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Rationale: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative., Patients and Methods: Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data., Results: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%., Conclusions: K-means clustering may be a powerful algorithm for classifying amyloid brain PET., Competing Interests: Conflicts of interest and sources of funding: This is a multisite project of the Toronto Dementia Research Alliance partly funded by Brain Canada, The Edward Foundation, the Canadian Institutes of Health Research, the LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, and the Dr Sandra Black Centre for Brain Resilience and Recovery. Phillip H. Kuo is a consultant for Novartis, Konica Minolta, and Bayer; is a consultant and speaker for Esai and General Electric Healthcare; and received a grant from Blue Earth Diagnostics. The other authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background/objective: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies., Methods: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies., Results: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study., Discussion: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Background and Purpose: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents., Materials and Methods: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter., Results: Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions ( P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus ( P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents., Conclusions: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration., (© 2018 by American Journal of Neuroradiology.)

Background: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia., Methods: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers., Findings: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1)., Interpretation: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials., Funding: Centres of Excellence in Neurodegeneration., (Copyright © 2015 Rohrer et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Importance: Noninvasive measures of activity within intrinsic brain networks may be clinically relevant, providing a marker of neurodegenerative disease and predicting clinical behaviors., Objective: To correlate baseline resting-state measures within the salience network and changes in behavior among patients with frontotemporal dementia., Design: Baseline resting-state functional magnetic resonance imaging data and longitudinal clinical measures were obtained from prospectively accrued patients during 8 weeks., Setting: Tertiary academic care center specializing in the assessment and management of patients with neurodegenerative disease., Participants: Fifteen patients with clinically diagnosed frontotemporal dementia (5 behavioral variant and 10 semantic dementia)., Main Outcomes and Measures: Baseline resting-state functional magnetic resonance imaging data measured within regions of interest were regressed on serial behavioral measures from prospectively accrued patients with frontotemporal dementia to determine the ability of baseline resting-state activity to account for changes in behavior., Results: Low-frequency fluctuations in the left insula significantly predicted changes in Frontal Behavioral Inventory scores (standard β = 0.51, P = .049), accounting for 28% of the change variance. The trend was driven by changes in measures of apathy independent of dementia severity., Conclusion and Relevance: Baseline measures of salience network connectivity involving the left insula may predict behavioral changes in patients with frontotemporal dementia.

Since the first development of diagnostic criteria for multiple sclerosis (MS), there have been regular revisions of disease definitions and diagnostic thresholds aimed at improving specificity while maintaining sensitivity. The central requirements for diagnosis of MS are dissemination in space (DIS) and dissemination in time (DIT) of lesions in the CNS, with the proviso that there should be no alternate diagnosis that better explains the clinical presentation. The most definitive diagnosis is the purely clinical one, with 2 separate attacks of symptoms (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). In patients who have had a first but not a second clinical attack, the McDonald criteria provide guidance on how paraclinical evidence can be used to support a diagnosis of MS. Recently, the McDonald criteria were revised and new definitions for DIS and DIT proposed. In response to that revision, a panel of Canadian MS neurologists and one neuroradiologist created this commentary regarding the clinical implications and applications of the 2010 McDonald criteria.

Autobiographical memory paradigms have been increasingly used to study the behavioral and neuroanatomical correlates of human remote memory. Although there are numerous functional neuroimaging studies on this topic, relatively few studies of patient samples exist, with heterogeneity of results owing to methodological variability. In this study, fronto-temporal lobar degeneration (FTLD), a form of dementia affecting regions crucial to autobiographical memory, was used as a model of autobiographical memory loss. We emphasized the separation of episodic (recollection of specific event, perceptual, and mental state information) from semantic (factual information unspecific in time and place) autobiographical memory, derived from a reliable method for scoring transcribed autobiographical protocols, the Autobiographical Interview [Levine, B., Svoboda, E., Hay, J., Winocur, G., & Moscovitch, M. Aging and autobiographical memory: Dissociating episodic from semantic retrieval. Psychology and Aging, 17, 677-689, 2002]. Patients with the fronto-temporal dementia (FTD) and mixed fronto-temporal and semantic dementia (FTD/SD) variants of FTLD were impaired at reconstructing episodically rich autobiographical memories across the lifespan, with FTD/SD patients generating an excess of generic semantic autobiographical information. Patients with progressive nonfluent aphasia were mildly impaired for episodic autobiographical memory, but this impairment was eliminated with the provision of structured cueing, likely reflecting relatively intact medial-temporal lobe function, whereas the same cueing failed to bolster the FTD and FTD/SD patients' performance relative to that of matched comparison subjects. The pattern of episodic, but not semantic, autobiographical impairment was enhanced with disease progression on 1- to 2-year follow-up testing in a subset of patients, supplementing the cross-sectional evidence for specificity of episodic autobiographical impairment with longitudinal data. This behavioral pattern covaried with volume loss in a distributed left-lateralized posterior network centered on the temporal lobe, consistent with evidence from other patient and functional neuroimaging studies of autobiographical memory. Frontal lobe volumes, however, did not significantly contribute to this network, suggesting that frontal contributions to autobiographical episodic memory may be more complex than previously appreciated.

