Susceptibility-Weighted Imaging Improves the Diagnostic Accuracy of 3T Brain MRI in the Work-Up of Parkinsonism

BACKGROUND AND PURPOSE:The differentiation between Parkinson disease and atypical parkinsonian syndromes can be challenging in clinical practice, especially in early disease stages. Brain MR imaging can help to increase certainty about the diagnosis. Our goal was to evaluate the added value of SWI in relation to conventional 3T brain MR imaging for the diagnostic work-up of early-stage parkinsonism.MATERIALS AND METHODS:This was a prospective observational cohort study of 65 patients presenting with parkinsonism but with an uncertain initial clinical diagnosis. At baseline, 3T brain MR imaging with conventional and SWI sequences was performed. After clinical follow-up, probable diagnoses could be made in 56 patients, 38 patients diagnosed with Parkinson disease and 18 patients diagnosed with atypical parkinsonian syndromes, including 12 patients diagnosed with multiple system atrophy–parkinsonian form. In addition, 13 healthy controls were evaluated with SWI. Abnormal findings on conventional brain MR imaging were grouped into disease-specific scores. SWI was analyzed by a region-of-interest method of different brain structures. One-way ANOVA was performed to analyze group differences. Receiver operating characteristic analyses were performed to evaluate the diagnostic accuracy of conventional brain MR imaging separately and combined with SWI.RESULTS:Disease-specific scores of conventional brain MR imaging had a high specificity for atypical parkinsonian syndromes (80%–90%), but sensitivity was limited (50%–80%). The mean SWI signal intensity of the putamen was significantly lower for multiple system atrophy–parkinsonian form than for Parkinson disease and controls (P < .001). The presence of severe dorsal putaminal hypointensity improved the accuracy of brain MR imaging: The area under the curve was increased from 0.75 to 0.83 for identifying multiple system atrophy–parkinsonian form, and it was increased from 0.76 to 0.82 for identifying atypical parkinsonian syndromes as a group.CONCLUSIONS:SWI improves the diagnostic accuracy of 3T brain MR imaging in the work-up of parkinsonism by identifying severe putaminal hypointensity as a sign indicative of multiple system atrophy–parkinsonian form.

In clinical practice, the differentiation between Parkinson disease (PD) and atypical parkinsonian syndromes (AP), such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB), can be challenging. For adequate patient counseling and treatment planning, it is important to make the correct diagnosis at an early disease stage. Ancillary investigations such as brain MR imaging can be performed to increase certainty about the diagnosis. In the diagnostic work-up of parkinsonism, performing brain MR imaging is advised because it can support the diagnosis of AP or vascular parkinsonism.¹ Also, brain MR imaging can demonstrate other more rare causes of parkinsonism such as normal pressure hydrocephalus or multiple sclerosis.Conventional brain MR imaging findings, including those of T1, T2, T2 FLAIR, and proton-attenuation sequences, are usually normal in PD or will show age-related changes.² Atrophy orsignal-intensity (SI) changes of specific regions of the brain identified on brain MR imaging can have high specificity for the different forms of AP. Examples include putaminal or pontine atrophy in MSA and midbrain atrophy (hummingbird sign) in PSP. The sensitivity of brain MR imaging for AP is generally limited, especially in early disease stages.^3–5New MR imaging techniques have become available for clinical practice in recent years, including susceptibility-weighted imaging. SWI is sensitive to magnetic susceptibility differences in tissues such as blood, calcification, and iron deposition. Because SWI makes use of both magnitude and phase information during image acquisition, it is superior in detecting brain susceptibility changes in comparison with T2* gradient-echo sequences.^6,7 SWI is emerging as a useful technique in a wide variety of intracranial pathologies, including neurodegenerative diseases.⁸ In parkinsonian syndromes, there are different patterns of abnormal brain iron metabolism in PD and AP. Examples include increased iron accumulation in the substantia nigra in PD and increased striatal iron content in MSA.⁹ These patterns of abnormal brain iron content should be differentiated from physiologic age-related iron accumulation.^10,11 Also, there still is debate about whether disturbances in iron levels in PD constitute representation of the primary pathologic process or are a secondary consequence.¹² This debate is highly relevant for SWI because it influences whether abnormal iron content in brain structures can be identified in early-stage PD or AP. Initial reports on SWI in parkinsonism indicate that SWI may provide new diagnostic markers for clinical use.^13,14The goal of our study was to evaluate whether SWI is of added value in relation to conventional 3T brain MR imaging in the diagnostic work-up of early-stage parkinsonism.     

Intracranial Arteriovenous Shunting: Detection with Arterial Spin-Labeling and Susceptibility-Weighted Imaging Combined

BACKGROUND AND PURPOSE:Arterial spin-labeling and susceptibility-weighted imaging are 2 MR imaging techniques that do not require gadolinium. The study aimed to assess the accuracy of arterial spin-labeling and SWI combined for detecting intracranial arteriovenous shunting in comparison with conventional MR imaging.MATERIALS AND METHODS:Ninety-two consecutive patients with a known (n = 24) or suspected arteriovenous shunting (n = 68) underwent digital subtraction angiography and brain MR imaging, including arterial spin-labeling/SWI and conventional angiographic MR imaging (3D TOF, 4D time-resolved, and 3D contrast-enhanced MRA). Arterial spin-labeling/SWI and conventional MR imaging were reviewed separately in a randomized order by 2 blinded radiologists who judged the presence or absence of arteriovenous shunting. The accuracy of arterial spin-labeling/SWI for the detection of arteriovenous shunting was calculated by using the area under receiver operating curve with DSA as reference standard. κ coefficients were computed to determine interobserver and intermodality agreement.RESULTS:Of the 92 patients, DSA showed arteriovenous shunting in 63 (arteriovenous malformation in 53 and dural arteriovenous fistula in 10). Interobserver agreement was excellent (κ =0.83–0.95). In 5 patients, arterial spin-labeling/SWI correctly detected arteriovenous shunting, while the conventional angiographic MR imaging did not. Compared with conventional MR imaging, arterial spin-labeling/SWI was significantly more sensitive (0.98 versus 0.90, P = .04) and equally specific (0.97) and showed significantly higher agreement with DSA (κ = 0.95 versus 0.84, P = .01) and higher area under the receiver operating curve (0.97 versus 0.93, P = .02).CONCLUSIONS:Our study showed that the combined use of arterial spin-labeling and SWI may be an alternative to contrast-enhanced MRA for the detection of intracranial arteriovenous shunting.

Intracranial arteriovenous shunting (AVS) related to dural arteriovenous fistulas (DAVFs) or AVMs may lead to several neurologic complications, including acute intracranial hemorrhage (ICH).^1–3 DSA remains the reference standard to confirm AVS and assess its angioarchitecture. However, conventional brain MR imaging, including time-of-flight and contrast-enhanced MR angiography, is commonly performed in patients with suspected AVS, particularly in the setting of acute ICH. Time-resolved (4D) contrast-enhanced MRA is routinely performed in patients suspected of having AVS or for characterizing a known AVM or DAVF.^4–6 Limitations of this approach include low spatial resolution, incomplete brain coverage, and technical difficulties.^4–7Recently, 2 noncontrast MR imaging techniques, namely SWI and arterial spin-labeling (ASL), were also reported useful for the detection of intracranial AVS. SWI can demonstrate the venous drainage as high signal intensity because of increased blood flow and the presence of a large amount of oxyhemoglobin,^8–11 while ASL can improve the detection of AVS by showing venous ASL signal.^12–16 To our knowledge, no previous study has yet compared the accuracy for detecting AVS of these noncontrast techniques with the conventional MR imaging protocol, including contrast-enhanced MRA. During a 4-year period, we have systematically performed 3T MR imaging, including SWI, ASL, and conventional angiographic MR imaging (ie, TOF-MRA, 3D and 4D contrast-enhanced MRA), in all consecutive patients referred for DSA (considered the reference standard in the present study) for known or suspected AVS. This study sought to determine the accuracy of the combined use of ASL and SWI (ASL/SWI) for the detection of AVS in comparison with conventional MR imaging, including contrast-enhanced MRA.     

SWI or T2*: Which MRI Sequence to Use in the Detection of Cerebral Microbleeds? The Karolinska Imaging Dementia Study

BACKGROUND AND PURPOSE:Cerebral microbleeds are thought to have potentially important clinical implications in dementia and stroke. However, the use of both T2* and SWI MR imaging sequences for microbleed detection has complicated the cross-comparison of study results. We aimed to determine the impact of microbleed sequences on microbleed detection and associated clinical parameters.MATERIALS AND METHODS:Patients from our memory clinic (n = 246; 53% female; mean age, 62) prospectively underwent 3T MR imaging, with conventional thick-section T2*, thick-section SWI, and conventional thin-section SWI. Microbleeds were assessed separately on thick-section SWI, thin-section SWI, and T2* by 3 raters, with varying neuroradiologic experience. Clinical and radiologic parameters from the dementia investigation were analyzed in association with the number of microbleeds in negative binomial regression analyses.RESULTS:Prevalence and number of microbleeds were higher on thick-/thin-section SWI (20/21%) compared with T2*(17%). There was no difference in microbleed prevalence/number between thick- and thin-section SWI. Interrater agreement was excellent for all raters and sequences. Univariate comparisons of clinical parameters between patients with and without microbleeds yielded no difference across sequences. In the regression analysis, only minor differences in clinical associations with the number of microbleeds were noted across sequences.CONCLUSIONS:Due to the increased detection of microbleeds, we recommend SWI as the sequence of choice in microbleed detection. Microbleeds and their association with clinical parameters are robust to the effects of varying MR imaging sequences, suggesting that comparison of results across studies is possible, despite differing microbleed sequences.

