Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study.

BACKGROUND AND PURPOSE: The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation. MATERIALS AND METHODS: We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using 11C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation. RESULTS: Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation. CONCLUSIONS: Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans.

Multimodality Imaging in Primary Progressive Aphasia.

Primary progressive aphasia is a clinically and neuropathologically heterogeneous group of progressive neurodegenerative disorders, characterized by language-predominant impairment and commonly associated with atrophy of the dominant language hemisphere. While this clinical entity has been recognized dating back to the 19th century, important advances have been made in defining our current understanding of primary progressive aphasia, with 3 recognized subtypes to date: logopenic variant, semantic variant, and nonfluent/agrammatic variant. Given the ongoing progress in our understanding of the neurobiology and genomics of these rare neurodegenerative conditions, accurate imaging diagnoses are of the utmost importance and carry implications for future therapeutic triaging. This review covers the diverse spectrum of primary progressive aphasia and its multimodal imaging features, including structural, functional, and molecular neuroimaging findings; it also highlights currently recognized diagnostic criteria, clinical presentations, histopathologic biomarkers, and treatment options of these 3 primary progressive aphasia subtypes.

Quantitative Susceptibility Mapping of the Thalamus: Relationships with Thalamic Volume, Total Gray Matter Volume, and T2 Lesion Burden.

BACKGROUND AND PURPOSE: Both thalamic iron deposition and atrophy have been reported in patients with multiple sclerosis compared with healthy controls, but how they are related is unclear. The purpose of this study was to understand the pathophysiologic basis for this iron deposition. MATERIALS AND METHODS: Ninety-five patients with relapsing-remitting multiple sclerosis underwent 3T MR imaging with a standardized protocol that included quantitative susceptibility mapping to measure iron concentration and a 3D T1 echo-spoiled gradient-echo sequence to obtain thalamic volumes. Volumes of interest were manually delineated on the quantitative susceptibility map to encompass both thalami. Multivariate regression analyses were performed to identify the association between thalamic susceptibility and volume. Associations between thalamic susceptibility and total gray matter volume, cortical thickness, and T2 lesion volume were also assessed. RESULTS: The relative susceptibility of the thalamus was associated with T2 lesion volume (P = .015) and was higher in the presence of enhancing lesions (P = .013). The relative susceptibility of the thalami was not associated with thalamic volumes, total gray matter volumes, or cortical thickness (P > .05). CONCLUSIONS: Iron levels in the thalami are associated with T2 lesion burden and the presence of enhancing lesions, but not with thalamic or gray matter volumes, suggesting that iron accumulation is associated with white matter inflammation rather than gray matter neurodegeneration.

Relationships among Cortical Glutathione Levels, Brain Amyloidosis, and Memory in Healthy Older Adults Investigated In Vivo with 1H-MRS and Pittsburgh Compound-B PET.

BACKGROUND AND PURPOSE: Oxidative stress has been implicated as an important pathologic mechanism in the development of Alzheimer disease. The purpose of this study was to assess whether glutathione levels, detected noninvasively with proton MR spectroscopy, are associated with brain amyloidosis and memory in a community-dwelling cohort of healthy older adults. MATERIALS AND METHODS: Fifteen cognitively healthy subjects were prospectively enrolled in this study. All subjects underwent 1H-MR spectroscopy of glutathione, a positron-emission tomography scan with an amyloid tracer, and neuropsychological testing by using the Repeatable Battery for the Assessment of Neuropsychological Status. Associations among glutathione levels, brain amyloidosis, and memory were assessed by using multivariate regression models. RESULTS: Lower glutathione levels were associated with greater brain amyloidosis in the temporal (P = .03) and parietal (P = .05) regions, adjusted for apolipoprotein E ε4 carrier status. There were no significant associations between glutathione levels and cognitive scores. CONCLUSIONS: This study found an association between cortical glutathione levels and brain amyloidosis in healthy older adults, suggesting a potential role for 1H-MR spectroscopy measures of glutathione as a noninvasive biomarker of early Alzheimer disease pathogenesis.