Background: Glatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients., Objective: To determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy., Design/methods: 40 RRMS patients, aged 18 to 55 years, with 1-15 Gd-enhancing lesions on screening MRI and EDSS score 0-6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15., Results: At baseline, mean (+/- SD) age was 37.2 +/- 9.7 years; disease duration, 3.5 +/- 4.8 years; EDSS score, 2.3 +/- 1.1; and number of Gd-enhancing lesions, 3.75 +/- 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11-0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone., Conclusions: Longterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.

We present a new method for advanced image processing to separately quantify significant decreases and increases in the magnetization transfer ratio (MTR) of individual voxels of MS lesions as markers of demyelination and remyelination. We used this method to analyze the evolution of MTR in individual voxels of an acute, Gadolinium (Gd)-enhancing lesion that was available for pathology. Over 6.5 months following enhancement, MTR was low and stable in the lesion center (81% of the initially Gd-enhancing lesion volume (GdLV)) and MTR increased at the lesion border with normal-appearing white matter (14%GdLV). The estimated error of these measurements was less than 1.8%GdLV based on scan/rescan analysis. Histopathological analysis confirmed a demyelinated lesion centre with diffuse presence of macrophages/microglia and marked loss of oligodendrocytes and a partially remyelinated lesion border with diffuse presence of macrophages/microglia and relatively more oligodendrocytes compared to the lesion centre. The correlation of imaging and histopathological findings support the validity and sensitivity of our method of voxel-based MTR image processing for monitoring demyelination and remyelination in vivo.

Frontotemporal dementia (FTD) is one of three neurobehavioural syndromes produced by frontotemporal lobar degeneration. Despite the importance of FTD as a cause of dementia, especially in younger age groups, and a rationale for therapies targeting serotonergic and dopaminergic systems, there have been no large scale treatment trials in FTD. Moreover, there is no consensus on standards to facilitate comparison across therapeutic trials. This paper reviews the literature on therapeutic trials in FTD and outlines general recommendations for standards related to the development of future treatment studies in this disorder. Drugs tested in FTD include trazodone, galantamine, idazoxan, lithium plus fluoxetine, lithium plus paroxetine, SSRIs, 1-deprenyl, moclobemide, methylphenidate, piracetam, rivastigmine, donepezil, olanzapine, risperidone, amantadine, guanfacine, allopurinol, and bromocriptine. Improvement has been reported in FTD for all drugs except piracetam, guanfacine and galantamine, although there was improvement on galantamine in primary progressive aphasia. Whereas improvement has been reported for paroxetine and other SSRIs, as well as idazoxan and methylphenidate, paroxetine and idazoxan have also been reported to cause a decline in function, and a marginally significant decline has been reported for methylphenidate. In addition, patients with Pick's disease, which is part of the spectrum of frontotemporal lobar degeneration, showed improvement on calcium EDTA. Six studies are double-blind placebo-controlled trials: two reports of cases using idazoxan and group trials using trazodone, paroxetine, galantamine and methylphenidate. It is recommended that experts in FTD arrive at a consensus to define standards for all clinical trials in FTD. These should include standards for diagnostic criteria, tests of severity, experimental design, and outcome measures.

The authors measured brain atrophy in nine patients undergoing immunoablation and autologous hematopoietic stem cell transplantation for multiple sclerosis. From baseline to 1 month after treatment, atrophy was 10 times faster than before treatment. A patient with non-CNS lymphoma showed comparable acute brain atrophy after analogous therapy. These observations suggest that brain atrophy after immunoablation may not be due entirely to the resolution of edema but may be related to chemotoxicity.

Multiple sclerosis (MS) lesions show differing degrees of demyelination and remyelination. Changes in myelin content are associated with changes in magnetization transfer on MRI. Since acute inflammation and demyelination are spatially and temporally inhomogeneous, we hypothesized that local magnetic transfer ratio (MTR) heterogeneity might be predictive of subsequent changes in MTR. To test this hypothesis, we analyzed MTR images obtained in 14 subjects, at baseline and after 2 months follow-up. We segmented lesions and normal-appearing white-matter (NAWM), calculated MTR signal inhomogeneity maps at baseline and MTR lesion difference maps between baseline and follow-up. We found that regions with low MTR inhomogeneity at baseline experienced little further change in MTR on follow-up. The mean change in lesion MTR between baseline and follow-up was 0.10 +/- 3.70; in NAWM it was -0.09 +/- 2.02. We found that regions with high MTR inhomogeneity at baseline would change MTR on follow-up: (1) voxels with significantly high MTR in regions of high MTR inhomogeneity at baseline showed a mean decrease in MTR between baseline and follow-up of -2.51 +/- 4.68 in lesions and -1.41 +/- 3.00 in NAWM; (2) voxels with low MTR in regions of high MTR inhomogeneity at baseline showed a mean increase in MTR between baseline and follow-up of 2.61 +/- 6.07 in lesions. These changes in MTR were significantly different (P < 0.001). These results suggest that calculation of MTR signal inhomogeneity may provide a method for quantifying the potential for remyelination and demyelination, and thus could provide an important MRI biomarker for assessing the efficacy of therapies targeting remyelination.