Cerebral microbleeds (CMBs) have lately become a focus of growing interest. Mainly related to small-vessel disease and seen as a result of hypertensive arteriopathy and cerebral amyloid angiopathy, CMBs have been proposed to have potentially important clinical implications.^1–3 Theories have proposed that CMBs have a possible important role in the dementia pathophysiology, and additionally, CMBs have shown associations with intracerebral hemorrhage.⁴Intracerebral hemorrhage and dementia share common characteristics with CMBs. The incidence of cerebral amyloid angiopathy in patients with Alzheimer disease is up to 98%,⁵ and hypertension has been related to the development of dementia.⁶ Additionally, cerebral amyloid angiopathy and hypertension are the 2 main pathologies behind spontaneous intracerebral hemorrhage, and CMBs are thereby hypothesized to be a possible predictor for intracerebral hemorrhage.⁷Correct and validated detection is essential to determine and understand CMBs and their associated clinical implications. CMBs are, due to their microscopic appearance, not visualized on CT or conventional MR imaging.¹ Detection has, up until now, been with hemosiderin-sensitive sequences, T2* and SWI. Hemosiderin is a paramagnetic substance, causing inhomogeneity in the magnetic field surrounding the CMB, leading to quick decay of the MR imaging signal, called the “susceptibility effect.” T2* is a gradient recalled-echo sequence, without a refocusing 180° radiofrequency pulse, thus making it sensitive to the susceptibility effect.⁸ The SWI sequence, in turn, is a technique that has recently been increasingly incorporated in clinical MRI protocols. SWI maximizes the susceptibility effect by combining a long TE, fully flow-compensated 3D gradient echo, and using both the magnitude and filtered phase information.^9,10 On sequences sensitive to the susceptibility effect, CMBs are represented by round hypointense dots. Factors of importance in increasing the sensitivity of CMB detection include higher spatial resolution and field and increased TE, with a longer TE increasing the susceptibility effect.³ However, this increased sensitivity may come at a cost, possibly contributing to an increased number of false-positive CMBs. Mimics of CMBs include both calcium and iron deposits, flow voids in blood vessels, and cavernomas and partial volume artifacts.³ Other reasons for CMBs may be trauma, such as diffuse axonal injury.³While both T2* and SWI have demonstrated good histopathologic correlation,^11–13 the use of the 2 different CMB sequences in CMB detection has complicated the comparison of results across studies. SWI has been shown to increase the number of CMBs detected,^3,14,15 and studies using the SWI sequence rather than T2* show a higher number and, in some cases, prevalence of CMBs.^14,16,17 The conventional SWI sequence has a thinner section thickness than the T2* sequence. A thin section thickness has been shown to increase CMB detection¹⁵; thus, this might contribute to the increased CMB detection seen with SWI. Furthermore, higher field strengths have been shown to increase the number of CMBs detected.¹⁵ However, whether the increased sensitivity for CMBs with SWI on 3T increases the association of CMBs with clinical parameters remains unknown.In this study, we aimed to disentangle the effect of sequence from that of section thickness by comparing CMB detection on the conventional thick-section T2*, a reconstructed thick-section SWI (TSWI), and the conventional thin-section SWI (tSWI) at 3T. By doing so, we aimed to determine the impact on CMB rating of the different MR imaging sequences and their various effects on clinical associations.     

MRI of the Swallow Tail Sign: A Useful Marker in the Diagnosis of Lewy Body Dementia?

BACKGROUND AND PURPOSE:There are, to date, no MR imaging diagnostic markers for Lewy body dementia. Nigrosome 1, containing dopaminergic cells, in the substantia nigra pars compacta is hyperintense on SWI and has been called the swallow tail sign, disappearing with Parkinson disease. We aimed to study the swallow tail sign and its clinical applicability in Lewy body dementia and hypothesized that the sign would be likewise applicable in Lewy body dementia.MATERIALS AND METHODS:This was a retrospective cross-sectional multicenter study including 97 patients (mean age, 65 ± 10 years; 46% women), consisting of the following: controls (n = 21) and those with Lewy body dementia (n = 19), Alzheimer disease (n = 20), frontotemporal lobe dementia (n = 20), and mild cognitive impairment (n = 17). All patients underwent brain MR imaging, with susceptibility-weighted imaging at 1.5T (n = 46) and 3T (n = 51). The swallow tail sign was assessed independently by 2 neuroradiologists.RESULTS:Interrater agreement was moderate (κ = 0.4) between raters. An abnormal swallow tail sign was most common in Lewy body dementia (63%; 95% CI, 41%–85%; P < .001) and had a predictive value only in Lewy body dementia with an odds ratio of 9 (95% CI, 3–28; P < .001). The consensus rating for Lewy body dementia showed a sensitivity of 63%, a specificity of 79%, a negative predictive value of 89%, and an accuracy of 76%; values were higher on 3T compared with 1.5T. The usefulness of the swallow tail sign was rater-dependent with the highest sensitivity equaling 100%.CONCLUSIONS:The swallow tail sign has diagnostic potential in Lewy body dementia and may be a complement in the diagnostic work-up of this condition.

Lewy body dementia (LBD) is often regarded as the second most common dementia in older individuals after Alzheimer disease,^1,2 possibly sharing the second place with vascular dementia.³ Clinical symptoms of LBD are similar to those of Parkinson disease (PD) dementia and include fluctuating cognitive decline, recurrent visual hallucinations, and parkinsonism.^2,4 LBD and PD dementia are separated by the arbitrary 1-year rule: If dementia exists within 12 months of parkinsonism, the patient is classified as having LBD.^2,4 More than 12 months of parkinsonism before the onset of dementia is termed “PD dementia.”^2,4Differential diagnostics between LBD and Alzheimer disease (AD) can be difficult, with both clinical and pathologic overlap.^2,5,6 LBD distinguishes itself from AD on MR imaging by having a lesser degree of generalized atrophy and commonly sparing or having less severe atrophy of the medial temporal lobes.⁶ Besides the loss of atrophy, which in itself is nonspecific, no accurate MR imaging signs for the distinction of LBD and other neurodegenerative diagnoses exist. Functional imaging is useful in diagnostic differentiation and typically shows reduced perfusion and glucose metabolism in an AD-like pattern, sparing the medial temporal lobes, with additional involvement of the occipital regions.^6–9 Dopaminergic transporter imaging with SPECT is another reliable method of differentiation, with less binding in the striatum suggesting LBD.⁶In recent years, MR imaging of the substantia nigra has shown great promise as a diagnostic tool in Parkinson disease.^10–14 Pathophysiologically, PD is characterized by loss of pigmented dopaminergic neurons of the substantia nigra pars compacta; 60%–80% of neurons are lost even before manifestation of motor symptoms.¹⁵ Clusters of dopamine-containing neurons in calbindin-poor zones in the substantia nigra are termed nigrosomes.¹⁶ Nigrosome 1, located in the caudal and posterolateral part of the substantia nigra pars compacta, is the largest dopamine-containing cluster and is mostly affected by PD.¹⁷ Recently, nigrosome 1 has been described as hyperintense on iron-sensitive SWI sequences,¹⁴ resembling a swallow tail.¹¹ The presence of a swallow tail sign has been shown to be sensitive and specific and has a high negative predictive value in PD on 3T MR imaging,¹¹ but its clinical applicability in LBD warrants further investigation.Due to the similarity in pathophysiology of PD and LBD, the swallow tail sign should be of diagnostic value even in LBD.¹⁸ We aimed to determine the clinical applicability of the swallow tail sign in a memory clinic population with a focus on LBD.     

Tractography at 3T MRI of Corpus Callosum Tracts Crossing White Matter Hyperintensities

BACKGROUND AND PURPOSE:The impact of white matter hyperintensities on the diffusion characteristics of crossing tracts is unclear. This study used quantitative tractography at 3T MR imaging to compare, in the same individuals, the diffusion characteristics of corpus callosum tracts that crossed white matter hyperintensities with the diffusion characteristics of corpus callosum tracts that did not pass through white matter hyperintensities.MATERIALS AND METHODS:Brain T2 fluid-attenuated inversion recovery–weighted and diffusion tensor 3T MR imaging scans were acquired in 24 individuals with white matter hyperintensities. Tractography data were generated by the Fiber Assignment by Continuous Tracking method. White matter hyperintensities and corpus callosum tracts were manually segmented. In the corpus callosum, the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts crossing white matter hyperintensities were compared with the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts that did not cross white matter hyperintensities. The cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers were included for comparison.RESULTS:Within the corpus callosum, tracts that crossed white matter hyperintensities had decreased fractional anisotropy compared with tracts that did not pass through white matter hyperintensities (P = .002). Within the cingulum, tracts that crossed white matter hyperintensities had increased radial diffusivity compared with tracts that did not pass through white matter hyperintensities (P = .001).CONCLUSIONS:In the corpus callosum and cingulum, tracts had worse diffusion characteristics when they crossed white matter hyperintensities. These results support a role for white matter hyperintensities in the disruption of crossing tracts.

The corpus callosum (CC) is the largest commissural tract with >200 million axons connecting the cerebral hemispheres.¹ Atrophy of the CC is a marker of neurodegeneration and has been reported in cerebrovascular disease.^2–8 White matter hyperintensities (WMH) are high-signal lesions on T2-weighted MR imaging that represent cerebral small vessel disease and have been associated with CC atrophy.^7,9–14 The reason for changes in the corpus callosum with WMH is unclear. Earlier studies have suggested that WMH may be an incidental finding and that CC atrophy results from a coexisting disease process.^7,10–17 For example, WMH are seen with Alzheimer disease, in which CC atrophy can occur by cortical atrophy and subsequent Wallerian degeneration of corpus callosum fibers originating from pyramidal neurons.^{7,10,13,15,16} These studies also suggest that WMH may directly cause CC atrophy by disrupting fibers of the corpus callosum as they are passing through the ischemic lesions in the deep white mater.^7,10–17Diffusion tensor imaging can detect early changes in white matter microstructure before atrophy occurs and could clarify the relationship between WMH and the CC.¹⁸ In DTI, pathologic processes that alter the structural integrity of tracts lead to changes in water diffusion and mean diffusivity (MD) and radial diffusivity (RD) as well as changes in the directionality of diffusion and fractional anisotropy (FA).^18,19 In patients with WMH, decreased FA and increased MD were found in the CC.¹³ Another study demonstrated correlations among CC atrophy, the FA/MD of deep white matter, and the FA/MD of the CC.¹⁷ These results confirm an association between WMH and the entire CC but do not distinguish between the effects of WMH on callosum tracts that cross WMH (CC-WMH) and those that do not cross WMH. If CC-WMH tracts had worse diffusion characteristics than CC tracts not crossing WMH, this feature would support an increased role for WMH in changes in the corpus callosum.Tractography is an application of DTI that allows the reconstruction of white matter tracts.¹⁸ In quantitative tractography, the diffusion characteristics (MD, RD, and FA) along the full trajectory of select fiber tracts can be assessed.¹⁸ This study used quantitative tractography to compare the diffusion characteristics of CC-WMH tracts with those of CC tracts not crossing WMH. For comparison, this study also performed a similar analysis in tracts that crossed WMH (WMH tracts) compared with those that did not cross WMH (lesion-free tracts) in the cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers. We hypothesized that CC-WMH tracts would have worse diffusion characteristics (increased MD and RD and decreased FA) compared with CC tracts not crossing WMH.     

