.
Cognitively normal middle to older age individuals with and without a FH for AD (n=269).
Main Outcome Measures
Clinical and cognitive measures, magnetic resonance imaging (MRI)-based brain volumes, diffusion tensor imaging (DTI)-based white matter microstructure, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PIB).
A positive FH for AD was associated with an age-related decrease of CSF Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted CSF Aβ42 was decreased for individuals with APOE4 compared with those without, and the decrease was larger for individuals with a positive FH compared with those without. The variation of CSF tau and PIB mean cortical binding potential (MCBP) increased by age. For individuals younger than 55, an age-related increase in MCBP was associated with APOE4, but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in MCBP. A positive FH was associated with decreased fractional anisotropy from DTI in the genu and splenium of the corpus callosum.
Independent of APOE4, FH is associated with age-related change of several CSF, PIB and DTI biomarkers in cognitively normal middle to older age individuals, suggesting that non-APOE susceptibility genes for AD influence AD biomarkers.
Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords.
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.
DTI was performed at 4.7 Tesla 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).
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.
Multiple Sclerosis; Diffusion Tensor Imaging; Post mortum; Spinal cord
Background and Purpose
To determine the accuracy of susceptibility-weighted magnetic resonance imaging (SWI) for the detection of arteriovenous shunting (AVS) in vascular malformations of the brain (BVM).
We retrospectively identified 60 patients who had been evaluated for known or suspected BVM by both SWI and digital subtraction angiography (DSA), without intervening treatment, during a 3-year period. SWI images were retrospectively assessed by two independent reviewers for the presence of AVS as determined by the presence of signal hyperintensity within a venous structure in the vicinity of the BVM. Discrepancies were resolved by consensus among a panel of three neuroradiologists. Accuracy parameters of SWI for the detection of AVS were calculated utilizing DSA as the reference standard.
A total of 80 BVMs were identified in the 60 patients included in our study. Of the 29 BVMs with AVS on DSA, 14 were untreated AVMs, 10 were previously-treated AVMs, and 5 were untreated dural arteriovenous fistulas. Overall, SWI was 93% sensitive and 98% specific for the detection of AVS in BVMs, with excellent inter-observer agreement (kappa 0.94). In the 14 previously-treated AVMs, SWI was 100% sensitive and specific for the detection of AVS. In the 28 BVMs associated with intracerebral hemorrhage, SWI was 100% sensitive and 96% specific for the detection of AVS.
SWI is accurate for the detection of arteriovenous shunting in vascular malformations of the brain and, for some patients, SWI may offer a non-invasive alternative to angiography in screening for or follow-up of treated BVMs.
Susceptibility-weighted imaging (SWI); Arteriovenous shunting; Arteriovenous malformation (AVM); Developmental venous anomalies (DVA)
Blast-related traumatic brain injury (bTBI) and post-traumatic stress disorder (PTSD) have been of particular relevance to the military and civilian health care sectors since the onset of the Global War on Terror, and TBI has been called the “signature injury” of this war. Currently there are many questions about the fundamental nature, diagnosis, and long-term consequences of bTBI and its relationship to PTSD. This workshop was organized to consider these questions and focus on how brain imaging techniques may be used to enhance current diagnosis, research, and treatment of bTBI. The general conclusion was that although the study of blast physics in non-biological systems is mature, few data are presently available on key topics such as blast exposure in combat scenarios, the pathological characteristics of human bTBI, and imaging signatures of bTBI. Addressing these gaps is critical to the success of bTBI research. Foremost among our recommendations is that human autopsy and pathoanatomical data from bTBI patients need to be obtained and disseminated to the military and civilian research communities, and advanced neuroimaging used in studies of acute, subacute, and chronic cases, to determine whether there is a distinct pathoanatomical signature that correlates with long-term functional impairment, including PTSD. These data are also critical for the development of animal models to illuminate fundamental mechanisms of bTBI and provide leads for new treatment approaches. Brain imaging will need to play an increasingly important role as gaps in the scientific knowledge of bTBI and PTSD are addressed through increased coordination, cooperation, and data sharing among the academic and military biomedical research communities.
animal models of blast-related injury; blast physics; blast-related traumatic brain injury; brain imaging; post-traumatic stress disorder
Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter lesions (hyperintensities on T2-weighted imaging) 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 discrete lesions, i.e., in normal appearing white matter. We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects (n=73) and non-depressed control subjects (n=23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid and discrete white matter lesions. DTI parameters were calculated in white matter regions of interest after excluding the white matter lesions. Widespread LLD vs. control group differences were found, particularly in prefrontal regions, where the DTI abnormalities correlated with cognitive processing speed. These results suggest that further investigation is warranted to determine the basic pathophysiology and potential reversibility of LLD.
Depression; MRI; Diffusion Tensor Imaging; Geriatrics; segmentation; LLD