Unlabelled: Normative ethyl cysteinate dimer (ECD) SPECT data must be available to successfully apply ECD SPECT to clinical studies. The purpose of this study was to determine ECD SPECT scan patterns of healthy adults., Methods: Forty-eight healthy volunteers (22 men, 26 women; age range, 22-95 y; mean age, 47.6 +/- 19.2 y) underwent high-resolution ECD SPECT. For visual analysis of regional brain ECD uptake, we used a scale of +3 to -3, in which +3 and -3 indicated highest ECD uptake and deficit, respectively. For quantitative analysis, we measured the region-to-cerebellum ratio (R/CE) and the region-to-cerebral cortex ratio (R/CO) for 17 regions (13 cortical, 3 subcortical, and 1 cerebellar)., Results: On visual analysis, no subject had a score of -3. All subjects had a score of -2 for the hippocampus and a score of +3 for the medial occipital cortex, except for 2 subjects who had a score of +3 for the striatum and thalamus. A frontal eye field and posterior parieto-occipital junction were identified in 60% of subjects with a score of +1 and 79% of subjects with a score of +2. On quantitative analysis, a significant regional variation (ANOVA, P < 0.0001) was seen in R/CE, ranging from 0.709 (hippocampus) to 1.26 (medial occipital cortex). However, regional right-to-left differences and intersubject variability of R/CE were small (asymmetry index, 3.6% +/- 0.8%; coefficient variation, 6.6% +/- 0.7%). R/CE declined significantly with age in 6 regions, including the anterior and posterior cingulate cortex, superior prefrontal and parietal cortex, striatum, and hippocampus (1.0%-2.0% per decade, P < 0.05), whereas R/CO in the cerebellum increased significantly with age (1.0% per decade, P < 0.05)., Conclusion: Although regional ECD brain perfusion patterns vary significantly, including variability caused by the age-related effect, intersubject variability is small. Recognition of these normal patterns is important for clinical interpretation of ECD SPECT studies.

Meta-analytic methods were used to determine the most sensitive indexes to fronto-subcortical deficit in progressive supranuclear palsy (PSP) and to further characterize the neurocognitive and related features of PSP that can provide a basis of comparison to other disorders with prominent subcortical brain lesions. Studies dating back to 1984 were gathered and calibrated to compare the neuropsychological, neuroimaging, and neurophysiological test results from 229 patients with PSP, and 357 healthy controls. The tests most sensitive to fronto-subcortical deficit in PSP were mostly neuropsychological measures that include such tests as the Stroop Task, Trail Making Test Part A, and Purdue pegboard performance. We conclude that although neuropsychological measures may be most sensitive to deficits in PSP, they are also less specific and valid indicators of fronto-subcortical brain system integrity., (Copyright 1998 Academic Press.)

We studied brain glucose metabolism in patients with Alzheimer's disease and age-matched controls in vivo by PET and assessed brain glucose utilization and the phosphorylation constant K3 for hexokinase. In addition we determined in vitro the binding of 2DG and measured its phosphorylation to 2DG-phosphate in cerebral microvessels obtained at autopsy from subjects with Alzheimer's disease and age-matched controls. In patients with Alzheimer's disease we found a marked decrease in the kinetic constant K3 for the hexokinase, and a marked decrease in the overall metabolism of glucose in our PET studies; in microvessels there was a marked decrease in the affinity of 2DG and a decrease in hexokinase activity. Alzheimer's disease may be related to a complex alteration in brain glucose metabolism.

In vitro determination of brain glucose metabolism in the temporal cortex from patients with Alzheimer's disease showed a marked decrease when compared with nondemented, age-matched control subjects. Additional determinations on normal human temporal cortex obtained at autopsy demonstrated an age-dependent decline in the rate of glucose use. These data provide an in vitro correlate for positron emission tomography studies that suggest decreased brain glucose use in Alzheimer's disease.