Linking Stage-Specific Plasma Biomarkers to Gray Matter Atrophy in Parkinson Disease

BACKGROUND AND PURPOSE:The shortcomings of synucleinopathy-based Parkinson disease staging highlight the need for systematic clinicopathologic elucidation and biomarkers. In this study, we investigated associations of proteinopathy and inflammation markers with changes in gray matter volume that accompany Parkinson disease progression.MATERIALS AND METHODS:We prospectively enrolled 42 patients with idiopathic Parkinson disease, subdivided into early-/late-stage groups and 27 healthy controls. Parkinson disease severity and participants'' functional and cognitive performance were evaluated. Peripheral plasma α-synuclein, β-amyloid₄₂, and tau were quantified with immunomagnetic reduction assays, and nuclear DNA by polymerase chain reaction, and regional gray matter volumes were determined by MR imaging. Statistical tests identified stage-specific biomarkers and gray matter volume patterns in the early-stage Parkinson disease, late-stage Parkinson disease_, and control groups. Correlations between gray matter volume atrophy, plasma biomarkers, Parkinson disease severity, and cognitive performance were analyzed.RESULTS:Patients with Parkinson disease had significantly elevated α-synuclein, tau, and β-amyloid₄₂ levels compared with controls; nuclear DNA levels were similar in early-stage Parkinson disease and controls, but higher in late-stage Parkinson disease (all P < .01). We identified 3 stage-specific gray matter volume atrophy patterns: 1) control > early-stage Parkinson disease = late-stage Parkinson disease: right midfrontal, left lingual, and fusiform gyri, left hippocampus, and cerebellum; 2) control > early-stage Parkinson disease > late-stage Parkinson disease: precentral, postcentral, parahippocampal, left superior-temporal, right temporal, right superior-frontal, and left cingulate gyri, occipital lobe, and bilateral parts of the cerebellum; 3) control = early-stage Parkinson disease > late-stage Parkinson disease: left midfrontal, superior-frontal and temporal, amygdala, and posterior cingulate gyri, caudate nucleus, and putamen. We discovered stage-specific correlations among proteinopathy, inflammation makers, topographic gray matter volume patterns, and cognitive performance that accompanied Parkinson disease progression.CONCLUSIONS:Identifying associations linking peripheral plasma biomarkers, gray matter volume, and clinical status in Parkinson disease may facilitate earlier diagnosis and improve prognostic accuracy.

The degree of pathology from the onset of Parkinson disease (PD) to death is conventionally graded according to Braak staging, a neuroanatomic scheme based on the presence and spread of α-synuclein deposits in the brain (Lewy pathology).¹ However, the validity of this “pure” synucleinopathy-based staging approach is controversial due to inconsistencies such as discrepancies between the pathologic stage and clinical symptoms.² Recent studies have suggested that several coexisting misfolding proteins play important roles in the pathogenesis of PD, including cortical and limbic Lewy bodies,³ neurofibrillar tangles, senile plaques,⁴ and microglia.⁵ These heterogeneous etiologic pathways present challenges to formulating a unified staging model that encapsulates the entire disease course. Therefore, the systematic evaluation of sequential pathophysiologic and clinical changes in PD and of their mutual interactions is crucial.In addition to synucleinopathy, it has been reported that cytotoxic intermediates of β-amyloid (Aβ) fibril formation and tau protein aggregates lead to neuronal disruption and death, while also causing symptoms commonly observed in Alzheimer disease (AD).⁶ Postmortem studies have confirmed the coexistence of AD-related misfolding proteins from early-to-late stage PD, indicating that rapid cognitive decline predicts poor prognosis in early PD.^7,8 Furthermore, studies of CSF and serum biomarkers that indicate both Lewy body and AD pathology have garnered considerable interest.^9-11 Although CSF Aβ and tau levels in patients with PD have been reported to independently predict cognitive decline,¹² data are inconclusive.¹³ The results of studies of the total α-synuclein level in CSF and peripheral plasma are also controversial.^10,11 Explanations for such uncertainty may include, but are not limited to, methodologic variables and heterogeneous disease stages across participants in different studies. Moreover, levels of α-synuclein are exceptionally low in plasma compared with CSF, thereby limiting the capability of enzyme-linked immunosorbent assays to accurately detect plasma α-synuclein.¹⁴ More recently, immunomagnetic reduction (IMR), which has higher sensitivity than the conventional enzyme-linked immunosorbent assay,¹¹ has been applied to assay Aβs, tau, and α-synuclein in human plasma^11,15,16 and to confirm PD and AD diagnoses.^11,17,18 These results suggest that IMR may help to clarify the relationship between different misfolding proteins and the progression of PD.Apart from proteinopathy, inflammation in the CNS and peripheral blood could also contribute to neurodegeneration in PD.¹⁹ Cross-talk between the brain and peripheral inflammatory markers has been implicated in numerous psychologic, behavioral, and physiologic processes.²⁰ However, research into the association between systemic inflammation and disease progression and their interactions with proteinopathy contributing to regional gray matter volume (GMV) changes is limited and warrants further investigation.In the present study, we systematically investigated the complex associations among multiple plasma proteinopathies, Aβ₄₂, total tau (T-tau), and α-synuclein; nuclear DNA (nDNA), as a marker of inflammation; and regional GMV changes during PD progression. We aimed to identify stage-specific patterns of plasma biomarkers and regional GMVs and stage-specific associations linking GMV patterns, biomarker levels, and clinical status.     

Double Inversion Recovery MR Sequence for the Detection of Subacute Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE:The diagnosis of subacute subarachnoid hemorrhage is important because rebleeding may occur with subsequent life-threatening hemorrhage. Our aim was to determine the sensitivity of the 3D double inversion recovery sequence compared with CT, 2D and 3D FLAIR, 2D T2*, and 3D SWI sequences for the detection of subacute SAH.MATERIALS AND METHODS:This prospective study included 25 patients with a CT-proved acute SAH. Brain imaging was repeated between days 14 and 16 (mean, 14.75 days) after clinical onset and included MR imaging (2D and 3D FLAIR, 2D T2*, SWI, and 3D double inversion recovery) after CT (median delay, 3 hours; range, 2–5 hours). A control group of 20 healthy volunteers was used for comparison. MR images and CT scans were analyzed independently in a randomized order by 3 blinded readers. For each subject, the presence or absence of hemorrhage was assessed in 4 subarachnoid areas (basal cisterns, Sylvian fissures, interhemispheric fissure, and convexity) and in brain ventricles. The diagnosis of subacute SAH was defined by the presence of at least 1 subarachnoid area with hemorrhage.RESULTS:For the diagnosis of subacute SAH, the double inversion recovery sequence had a higher sensitivity compared with CT (P < .001), 2D FLAIR (P = .005), T2* (P = .02), SWI, and 3D FLAIR (P = .03) sequences. Hemorrhage was present for all patients in the interhemispheric fissure on double inversion recovery images, while no signal abnormality was noted in healthy volunteers. Interobserver agreement was excellent with double inversion recovery.CONCLUSIONS:Our study showed that the double inversion recovery sequence has a higher sensitivity for the detection of subacute SAH than CT, 2D or 3D FLAIR, 2D T2*, and SWI.

Nontraumatic subarachnoid hemorrhage accounts for 3% of all strokes, and 85% are related to a ruptured intracranial aneurysm.¹ CT is highly sensitive for the diagnosis of SAH at the acute stage.² However, clinical symptoms may be atypical and result in delayed admission. In such patients, the diagnosis of subacute SAH is important because rebleeding may occur with subsequent life-threatening intracranial hemorrhage.³When performed several days after symptom onset, CT does not appear reliable for the diagnosis of SAH^4,5 and is outperformed by brain MR imaging in this setting.⁶ Indeed, FLAIR MR imaging is more sensitive than CT for SAH detection at both acute^7–9 and subacute¹⁰ stages. 3D FLAIR is even more specific than 2D FLAIR by reducing flow-related artifacts, which are known to provide false-positive findings on 2D FLAIR.¹¹ Nevertheless, SAH can still be misdiagnosed by using FLAIR imaging due to the time interval after onset¹² or artifacts.^13,14 T2* gradient-echo sequences are useful for subacute or chronic SAH depiction.^6,15,16 Susceptibility-weighted imaging uses tissue magnetic-susceptibility differences to generate a unique contrast, based on a 3D flow-compensated gradient-echo sequence.¹⁷ Previous studies have suggested that SWI could accurately detect small amounts of SAH and intraventricular hemorrhage (IVH).^18–20 A recent study focusing on the detection of microbleeds also demonstrated that SWI had a greater sensitivity for blood products than the conventional T2* sequence.²¹ However, no study available compares the diagnostic performance of T2* and SWI for the detection of spontaneous SAH, to our knowledge.Double inversion recovery (DIR) MR imaging is useful for the detection of cortical lesions.^22–24 This technique is based on a 3D turbo spin-echo acquisition with variable refocusing flip angles (BrainView, Philips Healthcare, Best, the Netherlands; Cube, GE Healthcare, Milwaukee, Wisconsin; SPACE, Siemens, Erlangen, Germany). DIR includes 2 inversion recovery pulses designed for the suppression of both CSF and normal white matter.²⁴ Data are still not available on the value of 3D DIR for the detection of SAH. The purpose of our study was to determine the sensitivity of the 3D DIR sequence compared with CT, 2D and 3D FLAIR, 2D T2*, and 3D SWI sequences for the detection of subacute SAH.     

