Citations

Background and purposeMidbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. The aim of the present study was to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS.MethodsAll autopsy‐confirmed subjects were identified with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP‐PSPS), and 13 had a non‐PSPS clinical diagnosis (PSP‐other). Three subjects had PSPS and corticobasal degeneration pathology (CBD‐PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD‐CBS) were selected. The midbrain area was measured in all subjects. [Correction added on 21 June 2013, after first online publication: the abbreviation of corticobasal degeneration pathology was changed from CBD‐PSP to CBD‐PSPS.]ResultsThe midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non‐PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS than in those without PSPS (P < 0.0001), with an area under the receiver operator curve of 0.99 (0.88, 0.99). A midbrain area cut‐point of 92 mm2 provided optimum sensitivity (93%) and specificity (89%) for differentiation.ConclusionMidbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of clinical PSPS. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology.

ABSTRACTProgressive supranuclear palsy is a neurodegenerative disease with progressive brain atrophy over time. It is unknown which specific brain regions decline over time, whether regional volume loss occurs in a linear fashion, and whether regional atrophy correlates with clinical decline over time in progressive supranuclear palsy. Twenty‐eight subjects meeting probable progressive supranuclear palsy criteria were prospectively recruited and completed 96 MRI scans over 2 years. Mixed‐effect models were utilized to determine which regions had significant atrophy over time and whether decline was linear or nonlinear. We assessed 13 regions across the brain, as well as whole‐brain and ventricular volume. Regional trajectories were also correlated with change in clinical measures of executive function and gait and ocular motor impairment. A linear decline was observed in all frontal and temporal regions, the superior parietal lobe, the thalamus, the caudate nuclei, and the midbrain, as well as in the whole brain. Ventricular expansion was also linear. Nonlinear decline was observed for the caudal middle frontal lobe and globus pallidus. Rates of change in the superior frontal lobe, thalamus, and midbrain were beyond those expected in normal aging. Decline in frontal lobe volume and the midbrain area correlated best to decline in clinical measures. In progressive supranuclear palsy, atrophy is occurring in multiple brain regions, particularly in those that have previously been implicated in the disease. Decline is mainly linear but can be nonlinear for some regions. The frontal lobe and midbrain seem to be playing the most significant roles in the progressive worsening of clinical signs in progressive supranuclear palsy. © 2013 Movement Disorder Society

Abstract Background Microbleeds have been associated with Alzheimer's disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA. Methods Thirteen lvPPA subjects underwent 3T T2*‐weighted and fluid‐attenuated inversion recovery magnetic resonance imaging and Pittsburgh compound B (PiB) positron emission tomography imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured. Results Microbleeds were observed in four lvPPA subjects (31%), most commonly in the frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB positive. Conclusions Microbleeds occur in approximately one third of subjects with lvPPA, with older women at the highest risk.

BackgroundPrevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid‐modifying trials for treatment and prevention of Alzheimer's disease (AD).MethodsSubjects were cognitively normal (n = 171), early‐mild cognitive impairment (MCI) (n = 240), late‐MCI (n = 111), and AD (n = 40) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6, and 12 months. β‐amyloid load was assessed with 18F‐florbetapir positron emission tomography.ResultsPrevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (P < .001) and β‐amyloid load (P < .001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow‐up (rank correlation = 0.49; P < .001).ConclusionsFocal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β‐amyloid load.

ObjectiveThe new criteria for preclinical Alzheimer disease (AD) proposed 3 stages: abnormal levels of β‐amyloid (stage 1), stage 1 plus evidence of brain injury (stage 2), and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β‐amyloid biomarkers have evidence of brain injury; we labeled them as the “suspected non‐Alzheimer pathophysiology” (sNAP) group. The characteristics of the sNAP group are poorly understood.MethodsUsing the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain magnetic resonance (MR), 18fluorodeoxyglucose (FDG), and Pittsburgh compound B positron emission tomography (PET) were evaluated for FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity volume, and number of infarcts. We examined cross‐sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.ResultsThe sNAP group had a lower proportion (14%) with apolipoprotein E ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α‐synucleinopathy, or physical findings of parkinsonism.InterpretationCognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β‐amyloid, were indistinguishable on a variety of imaging markers, clinical features, and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β‐amyloidosis. ANN NEUROL 2013;73:472–480