99mTc-HM-PAO single photon emission computed tomography (SPECT) was used to image 30 patients referred for the assessment of dementia. SPECT images revealed various patterns of regional cerebral perfusion (rCBF) in the subgroups of patients with the clinical diagnoses of Alzheimer's disease (AD, n = 14), Pick's disease (n = 1), and multi-infarct dementia (n = 7). In three patients, SPECT clarified the clinical differential diagnostic possibilities. Using a relative rCBF quantification technique, the relationship between specific cognitive impairments and rCBF in the AD patients was determined. There was a significant correlation between language impairment and left hemisphere hypoperfusion, whereas, apraxia correlated with hypoperfusion in the left parietal region. Thus, HM-PAO SPECT is useful as an aid in the differential diagnosis of dementia and the technique of relative rCBF quantification with SPECT may contribute to the understanding of the clinico-anatomical relations of cognitive deficits in dementia.

Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable. Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P < 0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values. The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.

Gliomas in vitro exhibit density-limited growth upon the attainment of confluency, an effect usually attributed to cell-cell contact inhibition. Since gliomas have been demonstrated to secrete an array of soluble factors which can enhance tumor growth, we undertook this study to ascertain whether production of soluble factors by the tumor may also inhibit growth in an autocrine manner, and whether production of such factors is associated with the growth phase of the glioma. We observed that cell-conditioned medium (supernatants) from non-confluent glioma cultures induced growth, while confluent culture supernatants produced pronounced growth suppression. These latter supernatants enhanced proliferation of non-transformed astrocytes. Supernatants derived from all stages of confluency produced inhibition of lymphocyte proliferation. To characterize these factors, dialyzed supernatant was tested and found to continue to produce lymphocyte suppression but no glioma growth limitation. Growth of tumors in indomethacin or in acetylsalicylic acid to abolish prostanoid synthesis abrogated the inhibitory influence on glioma growth but only partially reversed the lymphocyte suppressive capacity. These studies suggest that gliomas do produce a growth phase dependent autocrine inhibitory factor(s), and that the production of these small molecular weight factors is at least partially under control of the cyclooxygenase pathway.

T cells are postulated to contribute to the injury of the oligodendrocyte-myelin complex underlying the demyelinating disease multiple sclerosis (MS). The apparent lack of class I or II major histocompatibility complex (MHC) expression in situ on human oligodendrocytes and the consistent failure to identify a universal myelin antigen in MS suggest that the immune damage might be mediated by effector T cells that are capable of reacting in an antigen-nonspecific and possibly MHC-unrestricted manner, such as T cells expressing the gamma-delta T-cell receptor. Since gamma-delta T cells are reported to be present in MS plaques and an increased number are found in the cerebrospinal fluid of patients with MS, we directly examined whether gamma-delta T cells are capable of inducing injury to human oligodendrocytes. We found, using a 6-hour 51Cr release assay, that oligodendrocytes cultured from surgically resected human brain specimens were effectively lysed in a dose-dependent manner by human gamma-delta T cells (28 +/- 5% mean specific lysis, n = 6, at an effector-target ratio of 20:1). Although heat shock protein HSP72, a putative gamma-delta T-cell recognition molecule, could be induced in vitro in our oligodendrocytes, an antibody to HSP72 did not inhibit gamma-delta T cell-mediated lysis of oligodendrocytes. These results suggest that gamma-delta T cells gaining entry into the central nervous system may be deleterious to oligodendrocytes and thus may contribute to the pathogenesis of MS.

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.

Analysis of language profiles and CT anatomy in transcortical motor aphasia (TCMA) suggests that the essential lesion is disruption of connections at sites between the supplementary motor area and the frontal perisylvian speech zone. If the lesion is extended, there may also be poor articulation (lesion deep to motor strip for face), impaired auditory comprehension (lesion in anterior head of caudate, anterior limb internal capsule, anterior putamen, and anterior portion of external capsule, claustrum, extreme capsule, and insula), or stuttering (lesion in pars opercularis and lower third of premotor region). This concept unifies disparate anatomic and psychophysiologic observations about three syndromes: classical TCMA, aphasia after left medial frontal infarction, and TCMA during recovery from Broca's aphasia.

Background/Aims: Automated, volumetrically defined atrophy in the left anterior cingulate (LAC) and anterior temporal regions (LAT) on MRI can be used to distinguish most patients with frontotemporal dementia (FTD) from controls. FTD and Alzheimer's disease (AD) can differ in the degree of anterior temporal atrophy. We explored whether clinicians can visually detect this atrophy pattern and whether they can use it to classify the 2 groups of dementia patients with the same accuracy. Methods: Four neurologists rated atrophy in the LAC and LAT regions on MRI slices from 21 FTD, 21 controls, and 14 AD participants. Inter-rater reliability and diagnostic accuracy were assessed. Results: All 4 raters agreed on the presence of clinically significant atrophy, and their atrophy scoring correlated with the volumes, but without translation into high inter-rater diagnostic agreement. Conclusions: Volumetric analyses are difficult to translate into routine clinical practice. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]