Nigrosome 1 Detection at 3T MRI for the Diagnosis of Early-Stage Idiopathic Parkinson Disease: Assessment of Diagnostic Accuracy and Agreement on Imaging Asymmetry and Clinical Laterality

BACKGROUND AND PURPOSE:In the early stages of idiopathic Parkinson disease, motor symptoms are usually asymmetric. We aimed to assess the feasibility of nigrosome 1 detection at 3T MR imaging to analyze the agreement of its asymmetry and clinical laterality.MATERIALS AND METHODS:High-resolution 3D multiecho imaging was performed at 3T MR imaging in 13 healthy subjects and 24 patients with idiopathic Parkinson disease confirmed by N-3-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane (¹⁸F-FP-CIT) PET. The nigrosome 1 detection findings by using the MR imaging data were rated as “normal,” “possibly abnormal,” and “abnormal” by 2 independent reviewers. The degree of ¹⁸F-FP-CIT binding was visually assessed in the caudate nucleus and putamen on PET images. Clinical laterality was evaluated by scores of the Unified Parkinson Disease Rating Scale, Part III. Asymmetry of the affected nigrosome 1 and the degree of ¹⁸F-FP-CIT binding were analyzed for agreement with clinical laterality.RESULTS:The diagnostic sensitivity, specificity, and accuracy of the nigrosome 1 detection at 3T MR imaging was 100%, 84.6%, and 94.6%, respectively. Interrater agreements for the abnormality and asymmetry of nigrosome 1 were excellent (κ = 0.863 and 0.835, respectively). In patients with idiopathic Parkinson disease, the agreement of asymmetry between clinical laterality and nigrosome 1 detection was good (κ = 0.724). The degree of the ¹⁸F-FP-CIT PET binding showed fair agreement (κ = 0.235) with clinical laterality.CONCLUSIONS:The abnormality involving nigrosome 1 can be detected at 3T MR imaging with an accuracy of 94.6%. The clinical laterality is in high concordance with the laterality of the nigrosome 1 detection at 3T (κ = 0.724).

Nigrosomes are calbindin-poor zones within the substantia nigra pars compacta.¹ The nigrosomes are primary subregions of the substantia nigra pars compacta where dopaminergic cells are lost in idiopathic Parkinson disease (IPD). Within the nigrosomes, the maximal cell loss occurs in nigrosome 1, which is the largest subgroup of the nigrosomes.²Recently, a few researchers have tried to visualize the nigrosome 1 area with 7T MR imaging and demonstrated its feasibility as an imaging biomarker for the diagnosis of IPD.^3–6 The results, however, had a limited clinical utility because of low availability of 7T MR imaging. Hence, several studies have tried to translate nigrosome 1 detection to 3T MR imaging, which is widely available.^7–9 In the previous studies at 3T, however, patients were confirmed as having IPD by clinical assessment, not by dopamine-transporter (DAT) imaging such as N-3-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane (¹⁸F-FP-CIT) PET or SPECT, which is commonly used for an early diagnosis of IPD.In clinical practice, it is more difficult to diagnose an early stage of parkinsonism than an advanced stage. Therefore, a confirmation by an imaging biomarker would be desirable in the diagnosis of a patient in an early stage. If the nigrosome 1 detection at 3T MR imaging is available for the diagnosis of early-stage IPD, it can minimize the need for the DAT PET or SPECT.In early stages of IPD, motor symptoms are usually asymmetric.¹⁰ Unilateral or asymmetric symptoms have been suggested to correspond to nigrostriatal degeneration in the contralateral hemisphere.¹¹ On the basis of this observation, we hypothesized that the asymmetric dopaminergic cell loss in the substantia nigra pars compacta reflects the contralateral symptoms in early-stage IPD, and the cell loss can be visualized by the signal change in the nigrosome 1 area at 3T MR imaging.In this study, we investigated the feasibility of the nigrosome 1 detection at 3T MR imaging for the diagnosis of patients with early-stage IPD with abnormal findings on DAT PET imaging.¹² Additionally, we assessed the agreement of asymmetry between the nigrosome 1 detection and patient symptoms, and the asymmetry between the DAT PET imaging and patient symptoms.     

Diffusion Tractography Biomarkers of Pediatric Cerebellar Hypoplasia/Atrophy: Preliminary Results Using Constrained Spherical Deconvolution

BACKGROUND AND PURPOSE:Advances in MR imaging modeling have improved the feasibility of reconstructing crossing fibers, with increasing benefits in delineating angulated tracts such as cerebellar tracts by using tractography. We hypothesized that constrained spherical deconvolution–based probabilistic tractography could successfully reconstruct cerebellar tracts in children with cerebellar hypoplasia/atrophy and that diffusion scalars of the reconstructed tracts could differentiate pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia, and progressive cerebellar atrophy.MATERIALS AND METHODS:Fifteen children with cerebellar ataxia and pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia or progressive cerebellar atrophy and 7 controls were included in this study. Cerebellar and corticospinal tracts were reconstructed by using constrained spherical deconvolution. Scalar measures (fractional anisotropy and mean, axial and radial diffusivity) were calculated. A general linear model was used to determine differences among groups for diffusion MR imaging scalar measures, and post hoc pair-wise comparisons were performed.RESULTS:Cerebellar and corticospinal tracts were successfully reconstructed in all subjects. Significant differences in diffusion MR imaging scalars were found among groups, with fractional anisotropy explaining the highest variability. All groups with cerebellar pathologies showed lower fractional anisotropy compared with controls, with the exception of cerebellar hypoplasia.CONCLUSIONS:This study shows the feasibility of constrained spherical deconvolution to reconstruct cerebellar and corticospinal tracts in children with morphologic cerebellar pathologies. In addition, the preliminary results show the potential utility of quantitative analysis of scalars of the cerebellar white matter tracts in children with cerebellar pathologies such as cerebellar hypoplasia and atrophy. Further studies with larger cohorts of patients are needed to validate the clinical significance of our preliminary results.

In past years, there has been an increasing interest in the application of advanced MR imaging techniques for in vivo investigation of WM microstructure by using diffusion MR imaging (dMRI).¹ dMRI provides image contrast based on differences in the magnitude of diffusion of water molecules in the brain.² By combining the directional information and magnitude of anisotropic diffusion of the individual voxels, the trajectories of the main WM tracts in the brain can be reconstructed^2,3 and quantitative analysis of WM organization can be performed.² dMRI scalars can be measured in specific anatomic ROIs or within/along reconstructed WM tracts to measure tissue properties.² Several studies have shown that advanced fiber tractography algorithms provide invaluable qualitative and quantitative information on the brain WM microstructure that cannot be obtained with conventional structural neuroimaging sequences.^2,4Developments in high-angular-resolution diffusion imaging^5,6 and progress in postprocessing software that take into account multiple fiber orientations in the same voxel have improved the correct anatomic reconstruction of WM tracts such as the afferent and efferent cerebellar pathways^5–9 by accommodating crossing fibers. Improvements in fiber tractography of the cerebellar pathways are important because a large number of congenital, acquired, or degenerative diseases of pediatric^10–26 and adult^27–31 populations affect the cerebellum.Currently, the diagnosis of nonprogressive cerebellar hypoplasia (CH) and progressive cerebellar atrophy (CA) is based on qualitative criteria that take into account conventional, structural MR imaging sequences.^32–35 CH refers to a developmental (nonprogressive) reduction of cerebellar volume with preserved near-normal shape,³² while CA is defined as progressive loss of cerebellar parenchyma, with secondary enlargement of the interfolia space.³³ In some diseases with prenatal onset, hypoplasia of the cerebellum may be associated with pontine hypoplasia (ie, pontocerebellar hypoplasia [PCH]¹⁷). Despite improvement of structural MR imaging techniques (eg, phased array and higher magnetic field), differentiation of CH and CA remains challenging, particularly when only 1 MR imaging study is available.^32–35 A correct distinction between CH and CA is important in terms of management, prognosis, and family counseling. Neuroimaging methods that may increase the sensitivity in the diagnosis of CH and CA are warranted.We aimed to study the feasibility of constraint spherical deconvolution fiber tractography to reconstruct cerebellar WM tracts and corticospinal tracts (CSTs) in children with PCH, CH, and CA. We hypothesized that despite different degrees of reduction of cerebellar volumes, our approach could successfully reconstruct cerebellar tracts. In addition, we aimed to measure microstructural properties of cerebellar tracts and CSTs in patients and age-matched controls. We expected that the reconstructed WM tracts would show altered scalar metrics in patients compared with controls. Differences in dMRI scalars of the cerebellar tracts and CSTs among the 3 groups of patients may shed light on the underlying pathomechanism causing macroscopic cerebellar abnormalities and may facilitate the differentiation among the 3 groups of diseases.     

Different Functional and Microstructural Changes Depending on Duration of Mild Cognitive Impairment in Parkinson Disease

BACKGROUND AND PURPOSE:The higher cortical burden of Lewy body and Alzheimer disease–type pathology has been reported to be associated with a faster onset of cognitive impairment of Parkinson disease. So far, there has been a few studies only about the changes of gray matter volume depending on duration of cognitive impairment in Parkinson disease. Therefore, our aim was to evaluate the different patterns of structural and functional changes in Parkinson disease with mild cognitive impairment according to the duration of parkinsonism before mild cognitive impairment.MATERIALS AND METHODS:Fifty-nine patients with Parkinson disease with mild cognitive impairment were classified into 2 groups on the basis of shorter (<1 year, n = 16) and longer (≥1 year, n = 43) durations of parkinsonism before mild cognitive impairment. Fifteen drug-naïve patients with de novo Parkinson disease with intact cognition were included for comparison. Cortical thickness, Tract-Based Spatial Statistics, and seed-based resting-state functional connectivity analyses were performed. Age, sex, years of education, age at onset of parkinsonism, and levodopa-equivalent dose were included as covariates.RESULTS:The group with shorter duration of parkinsonism before mild cognitive impairment showed decreased fractional anisotropy and increased mean and radial diffusivity values in the frontal areas compared with the group with longer duration of parkinsonism before mild cognitive impairment (corrected P < .05). The group with shorter duration of parkinsonism before mild cognitive impairment showed decreased resting-state functional connectivity in the default mode network area when the left or right posterior cingulate was used as a seed, and in the dorsolateral prefrontal areas when the left or right caudate was used as a seed (corrected P < .05). The group with longer duration of parkinsonism before mild cognitive impairment showed decreased resting-state functional connectivity mainly in the medial prefrontal cortex when the left or right posterior cingulate was used as a seed, and in the parieto-occipital areas when the left or right caudate was used as a seed (corrected P < .05). No differences in cortical thickness were found in all group contrasts.CONCLUSIONS:Resting-state functional connectivity and WM alterations might be useful imaging biomarkers for identifying changes in patients with Parkinson disease with mild cognitive impairment according to the duration of parkinsonism before mild cognitive impairment. The functional and microstructural substrates may topographically differ depending on the rate of cognitive decline in these patients.

