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Objective: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents., Methods: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial., Results: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale., Conclusions: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects., (© 2016 American Academy of Neurology.)

We compared the predictive value of cerebral perfusion as measured by arterial-spin labeling magnetic resonance imaging (ASL-MRI) with MRI-derived hippocampal volume for determining future cognitive and functional decline and subsequent conversion from mild cognitive impairment to dementia. Forty-eight mild cognitive impairment subjects received structural and ASL-MRI scans at baseline and clinical and neuropsychologic assessments annually. Thirteen subjects became demented during the period of longitudinal observation (2.7+/-1.0 y). Cox regression analyses suggest that baseline hippocampal volume [relative risk (RR)=0.99, P=0.004], baseline right inferior parietal (RR=0.64, P=0.01) and right middle frontal (RR=0.73, P=0.01) perfusion were associated with conversion to dementia. Results from linear mixed effects modeling suggest that baseline perfusion from the right precuneus predicted subsequent declines in Clinical Dementia Rating Sum of Boxes (P=0.002), Functional Activates Questionnaire (P=0.01), and selective attention (ie, Stroop switching, P=0.009) whereas baseline perfusion from the right middle frontal cortex predicted subsequent episodic memory decline (ie, total recognition discriminability score from the California Verbal Learning Test, P=0.03). These results suggest that hypoperfusion as detected by ASL-MRI can predict subsequent clinical, functional, and cognitive decline and may be useful for identifying candidates for future Alzheimer disease treatment trials.

Although early studies on mild cognitive impairment (MCI) focused on memory dysfunction; more recent studies suggest that MCI is clinically heterogeneous. The objective of this study is to examine patterns of cerebral perfusion in anmestic (N=12) and nonamnestic (N=12) single-domain MCI patients from 4 a priori regions of interest: middle and superior frontal cortex, posterior cingulate, and precuneus, to compare them relative to healthy controls (N=12), and to correlate perfusion with neuropsychologic measures. Relative to controls, all MCI patients had hypoperfusion in the posterior cingulate, bilaterally. MCI patients with executive dysfunctions also showed hypoperfusion in bilateral middle frontal cortex and the left precuneus relative to controls and in the left middle frontal cortex, left posterior cingulate, and left precuneus relative to amnestic MCI patients. Perfusion in the posterior cingulate correlated positively with memory performance whereas perfusion in all 4 a priori regions of interest, predominantly on the left side, correlated with executive function performance. The finding that single-domain MCI patients with prominent deficits in different cognitive domains exhibited different patterns of hypoperfusion relative to controls supports the existence of distinct subgroups of MCI. These data further suggest that cognitive impairment in MCI is related to cerebral hypoperfusion.

The goal was to assess regional patterns of metabolite abnormalities in mild cognitive impairment (MCI) and Alzheimer disease (AD) patients using proton magnetic resonance spectroscopy imaging at 1.5 Tesla. Fourteen MCI, 17 AD, and 16 healthy control (HC) subjects were studied. MCI was associated with higher myo-inositol (mIn) concentration in right parietal white matter compared with HC and lower mIn levels in frontal white matter compared with AD. AD was associated with higher mIn concentration in frontal and parietal white matter compared with HC. N-acetylaspartate (NAA) concentration of white matter was similar in all groups, whereas NAA concentration of gray matter showed a trend toward lower values in the right parietal lobe in AD compared with MCI and HC. A mIn increase in white matter in absence of significant NAA reduction suggests that mIn is a more robust and sensitive marker of white matter pathology in AD and MCI than NAA. Furthermore, the dissociation between mIn and NAA alterations in white matter could provide important information regarding the role of glial and neuronal damage in MCI and AD.

Background and Purpose: The relationship between subcortical ischemic vascular disease (SIVD) and cognition in normal elderly is unclear, in part because of methodological inconsistencies across studies. To clarify this relationship, the current study investigated a well characterized cognitively normal elderly sample (>or=55 years) with quantitative MRI and psychometrically robust neuropsychological measures within a multivariate model. Converging evidence suggests that SIVD selectively impairs frontal-executive tasks by disrupting frontal-subcortical circuits. We therefore hypothesized that MRI markers of SIVD would be selectively associated with worse executive functioning., Methods: We studied 94 participants who were cognitively and functionally normal. Volumetric measures of white matter signal hyperintensity (WMH), subcortical lacunes, hippocampal volume, and cortical gray matter were obtained to predict performance on composite measures of executive functioning and episodic memory., Results: Hierarchical regression demonstrated that after controlling for demographic variables, MMSE, and total intracranial volume, the total number of subcortical lacunes was the only significant predictor, with a greater number of lacunes associated with poorer executive performance. Hippocampal volume best predicted episodic memory performance., Conclusions: Results suggest that SIVD in the form of silent lacunes corresponds to poorer executive functioning even in otherwise normal elderly, which is consistent with the hypothesis that SIVD preferentially disrupts frontal-subcortical circuits. The clinical importance of these findings is highlighted by the fact that 33% of the normal elderly participants in this study had lacunar infarcts.

