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.

AbstractBackgroundHippocampal volumetry on magnetic resonance imaging is recognized as an Alzheimer's disease (AD) biomarker, and manual segmentation is the gold standard for measurement. However, a standard procedure is lacking. We operationalize and quantitate landmark differences to help a Delphi panel converge on a set of landmarks.MethodsOne hundred percent of anatomic landmark variability across 12 different protocols for manual segmentation was reduced into four segmentation units (the minimum hippocampus, the alveus/fimbria, the tail, and the subiculum), which were segmented on magnetic resonance images by expert raters to estimate reliability and AD‐related atrophy.ResultsIntra‐ and interrater reliability were more than 0.96 and 0.92, respectively, except for the alveus/fimbria, which were 0.86 and 0.77, respectively. Of all AD‐related atrophy, the minimum hippocampus contributed to 67%; tail, 24%; alveus/fimbria, 4%; and the subiculum, 5%.ConclusionsAnatomic landmark variability in available protocols can be reduced to four discrete and measurable segmentation units. Their quantitative assessment will help a Delphi panel to define a set of landmarks for a harmonized protocol.

Objective The newly proposed National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. Methods The Mayo Clinic Study of Aging (MCSA) is a population‐based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI‐1) to assess the applicability of the criteria in both settings and to assess their outcomes. Results Fourteen percent of MCSA and 16% of ADNI‐1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI‐1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI‐1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI‐1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. Interpretation The NIA‐AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored. Ann Neurol 2013;74:199–208

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.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.