Parkinson disease (PD) has been considered, until recently, primarily a motor disorder. It is now recognized that a substantial portion of patients with PD have measurable cognitive deficits ranging from mild cognitive impairment (PD-MCI) to dementia.^1,2 Although the exact pathologic substrates for cognitive impairment in PD are still under debate, limbic and cortical Lewy body– and Alzheimer disease (AD)–type pathology have been suggested as the main contributors to PD-MCI^3–6 as well as PD with dementia.^7–9 In terms of the rate of cognitive decline, a higher burden of these cortical pathologies^9,10 has been reported associated with a faster onset of cognitive impairment in PD.In contrast to pathologic studies, imaging studies are noninvasive and useful for discovering biomarkers in living humans. However, only a few structural imaging studies^11,12 have been conducted thus far to define anatomic candidates influencing the rate of cognitive decline in PD. These studies have revealed atrophy of the posterior cingulate cortex (PCC)¹¹ and inferior parietal and orbitofrontal areas¹² in patients with PD with shorter durations of parkinsonism before dementia and MCI, compared with those with longer durations of parkinsonism. These regions show considerable overlap with the default mode network (DMN), which is well-known to be disrupted in patients with AD.¹³ Some authors have suggested that impairment of axonal transport causes accumulation of axonally transported substances followed by cortical Lewy body formation.^14,15 In other words, alterations in WM, such as swelling and degeneration of the axonal projections, may precede cortical atrophy. Functional imaging is a more sensitive biomarker that detects earlier stages of disease than that seen structurally for both AD and PD.^16–18 However, there has been no study on the changes in WM integrity or resting-state functional connectivity (RSFC) according to the duration of parkinsonisim before cognitive impairment in PD.Therefore, we aimed to determine the structural and functional changes in patients with PD-MCI according to the duration of parkinsonism before MCI. During the resting-state fMRI analysis, we particularly focused on the DMN, which is highly associated with cognitive dysfunction in patients with AD¹³ and other neurodegenerative disorders.¹⁹ Furthermore, we also analyzed the corticostriatal loop, which is considered one of the primary areas of cognitive dysfunction in patients with PD.¹⁷     

Comparison of 3T and 7T Susceptibility-Weighted Angiography of the Substantia Nigra in Diagnosing Parkinson Disease

BACKGROUND AND PURPOSE:Standard neuroimaging fails in defining the anatomy of the substantia nigra and has a marginal role in the diagnosis of Parkinson disease. Recently 7T MR target imaging of the substantia nigra has been useful in diagnosing Parkinson disease. We performed a comparative study to evaluate whether susceptibility-weighted angiography can diagnose Parkinson disease with a 3T scanner.MATERIALS AND METHODS:Fourteen patients with Parkinson disease and 13 healthy subjects underwent MR imaging examination at 3T and 7T by using susceptibility-weighted angiography. Two expert blinded observers and 1 neuroradiology fellow evaluated the 3T and 7T images of the sample to identify substantia nigra abnormalities indicative of Parkinson disease. Diagnostic accuracy and intra- and interobserver agreement were calculated separately for 3T and 7T acquisitions.RESULTS:Susceptibility-weighted angiography 7T MR imaging can diagnose Parkinson disease with a mean sensitivity of 93%, specificity of 100%, and diagnostic accuracy of 96%. 3T MR imaging diagnosed Parkinson disease with a mean sensitivity of 79%, specificity of 94%, and diagnostic accuracy of 86%. Intraobserver and interobserver agreement was excellent at 7T. At 3T, intraobserver agreement was excellent for experts, and interobserver agreement ranged between good and excellent. The less expert reader obtained a diagnostic accuracy of 89% at 3T.CONCLUSIONS:Susceptibility-weighted angiography images obtained at 3T and 7T differentiate controls from patients with Parkinson disease with a higher diagnostic accuracy at 7T. The capability of 3T in diagnosing Parkinson disease might encourage its use in clinical practice. The use of the more accurate 7T should be supported by a dedicated cost-effectiveness study.

Parkinson disease (PD) is a common neurodegenerative disease whose pathologic substrate is nigrostriatal dopaminergic degeneration due to the neuronal loss in the pars compacta of the substantia nigra (SN).¹On the basis of the correlation between MR signal intensity at conventional field strengths and Perls staining for iron distribution, the medial portion of the midbrain with lower MR signal is attributed to the pars reticulata of the substantia nigra, and the lateral region (with higher MR signal), to the substantia nigra pars compacta.² However, Perls staining and T2WI signal hypointensity do not match precisely,³ and the hypointense area on T2WI does not match the substantia nigra pars reticulata.⁴ Moreover, conventional MR imaging techniques, including segmented inversion recovery ratio imaging,⁵ fail to distinguish the inner structure of the substantia nigra.⁶ More advanced and recently proposed SN-derived biomarkers such as relaxometry,^7,8 DTI,⁹ and neuromelanin imaging¹⁰ are currently not yet accepted in evaluating patients with PD in clinical practice.¹¹Recently, by using high-resolution 3D susceptibility-weighted angiography (SWAN),¹² the ultra-high-field (UHF) anatomy of the SN with its inner organization has been described¹³ as a 3-layer structure of different signal intensities along the posterior-anterior axis of the midbrain, resembling the dorsal and ventral components of the substantia nigra pars compacta and the substantia nigra pars reticulata, respectively. By using calbindin immunostaining, one can distinguish calbindin-positive (matrix) and calbindin-negative structures (nigrosomes)¹⁴ within the substantia nigra. In a recent MR imaging study at 7T,¹⁵ nigrosome 1, the largest and highly attenuated cluster of calbindin-negative neurons within the substantia nigra pars compacta ventralis, corresponded to the round hyperintense area observed in the intermediate and lateral portion of the substantia nigra pars compacta.¹⁶In patients with PD the 3-layer organization and the hyperintense lateral spot within the SN (nigrosome 1) are lost, and this radiologic sign distinguishes patients with PD from healthy subjects (HS) on an individual basis with high accuracy.¹³The diagnostic gain provided by 7T imaging is a prerequisite for the clinical acceptance of UHF, but until now, 7T MR imaging examinations have been confined to the research environment. The neuroimaging-based diagnosis of PD might constitute an important addition to the clinical diagnosis of extrapyramidal disorders. Therefore, the diagnostic role of SWI performed with a clinical MR imaging scanner at 3T has been tested recently,^17,18 with promising results. A direct comparison of 3T and 7T evaluation of the SN is mentioned in a pilot experience including 2 patients with PD.¹⁵Here, we describe a comparative study with a case control design that prospectively evaluates the diagnostic accuracy of SWAN at 3T and 7T.     

Changes in the Thalamus in Atypical Parkinsonism Detected Using Shape Analysis and Diffusion Tensor Imaging

BACKGROUND AND PURPOSE:The thalamus is interconnected with the nigrostriatal system and cerebral cortex and has a major role in cognitive function and sensorimotor integration. The purpose of this study was to determine how regional involvement of the thalamus differs among Parkinson disease, progressive supranuclear palsy, and corticobasal syndrome.MATERIALS AND METHODS:Nine patients with Parkinson disease, 5 with progressive supranuclear palsy, and 6 with corticobasal syndrome underwent 3T MR imaging along with 12 matched, asymptomatic volunteers by using a protocol that included volumetric T1 and diffusion tensor imaging. Acquired data were automatically processed to delineate the margins of the motor and nonmotor thalamic nuclear groups, and measurements of ADC were calculated from the DTI data within these regions. Thalamic volume, shape, and ADC were compared across groups.RESULTS:Thalamic volume was smaller in the progressive supranuclear palsy and corticobasal syndrome groups compared with the Parkinson disease and control groups. Shape analysis revealed that this was mainly due to the diminished size of the lateral thalamus. Overall, ADC measurements were higher in the progressive supranuclear palsy group compared with both the Parkinson disease and control groups, and anatomic subgroup analysis demonstrated that these changes were greater within the motor regions of the thalamus in progressive supranuclear palsy and corticobasal degeneration.CONCLUSIONS:Reduced size and increased ADC disproportionately involve the lateral thalamus in progressive supranuclear palsy and corticobasal syndrome, consistent with selective neurodegeneration and atrophy in this region. Because these findings were not observed in Parkinson disease, they may be more specific markers of tau-related neurodegeneration.

The neurodegenerative movement disorders Parkinson disease (PD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are distinguished postmortem by differing histologic abnormalities and regional patterns of neuropathologic changes. PSP and corticobasal syndrome (CBS) exhibit neuronal and glial cytoplasmic inclusions from accumulation of highly phosphorylated microtubule-associated tau protein, which is not evident in PD.^1–3 Paralleling these differences, typical clinical phenotypes help to distinguish these disorders. However, classic presentations are consistent only in advanced disease, and misdiagnosis is frequent in patients with early symptoms.^4,5 The diagnosis of CBD is particularly problematic⁶; for this reason, the term “corticobasal syndrome” is applied in lieu of CBD to convey the fact that disorders including Alzheimer disease, certain variants of frontotemporal lobar degeneration, and prion disease can present similarly.Various observations on MR imaging have been reported to differentiate PD, PSP, and CBD. Alterations in the shape or volume of several subcortical brain regions correlate with gross inspection of the brain in pathologically confirmed cases.⁷ However, such changes are subject to observer bias and are reliably found only in late disease. Unbiased approaches by using voxel-based morphometry and automated segmentation have also been applied with some success.^8–13 DTI studies have revealed increased diffusivity within the superior cerebellar peduncles in PSP,^14–16 along with more widespread changes within supratentorial white matter.^17,18 A number of groups have also described alterations in deep gray matter diffusion. For example, measurements of ADC are elevated within the putamen in up to 90% of patients with atypical parkinsonism but not significantly different from controls in patients with PD.^16,19The shared anatomic involvement of the basal ganglia and other brain regions in these disorders likely contributes to their frequent clinical overlap. Few studies have focused specifically on the thalamus, which, through the nigrostriatal system and thalamocortical circuits, plays a major role in cognition and sensorimotor integration. Alterations in thalamic volume have not been shown in prior studies of CBS, but significantly lower thalamic volume has been observed in PSP compared with both patients with PD²⁰ and controls.^10,20 Diminished volume by itself does not provide insight into how separate nuclear groups within the thalamus are selectively affected, however. One study suggested that thalamic shape differs between subjects with PD and healthy elders, though these changes were challenging to interpret because there was multifocal involvement over the entire surface of the thalamus without a corresponding difference in volume.²¹ Using DTI, Erbetta et al²² measured higher ADC within the anterior and lateral thalami in PSP and CBS compared with controls, but their analysis was based on relatively imprecise atlas-based estimates of nuclear boundaries.²²We hypothesized that regional thalamic morphology and tissue microstructure, measured with volumetric T1-weighted MR imaging and DTI, respectively, would be different in patients with PSP and CBS compared with patients with PD and controls. Using fully automated analysis of 3T T1 and DTI data, we evaluated thalamic shape and diffusion within motor and nonmotor thalamic nuclear groups and compared these measurements in patients with CBS, PSP, and PD and in healthy control subjects.     