Background: Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions., Objective: To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI., Methods: DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects., Results: FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN., Conclusion: Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

Previous magnetic resonance (MR) spectroscopy studies of Alzheimer disease (AD) reporting reduced N-acetyl aspartate (NAA) and increased myo-Inositol (mI) used single voxel techniques, which have limited ability to assess the regional distribution of the metabolite abnormalities. The objective of this study was to determine the regional distribution of NAA and mI alterations in AD by using MR spectroscopic imaging. Fourteen patients with AD and 22 cognitively normal elderly were studied using structural MR imaging and MR spectroscopic imaging. Changes of NAA, mI, and various metabolite ratios were measured in frontal and parietal lobe gray matter (GM) and white matter. This study found: (1) when compared with cognitively normal subjects, AD patients had increased mI and mI/creatine (Cr) ratios primarily in parietal lobe GM, whereas frontal lobe GM and white matter were spared; (2) in the same region where mI was increased, AD patients had also decreased NAA and NAA/Cr ratios, replicating previous findings; (3) however, increased mI or mI/Cr ratios did not correlate with decreased NAA or NAA/Cr ratios; and (4) using mI/Cr and NAA/Cr together improved sensitivity and specificity to AD from control as compared with NAA/Cr alone. In conclusion, decreased NAA and increased mI in AD are primarily localized in parietal lobe GM regions. However, the NAA and mI changes are not correlated with each other, suggesting that they represent different processes that might help staging of AD.

The objectives of this study were to (1) compare atrophy rates associated with normal aging and Alzheimer disease (AD) using the semi-automated Boundary Shift Integral (BSI) method and manual tracing of the entorhinal cortex (ERC) and hippocampus and (2) calculate power of BSI vs. ERC and hippocampal volume changes for clinical trials in AD. We quantified whole brain and ventricular BSI atrophy rates and ERC and hippocampal atrophy rates from longitudinal MRI data in 20 AD patients and 22 age-matched healthy controls. All methods revealed significant brain atrophy in controls and AD patients. AD patients had approximately 2.5 times greater whole brain BSI atrophy rates and more than 5 times greater ERC and hippocampal atrophy rates than controls. ERC and hippocampal atrophy rates were higher in both groups than whole brain BSI atrophy rates, but lower than ventricular BSI atrophy rates. Effect size and power calculations suggest that ERC and hippocampal measurements may be more sensitive than ventricular or whole brain BSI for detecting AD progression and the potential effects of disease modifying agents. Logistic regression analysis revealed that combined rates of ERC and ventricular BSI were the best explanatory variables for classifying AD from controls.

Previous reports showed that patients with Alzheimer disease (AD) frequently have coexisting vascular-related pathologies, such as cerebral infarcts and white matter lesions. The aim of this study was to determine the effects of subcortical lacunar infarcts on brain structure in patients with AD. Semi-automated tissue segmentation and volumetry of magnetic resonance imaging data were performed in 38 AD patients without lacunes (AD-L), 24 AD patients with subcortical lacunes (AD+L), and 40 age-matched cognitively healthy subjects without lacunes. The following tissue volumes were quantified, expressed as percentage of total intracranial volume: ventricular cerebrospinal fluid (CSF), sulcal CSF, cortical gray matter (GM), subcortical GM, white matter (WM), white matter signal hyperintensities (WMSH), lacunes, and hippocampus. There was no difference in the Mini-Mental State Examination between the two AD groups. AD+L patients compared with AD-L subjects had significantly greater volumes of WMSH and ventricular CSF spaces (as expected) but smaller sulcal CSF spaces and no significant increase in cortical GM atrophy (both unexpected). In the AD groups, ventricular CSF correlated inversely with cortical GM but not with WM; sulcal CSF correlated inversely with cortical GM and WM. Cognitive impairment was associated with sulcal CSF volume but not with volumes of WMSH or lacunes. In conclusion, the presence of subcortical lacunes in those with AD is associated with more WM lesions and ventriculomegaly but not with cortical atrophy.