Magnetic Susceptibility from Quantitative Susceptibility Mapping Can Differentiate New Enhancing from Nonenhancing Multiple Sclerosis Lesions without Gadolinium Injection.

BACKGROUND AND PURPOSE: Magnetic susceptibility values of multiple sclerosis lesions increase as they change from gadolinium-enhancing to nonenhancing. Can susceptibility values measured on quantitative susceptibility mapping without gadolinium injection be used to identify the status of lesion enhancement in surveillance MR imaging used to monitor patients with MS? MATERIALS AND METHODS: In patients who had prior MR imaging and quantitative susceptibility mapping in a current MR imaging, new T2-weighted lesions were evaluated for enhancement on conventional T1-weighted imaging with gadolinium, and their susceptibility values were measured on quantitative susceptibility mapping. Receiver operating characteristic analysis was used to assess the diagnostic accuracy of using quantitative susceptibility mapping in distinguishing new gadolinium-enhancing from new nonenhancing lesions. A generalized estimating equation was used to assess differences in susceptibility values among lesion types. RESULTS: In 54 patients, we identified 86 of 133 new lesions that were gadolinium-enhancing and had relative susceptibility values significantly lower than those of nonenhancing lesions (ß = -17.2; 95% CI, -20.2 to -14.2; P < .0001). Using susceptibility values to discriminate enhancing from nonenhancing lesions, we performed receiver operating characteristic analysis and found that the area under the curve was 0.95 (95% CI, 0.92-0.99). Sensitivity was measured at 88.4%, and specificity, at 91.5%, with a cutoff value of 11.2 parts per billion for quantitative susceptibility mapping-measured susceptibility. CONCLUSIONS: During routine MR imaging monitoring to detect new MS lesion activity, quantitative susceptibility mapping can be used without gadolinium injection for accurate identification of the BBB leakage status in new T2WI lesions.

Quantitative Susceptibility Mapping and R2* Measured Changes during White Matter Lesion Development in Multiple Sclerosis: Myelin Breakdown, Myelin Debris Degradation and Removal, and Iron Accumulation.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping and R2* are sensitive to myelin and iron changes in multiple sclerosis lesions. This study was designed to characterize lesion changes on quantitative susceptibility mapping and R2* at various gadolinium-enhancement stages. MATERIALS AND METHODS: This study included 64 patients with MS with different enhancing patterns in white matter lesions: nodular, shell-like, nonenhancing < 1 year old, and nonenhancing 1-3 years old. These represent acute, late acute, early chronic, and late chronic lesions, respectively. Susceptibility values measured on quantitative susceptibility mapping and R2* values were compared among the 4 lesion types. Their differences were assessed with a generalized estimating equation, controlling for Expanded Disability Status Scale score, age, and disease duration. RESULTS: We analyzed 203 lesions: 80 were nodular-enhancing, of which 77 (96.2%) were isointense on quantitative susceptibility mapping; 33 were shell-enhancing, of which 30 (90.9%) were hyperintense on quantitative susceptibility mapping; and 49 were nonenhancing lesions < 1 year old and 41 were nonenhancing lesions 1-3 years old, all of which were hyperintense on quantitative susceptibility mapping. Their relative susceptibility/R2* values were 0.5 ± 4.4 parts per billion/-5.6 ± 2.9 Hz, 10.2 ± 5.4 parts per billion/-8.0 ± 2.6 Hz, 20.2 ± 7.8 parts per billion/-3.1 ± 2.3 Hz, and 33.2 ± 8.2 parts per billion/-2.0 ± 2.6 Hz, respectively, and were significantly different (P < .005). CONCLUSIONS: Early active MS lesions with nodular enhancement show R2* decrease but no quantitative susceptibility mapping change, reflecting myelin breakdown; late active lesions with peripheral enhancement show R2* decrease and quantitative susceptibility mapping increase in the lesion center, reflecting further degradation and removal of myelin debris; and early or late chronic nonenhancing lesions show both quantitative susceptibility mapping and R2* increase, reflecting iron accumulation.

Cerebral Microbleeds, CSF p-Tau, and Cognitive Decline: Significance of Anatomic Distribution.

BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with aging, hypertension, and Alzheimer disease. Microbleeds in a lobar distribution are believed to reflect underlying amyloid angiopathy, whereas microbleeds in the deep gray matter and infratentorial brain are commonly seen with hypertension. However, it is unknown how microbleeds in either distribution are related to Alzheimer pathogenesis. The purpose of this analysis was to test whether lobar and deep gray/infratentorial microbleeds demonstrate differential associations with CSF amyloid-ß and phosphorylated tau 181 protein levels and longitudinal cognitive decline. MATERIALS AND METHODS: A total of 626 subjects (151 cognitively normal, 389 with mild cognitive impairment, and 86 with Alzheimer disease) from the Alzheimer's Disease Neuroimaging Initiative who had undergone 3T MR imaging and lumbar puncture were included in the analysis. The number and location of microbleeds were assessed visually. Associations between lobar or deep gray/infratentorial microbleeds with CSF amyloid-ß levels, abnormal CSF phosphorylated tau 181 protein levels, and longitudinal cognitive decline were assessed by using ordinary least-squares, logistic, and mixed-effects regression models while adjusting for covariates. RESULTS: Having ≥3 lobar microbleeds was associated with lower levels of CSF amyloid-ß (P = .001). After adjusting for CSF amyloid-ß level, lobar microbleeds were independently associated with a higher likelihood of having an abnormal CSF phosphorylated tau 181 protein level (P = .004). Lobar microbleeds were associated with accelerated longitudinal cognitive decline (P = .007). Deep gray/infratentorial microbleeds revealed no significant associations. CONCLUSIONS: The distribution of microbleeds revealed different associations with amyloid-ß and phosphorylated tau 181 protein levels and cognition. Lobar and deep gray/infratentorial microbleeds should be considered separately with regard to Alzheimer disease pathogenesis.

White matter alterations in cognitively normal apoE ε2 carriers: insight into Alzheimer resistance?

BACKGROUND AND PURPOSE: The basis for decreased vulnerability to AD among apoE ε2 carriers is unknown. The purpose of this study was to use diffusion tensor imaging to detect possible differences in white matter integrity between cognitively normal elderly apoE ε2 carriers and apoE ε3/ε3 controls. MATERIALS AND METHODS: Thirty-nine cognitively normal elderly individuals (19 heterozygous carriers of the apoE ε2 allele, 20 apoE ε3/ε3 subjects as controls) underwent diffusion tensor MR imaging on a 4T scanner. Fractional anisotropy, MD, and axial and radial diffusivity were compared using a ROI approach. In addition, an exploratory whole-brain analysis of fractional anisotropy between the 2 groups was undertaken using TBSS. RESULTS: apoE ε2 carriers had higher FA in the posterior cingulate white matter (P = .01) and anterior corpus callosum (P = .005) than apoE ε3/ε3 controls, secondary to lower radial diffusivity. No significant differences in the FA of the posterior corpus callosum, anterior cingulate white matter, or parahippocampal white matter were seen. Whole-brain TBSS analysis detected regions of higher FA in the apoE ε2 group in the superior longitudinal fasciculus, right thalamus, and the bilateral anterior limbs of the internal capsule, in addition to the posterior cingulum and corpus callosum (P < .005). There were no regions in which the apoE ε3/ε3 group had higher FA. CONCLUSIONS: apoE ε2 carriers harbor more robust white matter integrity that may be associated with decreased vulnerability to developing AD. This provides further evidence that regional DTI metrics may serve as early imaging biomarkers of AD risk.

Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects.

OBJECTIVE: To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. METHODS: We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimer's Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF ß-amyloid (Aß), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status. RESULTS: APOE2 carriers demonstrated slower rates of hippocampal atrophy (p = 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was -33 mm(3)/year (95% confidence interval -65 to +0.4), or -0.5%/year, compared to -86 mm(3)/year (95% confidence interval -102 to -71), or -1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p = 0.23) or overall cognitive change (p = 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF Aß (p = 0.01), lower p-tau (p = 0.02), and marginally lower tau (p = 0.12). CONCLUSION: A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.