Frontotemporal Cortical Thinning in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE:The extensive application of advanced MR imaging techniques has undoubtedly improved our knowledge of the pathophysiology of amyotrophic lateral sclerosis. Nevertheless, the precise extent of neurodegeneration throughout the central nervous system is not fully understood. In the present study, we assessed the spatial distribution of cortical damage in amyotrophic lateral sclerosis by using a cortical thickness measurement approach.MATERIALS AND METHODS:Surface-based morphometry was performed on 20 patients with amyotrophic lateral sclerosis and 18 age- and sex-matched healthy control participants. Clinical scores of disability and disease progression were correlated with measures of cortical thickness.RESULTS:The patients with amyotrophic lateral sclerosis showed a significant cortical thinning in multiple motor and extramotor cortical areas when compared with healthy control participants. Gray matter loss was significantly related to disease disability in the left lateral orbitofrontal cortex (P = .04), to disease duration in the right premotor cortex (P = .007), and to disease progression rate in the left parahippocampal cortex (P = .03).CONCLUSIONS:Cortical thinning of the motor cortex might reflect upper motor neuron impairment, whereas the extramotor involvement seems to be related to disease disability, progression, and duration. The cortical pattern of neurodegeneration depicted resembles what has already been described in frontotemporal dementia, thereby providing further structural evidence of a continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

Despite the common view of amyotrophic lateral sclerosis (ALS) as a neurodegenerative disease that exclusively affects motor functions, convincing evidence supports the notion that ALS is a multisystem disease also affecting behavior, language, and cognition.^1–6 Indeed, among patients with ALS, as many as 15% meet criteria for frontotemporal dementia (FTD), whereas up to 35% show a mild to moderate cognitive impairment.^5,7 From the histochemical and genetic points of view, recent findings suggest that ALS may belong to a broader clinicopathologic spectrum, known as transactivating responsive sequence DNA-binding protein 43-kDa (TDP-43) proteinopathy, which also includes FTD.^8–10Structural and functional MR imaging studies have corroborated the theory of a relevant frontotemporal impairment in ALS with approximately half of the patients displaying at least mild abnormalities.^11–20The development of advanced automated imaging analysis techniques, on the basis of construction of statistical parametric maps, has allowed detailed anatomic studies of brain morphometry. Voxel-based morphometry (VBM) allows a fully automated whole-brain measurement of regional brain atrophy by voxelwise comparison of GM and WM volumes between groups of participants.²¹ The most consistent finding of VBM studies in ALS involves GM atrophy in several regions of the frontal (ie, anterior cingulate, middle and inferior frontal gyrus) and temporal lobes (ie, temporal poles, superior temporal gyrus, temporal isthmus, hippocampus),^{11–13,16,17,19} reporting significant correlations between GM atrophy and cognitive dysfunction mainly in patients with an ALS-plus syndrome (ie, ALS with cognitive and behavioral symptoms).²⁰ However, the lack of agreement on cortical atrophy distribution²² has prompted the application of other advanced MR imaging approaches. Surface-based morphometry (SBM), allowing cortical thickness (CTh) measurements,²³ has shown several advantages compared with VBM in reconstructing the cortical surface. This technique, indeed, allows decomposition of cortical volume into both thickness and surface area, respecting the cortical topology and enhancing reliability and sensitivity.²⁴ Therefore, mainly to identify a more sensitive marker of upper motor neuron (UMN) degeneration, CTh analysis has been applied to the study of ALS, revealing cortical thinning not only in the precentral gyrus,^18,25–27 but also within the numerous frontotemporal, parietal, and occipital areas.^26–28 It is noteworthy that, so far, the correlation between regional cortical thinning and clinical features has not been fully assessed. On this background, we aimed to further investigate—without any a priori hypothesis—the pattern of both motor and extramotor cortical involvement in patients with sporadic ALS and to explore the relationship between MR imaging data and clinical and neuropsychological features.     

Age-related metabolic profiles in cognitively healthy elders: results from a voxel-based [18F]fluorodeoxyglucose-positron-emission tomography study with partial volume effects correction

BACKGROUND AND PURPOSE:Functional brain variability has been scarcely investigated in cognitively healthy elderly subjects, and it is currently debated whether previous findings of regional metabolic variability are artifacts associated with brain atrophy. The primary purpose of this study was to test whether there is regional cerebral age-related hypometabolism specifically in later stages of life.MATERIALS AND METHODS:MR imaging and FDG-PET data were acquired from 55 cognitively healthy elderly subjects, and voxel-based linear correlations between age and GM volume or regional cerebral metabolism were conducted by using SPM5 in images with and without correction for PVE. To investigate sex-specific differences in the pattern of brain aging, we repeated the above voxelwise calculations after dividing our sample by sex.RESULTS:Our analysis revealed 2 large clusters of age-related metabolic decrease in the overall sample, 1 in the left orbitofrontal cortex and the other in the right temporolimbic region, encompassing the hippocampus, the parahippocampal gyrus, and the amygdala. The division of our sample by sex revealed significant sex-specific age-related metabolic decrease in the left temporolimbic region of men and in the left dorsolateral frontal cortex of women. When we applied atrophy correction to our PET data, none of the above-mentioned correlations remained significant.CONCLUSIONS:Our findings suggest that age-related functional brain variability in cognitively healthy elderly individuals is largely secondary to the degree of regional brain atrophy, and the findings provide support to the notion that appropriate PVE correction is a key tool in neuroimaging investigations.

PET with FDG has emerged as a key tool for examining cerebral processes and is used to measure CMRglc, which indicates the level of neurosynaptic activity.¹ A thorough understanding of the influence of age on glucose metabolism is important to ensure a better distinction between normal and pathologic brain changes associated with the process of human aging. The first wave of PET studies designed to investigate normal brain aging was during the 1980s and was characterized by an overall agreement that there is no glucose hypometabolism in individuals without dementia.^2–6 Nevertheless, more recent studies have reported decrements in glucose metabolism in several prefrontal, parietal, and temporal areas during the life span, with relative preservation of limbic structures, the cerebellum, and occipital cortex.^7–12One possible explanation for the difference between newer and older reports of aging-associated brain functional variability is the improvement in PET scanners¹³ and the development of automated methods of analysis,¹⁴ which together have clearly increased the power to detect CMRglc changes associated with normal aging. However, it has been suggested that such aging-related CMRglc variability in cognitively healthy individuals could be due to PVE, which cause an apparent metabolic reduction in areas with steep GM atrophy and artificial metabolic preservation in areas with less pronounced GM reduction.^6,12,15–17 According to this view, CMRglc decrements that persist after correction of PET images for PVE, representing hypometabolism that exceeds brain atrophy, should be interpreted as indicative of pathologic brain aging,^18,19 thus placing PVE correction as a critical methodologic tool to differentiate normal and pathologic brain aging in PET studies. Accordingly, recent PET studies of glucose metabolism using PVE correction have suggested that regional hypometabolism exceeds brain atrophy in patients with MCI or AD,^20–22 but not in normal aging.^15,16 Nevertheless, to the best of our knowledge, no PET study has confirmed these findings in a representative sample of cognitively healthy elderly individuals.With the purpose of dealing with the above-mentioned issue, this study tested whether there is regional cerebral age-related hypometabolism specifically in later stages of life through the analysis of PET images from a sample comprising individuals older than 65 years of age. To ensure that the effects of brain atrophy and demographic variables were taken into consideration, we chose to perform our functional analysis with and without correction for PVE and accounted for the effects of demographic variables through statistical approaches described in the next section.     

Brain Parenchymal Signal Abnormalities Associated with Developmental Venous Anomalies in Children and Young Adults

BACKGROUND AND PURPOSE:Abnormal signal in the drainage territory of developmental venous anomalies has been well described in adults but has been incompletely investigated in children. This study was performed to evaluate the prevalence of brain parenchymal abnormalities subjacent to developmental venous anomalies in children and young adults, correlating with subject age and developmental venous anomaly morphology and location.MATERIALS AND METHODS:Two hundred eighty-five patients with developmental venous anomalies identified on brain MR imaging with contrast, performed from November 2008 through November 2012, composed the study group. Data were collected for the following explanatory variables: subject demographics, developmental venous anomaly location, morphology, and associated parenchymal abnormalities. Associations between these variables and the presence of parenchymal signal abnormalities (response variable) were then determined.RESULTS:Of the 285 subjects identified, 172 met inclusion criteria, and among these subjects, 193 developmental venous anomalies were identified. Twenty-six (13.5%) of the 193 developmental venous anomalies had associated signal-intensity abnormalities in their drainage territory. After excluding developmental venous anomalies with coexisting cavernous malformations, we obtained an adjusted prevalence of 21/181 (11.6%) for associated signal-intensity abnormalities in developmental venous anomalies. Signal-intensity abnormalities were independently associated with younger subject age, cavernous malformations, parenchymal atrophy, and deep venous drainage of developmental venous anomalies.CONCLUSIONS:Signal-intensity abnormalities detectable by standard clinical MR images were identified in 11.6% of consecutively identified developmental venous anomalies. Signal abnormalities are more common in developmental venous anomalies with deep venous drainage, associated cavernous malformation and parenchymal atrophy, and younger subject age. The pathophysiology of these signal-intensity abnormalities remains unclear but may represent effects of delayed myelination and/or alterations in venous flow within the developmental venous anomaly drainage territory.

Developmental venous anomalies (DVAs) are frequently identified on routine MR imaging of the brain with contrast. DVAs are typically considered normal variants of venous development and usually have no associated imaging findings. However, a subset of DVAs has been associated with findings such as cavernous malformations (CMs),^1–3 thrombosis with subsequent venous infarction,^4–8 lobar atrophy,⁹ T2 and FLAIR signal-intensity abnormalities,^9,10 and SWI hypointensities.¹¹ Signal abnormalities can occur in the drainage territory of DVAs and may produce diagnostic uncertainty with regard to the significance and relationship to presenting symptoms. Signal abnormalities on MR imaging have been described in 12.5%¹⁰ to 28.3%⁹ of DVAs in adults, with an increasing prevalence with older age. While well described in adults, this relationship has not been investigated in children, to our knowledge. The MR imaging appearance of the brain in children is quite different from that in adults during myelination, and the effect of DVAs on regional brain maturation has not been studied.The most commonly proposed etiologies for parenchymal abnormalities associated with DVAs are chronic venous hypertension/insufficiency leading to ischemia or microhemorrhage.^9–12 Although the effect of brain maturation is unknown, on the basis of these pathophysiologic mechanisms, we hypothesized that parenchymal abnormalities would be less common in children compared with adults. This study was performed to test this hypothesis and to investigate clinical factors and DVA characteristics associated with parenchymal signal abnormalities in children and young adults.     

Subcortical Atrophy Is Associated with Cognitive Impairment in Mild Parkinson Disease: A Combined Investigation of Volumetric Changes,Cortical Thickness,and Vertex-Based Shape Analysis

BACKGROUND AND PURPOSE:The involvement of subcortical deep gray matter and cortical thinning associated with mild Parkinson disease remains poorly understood. We assessed cortical thickness and subcortical volumes in patients with Parkinson disease without dementia and evaluated their associations with cognitive dysfunction.MATERIALS AND METHODS:The study included 90 patients with mild Parkinson disease without dementia. Neuropsychological assessments classified the sample into patients with mild cognitive impairment (n = 25) and patients without cognitive impairment (n = 65). Volumetric data for subcortical structures were obtained by using the FMRIB Integrated Registration and Segmentation Tool while whole-brain, gray and white matter volumes were estimated by using Structural Image Evaluation, with Normalization of Atrophy. Vertex-based shape analyses were performed to investigate shape differences in subcortical structures. Vertex-wise group differences in cortical thickness were also assessed. Volumetric comparisons between Parkinson disease with mild cognitive impairment and Parkinson disease with no cognitive impairment were performed by using ANCOVA. Associations of subcortical structures with both cognitive function and disease severity were assessed by using linear regression models.RESULTS:Compared with Parkinson disease with no cognitive impairment, Parkinson disease with mild cognitive impairment demonstrated reduced volumes of the thalamus (P = .03) and the nucleus accumbens (P = .04). Significant associations were found for the nucleus accumbens and putamen with performances on the attention/working memory domains (P < .05) and nucleus accumbens and language domains (P = .04). The 2 groups did not differ in measures of subcortical shape or in cortical thickness.CONCLUSIONS:Patients with Parkinson disease with mild cognitive impairment demonstrated reduced subcortical volumes, which were associated with cognitive deficits. The thalamus, nucleus accumbens, and putamen may serve as potential biomarkers for Parkinson disease–mild cognitive impairment.

Parkinson disease (PD) has traditionally been considered a motor disorder. However, the presence of cognitive dysfunction is increasingly recognized and known to occur even at early stages, and most patients develop dementia during the course of the disease. Recently, it has emerged that patients with PD show a wide and variable spectrum of cognitive deficits involving multiple domains such as executive function, attention, memory, visuospatial, and, less frequently, language.^1,2 While traditionally believed to occur only in advanced stages of PD, recent studies suggest that approximately 30%–35% of patients with early PD experience cognitive disturbances,^3,4 which have been defined as mild cognitive impairment (MCI).⁵ The Movement Disorder Society (MDS) Task Force reported a mean prevalence of Parkinson disease with mild cognitive impairment (PD-MCI) at 27%, ranging from 19% to 38%.⁶ Furthermore, the impact of MCI and dementia in patients with PD at any given stage of the disease is substantial, with adverse consequences for functioning,⁷ psychiatric morbidity, caregiver burden,⁸ and mortality.⁹ At present, there is much to be elucidated with regard to the etiology of cognitive impairment in PD.Initially, dementia in PD was described as subcortical. Cognitive dysfunction in patients without dementia has also been attributed to dopaminergic depletion disrupting the frontostriatal circuit¹⁰ or dopamine-acetylcholine synaptic imbalance.¹¹ Nevertheless, recent investigations by using structural MR imaging suggest that specific cognitive deficits, such as memory deficits, and dementia in PD may also be accompanied by structural cerebral abnormalities. In this regard, MR imaging studies have demonstrated cortical atrophy in patients with PD with dementia. A recent meta-analysis revealed regional gray matter reductions of the medial temporal lobe and the basal ganglia,¹² while other areas, including the caudate,¹³ hippocampus,¹⁴ and amygdala,¹⁵ have also been implicated. However, present findings on GM atrophy in patients without dementia with PD are inconclusive. While a few studies have demonstrated atrophy in the medial temporal lobes,¹⁶ amygdala,¹⁷ and frontal and parietal regions,¹⁸ others have reported no significant GM reductions in PD populations without dementia.¹⁹In addition, cortical thinning in PD represents a relatively new area of research, and it has been reported to be more sensitive than voxel-based morphometry.²⁰ Recent studies have shown that cortical thinning occurs in PD without dementia.²¹ A longitudinal study also reported that patients with early PD presented with a more aggressive rate of cortical thinning in the frontotemporal regions compared with healthy controls.²²These mixed neuroimaging findings could be due, in part, to cognitively heterogeneous groups of patients, particularly in studies in which patients with MCI were not distinguished from those with normal cognition. Therefore, to systematically compare the pattern of GM atrophy in mild PD and its impact on specific cognitive domains, we used the recent MDS Task Force criteria to classify patients with PD with MCI or as cognitively normal (PD-NCI). We estimated the volumes of the amygdala, hippocampus, nucleus accumbens, caudate nucleus, putamen, pallidum, and thalamus in a cohort of patients with PD by using the FMRIB Integrated Registration and Segmentation Tool (FIRST; http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FIRST).Furthermore, we assessed differences in subcortical deep gray matter (SDGM) structures between PD-MCI and PD-NCI and further examined associations between individual structures and cognitive performances across multiple domains. Because vertex analysis directly measures changes in geometry without any smoothing of the image data, it might have the potential to more precisely detect regional alterations of the subcortical GM than the conventional voxel-based morphometry approach.²³ Therefore, we used a vertex-based shape-analysis method to investigate potential shape differences of SDGM structures between PD-MCI and PD-NCI. Last, vertex-wise cortical thickness analysis was performed by using FreeSurfer (http://surfer.nmr.mgh.harvard.edu) to assess and compare patterns of regional cortical alterations between both PD groups.     

Progression of Microstructural Damage in Spinocerebellar Ataxia Type 2: A Longitudinal DTI Study

BACKGROUND AND PURPOSE:The ability of DTI to track the progression of microstructural damage in patients with inherited ataxias has not been explored so far. We performed a longitudinal DTI study in patients with spinocerebellar ataxia type 2.MATERIALS AND METHODS:Ten patients with spinocerebellar ataxia type 2 and 16 healthy age-matched controls were examined twice with DTI (mean time between scans, 3.6 years [patients] and 3.3 years [controls]) on the same 1.5T MR scanner. Using tract-based spatial statistics, we analyzed changes in DTI-derived indices: mean diffusivity, axial diffusivity, radial diffusivity, fractional anisotropy, and mode of anisotropy.RESULTS:At baseline, the patients with spinocerebellar ataxia type 2, as compared with controls, showed numerous WM tracts with significantly increased mean diffusivity, axial diffusivity, and radial diffusivity and decreased fractional anisotropy and mode of anisotropy in the brain stem, cerebellar peduncles, cerebellum, cerebral hemisphere WM, corpus callosum, and thalami. Longitudinal analysis revealed changes in axial diffusivity and mode of anisotropy in patients with spinocerebellar ataxia type 2 that were significantly different than those in the controls. In patients with spinocerebellar ataxia type 2, axial diffusivity was increased in WM tracts of the right cerebral hemisphere and the corpus callosum, and the mode of anisotropy was extensively decreased in hemispheric cerebral WM, corpus callosum, internal capsules, cerebral peduncles, pons and left cerebellar peduncles, and WM of the left paramedian vermis. There was no correlation between the progression of changes in DTI-derived indices and clinical deterioration.CONCLUSIONS:DTI can reveal the progression of microstructural damage of WM fibers in the brains of patients with spinocerebellar ataxia type 2, and mode of anisotropy seems particularly sensitive to such changes. These results support the potential of DTI-derived indices as biomarkers of disease progression.

Spinocerebellar ataxia type 2 (SCA2) is the second most frequent autosomal dominant inherited ataxia worldwide, after SCA3.¹ It is caused by expansion in excess of 32 CAG repeats in the gene encoding the Ataxin-2 protein, which mainly targets several pontine neurons and Purkinje cells in the cerebellum,² and it is associated with a pathologic pattern of pontocerebellar atrophy.^1,3 MR T1-weighted imaging enables in vivo detection of brain stem and cerebellar atrophy in patients with SCA2 in cross-sectional^4–6 and longitudinal⁷ studies.Recently, DWI and DTI have enabled quantitative assessment of the microstructural changes in brain tissue that result from neurodegenerative diseases.^5,8–21 In particular, in longitudinal studies, DTI may be a sensitive instrument for tracking the progression of neurodegeneration (namely, neuronal damage and loss, Wallerian degeneration, demyelination, and gliosis) and, we hope, for detecting the efficacy (or lack of thereof) of new therapeutic strategies. So far, relatively few studies have addressed this point,^22–30 and none have addressed it in relation to autosomal dominant ataxias.We performed a longitudinal DTI study in 10 patients with SCA2 and 16 age-matched healthy controls to explore the ability of DTI to detect and map the progression of microstructural damage reflecting advance of neurodegeneration. In particular, we analyzed several DTI-derived indices, including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA), and mode of anisotropy (MO), by using tract-based spatial statistics (TBSS), which enable a robust and unbiased voxelwise whole-brain analysis of the main white matter tracts.^19,21,31,32     

Susceptibility-Weighted Imaging in Pediatric Arterial Ischemic Stroke: A Valuable Alternative for the Noninvasive Evaluation of Altered Cerebral Hemodynamics

BACKGROUND AND PURPOSE:SWI provides information about blood oxygenation levels in intracranial vessels. Prior reports have shown that SWI focusing on venous drainage can provide noninvasive information about the degree of brain perfusion in pediatric arterial ischemic stroke. We aimed to evaluate the influence of the SWI venous signal pattern in predicting stroke evolution and the development of malignant edema in a large cohort of children with arterial ischemic stroke.MATERIALS AND METHODS:A semiquantitative analysis of venous signal intensity on SWI and diffusion characteristics on DTI was performed in 16 vascular territories. The mismatch between areas with SWI-hypointense venous signal and restricted diffusion was correlated with stroke progression on follow-up. SWI-hyperintense signal was correlated with the development of malignant edema.RESULTS:We included 24 children with a confirmed diagnosis of pediatric arterial ischemic stroke. Follow-up images were available for 14/24 children. MCA stroke progression on follow-up was observed in 5/6 children, with 2/8 children without mismatch between areas of initial SWI hypointense venous signal and areas of restricted diffusion on DTI. This mismatch showed a statistically significant association (P = .03) for infarct progression. Postischemic malignant edema developed in 2/10 children with and 0/14 children without SWI-hyperintense venous signal on initial SWI (P = .07).CONCLUSIONS:SWI-DTI mismatch predicts stroke progression in pediatric arterial ischemic stroke. SWI-hyperintense signal is not useful for predicting the development of malignant edema. SWI should be routinely added to the neuroimaging diagnostic protocol of pediatric arterial ischemic stroke.

Acute arterial ischemic stroke (AIS) affects 2–5/100,000 children every year and is associated with high mortality and morbidity.¹ The mortality rate is estimated at 5%–13%, and moderate-to-severe neurologic deficits or epilepsy occur in >50% of children after AIS.^2,3 The Chest and American Heart Association guidelines support the use of anticoagulation in acute pediatric arterial ischemic stroke (PAIS) despite of the absence of large-scale clinical trials.^4,5 Antithrombotic therapy aims to prevent early propagation of the thrombus, inhibit the formation of new thrombus, and promote early recanalization to save hypoperfused tissue at risk of irreversible ischemic infarction. However, the diagnosis of PAIS should be made first, and tissue at risk for infarction should be detected. The diagnosis of PAIS is frequently delayed or missed.⁶ DWI/DTI is a highly sensitive MR imaging sequence in detecting early ischemic regions and is the diagnostic criterion standard for imaging acute PAIS.⁷ Neuroimaging techniques that allow early, reliable, noninvasive identification of potentially salvageable hypoperfused brain tissue—the so called ischemic penumbra—are imperative to guide treatment.SWI is a high-spatial-resolution, gradient-echo MR imaging sequence that accentuates the magnetic properties of various substances such as blood, blood products, nonheme iron, and calcification.⁸ In addition, SWI accentuates magnetic susceptibility differences between deoxygenated hemoglobin in the vessels and adjacent oxygenated tissues. A few previous reports have shown that SWI-hypointense signals in veins draining hypoperfused brain areas provide indirect evaluation of critically perfused tissue by focusing on venous drainage.^9–12 In addition, SWI-hyperintense signal was reported to detect regions of hyperperfusion and to be associated with an increased risk of developing postischemic malignant edema.¹³ SWI may consequently serve as a valuable alternative sequence to evaluate the hemodynamics of brain tissue in PAIS.The aims of this retrospective study were to evaluate the potential of acute SWI to identify potentially salvageable brain tissue and to predict the development of postischemic malignant edema in the largest cohort of PAIS reported so far, to our knowledge. We hypothesized that hypointense venous signal on acute SWI may identify brain tissue at risk of infarction progression by focusing on venous drainage and that the presence of SWI-hyperintense venous signal may predict the development of postischemic malignant edema.     

Symptom Differences and Pretreatment Asymptomatic Interval Affect Outcomes of Stenting for Intracranial Atherosclerotic Disease

BACKGROUND AND PURPOSE:Different types of symptomatic intracranial stenosis may respond differently to interventional therapy. We investigated symptomatic and pathophysiologic factors that may influence clinical outcomes of patients with intracranial atherosclerotic disease who were treated with stents.MATERIALS AND METHODS:A retrospective analysis was performed of patients treated with stents for intracranial atherosclerosis at 4 centers. Patient demographics and comorbidities, lesion features, treatment features, and preprocedural and postprocedural functional status were noted. χ² univariate and multivariate logistic regression analysis was performed to assess technical results and clinical outcomes.RESULTS:One hundred forty-two lesions in 131 patients were analyzed. Lesions causing hypoperfusion ischemic symptoms were associated with fewer strokes by last contact [χ² (1, n = 63) = 5.41, P = .019]. Nonhypoperfusion lesions causing symptoms during the 14 days before treatment had more strokes by last contact [χ² (1, n = 136), 4.21, P = .047]. Patients treated with stents designed for intracranial deployment were more likely to have had a stroke by last contact (OR, 4.63; P = .032), and patients treated with percutaneous balloon angioplasty in addition to deployment of a self-expanding stent were less likely to be stroke free at point of last contact (OR, 0.60; P = .034).CONCLUSIONS:More favorable outcomes may occur after stent placement for lesions causing hypoperfusion symptoms and when delaying stent placement 7–14 days after most recent symptoms for lesions suspected to cause embolic disease or perforator ischemia. Angioplasty performed in addition to self-expanding stent deployment may lead to worse outcomes, as may use of self-expanding stents rather than balloon-mounted stents.

Intracranial atherosclerotic disease (ICAD) causes considerable morbidity and mortality, accounting for up to one-third of ischemic strokes in some series, particularly in certain populations.^1–3 Some lesions prove recalcitrant to first-line medical management, and, in recent decades, endovascular treatments have emerged and evolved as complementary therapies.^4,5 Early series demonstrated technical feasibility and acceptable safety for percutaneous transluminal angioplasty (PTA) and then stent placement of lesions in ICAD.^5–17 Initially, intracranial procedures were performed with devices designed and approved for coronary interventions, with subsequent release of angioplasty balloons specifically engineered for intracranial use.^5,12,17–33 In 2005, the Wingspan stent system with Gateway PTA balloon catheter (Stryker, Kalamazoo, Michigan) became the first stent approved for treatment of ICAD in the United States.^{5,12,18–22,25,34} Numerous studies reported progressively improved outcomes and low complication rates, but randomized data proving efficacy were lacking.^{5,12,18,20,24,25,35,36} In 2011, enrollment in the first randomized, controlled trial to evaluate stent placement versus medical management of ICAD, the Stent placement and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, was halted early due to high complication rates in the stent placement group as compared with the medical management group.⁴The results of SAMMPRIS have elicited strong responses from both proponents and detractors of stent placement, with clinical decisions now changing.⁵ This current study retrospectively analyzes results of stent placement procedures performed for ICAD at 4 centers, with attention given to factors not specifically assessed in SAMMPRIS that may help guide further investigations of endovascular ICAD management.     

Longitudinal Study of Gray Matter Changes in Parkinson Disease

BACKGROUND AND PURPOSE:The pathology of Parkinson disease leads to morphological brain volume changes. So far, the progressive gray matter volume change across time specific to patients with Parkinson disease compared controls remains unclear. Our aim was to investigate the pattern of gray matter changes in patients with Parkinson disease and to explore the progressive gray matter volume change specific to patients with Parkinson disease with disease progression by using voxel-based morphometry analysis.MATERIALS AND METHODS:Longitudinal cognitive assessment and structural MR imaging of 89 patients with Parkinson disease (62 men) and 55 healthy controls (33 men) were from the Parkinson''s Progression Markers Initiative data base, including the initial baseline and 12-month follow-up data. Two-way analysis of covariance was performed with covariates of age, sex, years of education, imaging data from multiple centers, and total intracranial volume by using Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra tool from SPM8 software.RESULTS:Gray matter volume changes for patients with Parkinson disease were detected with decreased gray matter volume in the frontotemporoparietal areas and the bilateral caudate, with increased gray matter volume in the bilateral limbic/paralimbic areas, medial globus pallidus/putamen, and the right occipital cortex compared with healthy controls. Progressive gray matter volume decrease in the bilateral caudate was found for both patients with Parkinson disease and healthy controls, and this caudate volume was positively associated with cognitive ability for both groups. The progressive gray matter volume increase specific to the patients with Parkinson disease was identified close to the left ventral lateral nucleus of thalamus, and a positive relationship was found between the thalamic volume and the tremor scores in a subgroup with tremor-dominant patients with Parkinson disease.CONCLUSIONS:The observed progressive changes in gray matter volume in Parkinson disease may provide new insights into the neurodegenerative process. The current findings suggest that the caudate volume loss may contribute to cognitive decline in patients with Parkinson disease and the progressive thalamus enlargement may have relevance to tremor severity in Parkinson disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopamine neurons in the substantia nigra, with other neurons in the cortex and subcortical nuclei also affected during the course of the disease. This pathology might lead to morphologic brain changes.Voxel-based morphometry (VBM) analysis has been used to assess the cortical gray matter changes in patients with PD. Some cross-sectional studies were performed to compare the differences between patients with PD and healthy controls. However, these PD-VBM studies have not yet drawn any congruent conclusions. Some studies have shown distributed brain atrophy in cortical and subcortical regions, including the frontal lobe, temporal lobe, parietal lobe, occipital lobe, and the limbic/paralimbic areas.^1–8 On the other hand, 1 study reported an increase of GM in the thalamus in patients with PD with unilateral resting tremor compared with controls.⁹ A recent study has observed not only brain volume loss in the occipital region but also volume increase in the limbic/paralimbic system.¹⁰ In addition, some studies have failed to find any GM change.^11–14 In fact, few of these previous findings were wholly consistent with each other. These inconsistencies may result from the patient heterogeneity, such as the age, disease duration, disease severity, and variable covariates used in VBM analysis, which may confound the effect of results in between-group differences. Therefore, this issue of brain volume change in PD groups required further examination.To our knowledge, few studies have focused on the progression of regional volume changes in PD by using VBM. One longitudinal study showed a progressive gray matter volume (GMV) decrease in patients with PD with and without dementia with disease progression during a mean follow-up period of 25 months.¹⁵ In that study, a progressive GMV decrease in the limbic/paralimbic and temporo-occipital regions was observed in patients with PD, while in patients with dementia, the loss mainly involved the neocortical regions. However, in that study, no healthy matched controls were included. So far, the progressive GMV change across time specific to patients with PD compared with controls remains unclear.Thus, the main goals of the present study were to examine the GMV change in the PD group compared with healthy controls and to explore the progressive GMV change specific to patients with PD compared with controls with disease progression.