Progressive Brain Atrophy Research Articles

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. Invitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The invivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis

The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.

Alzheimer’s Anti-Tau Drug Fails Phase III, Shows Benefit in Monotherapy

TORONTO — A phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefi ts when given in conjunction with standard-of-care Alzheimer’s disease medications. The drug, LTMX (TauRx), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release. Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild to moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy. Among these patients, LMTX was associated with dose-dependent, statistically signifi cant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass. Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, of the Mayo Clinic, Rochester, MN, who moderated a press briefing where the data were presented. “I think the secondary results are interesting, especially imaging fi ndings. But ... because this is a small subset of just 15%, it’s very diffi cult to interpret.”

Localizing Sources of Brain Disease Progression with Network Diffusion Model.

Pinpointing the sources of dementia is crucial to the effective treatment of neurodegenerative diseases. In this paper, we propose a diffusion model with impulsive sources over the brain connectivity network to model the progression of brain atrophy. To reliably estimate the atrophy sources, we impose sparse regularization on the source distribution and solve the inverse problem with an efficient gradient descent method. We localize the possible origins of Alzheimer's disease (AD) based on a large set of repeated magnetic resonance imaging (MRI) scans in Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The distribution of the sources averaged over the sample population is evaluated. We find that the dementia sources have different concentrations in the brain lobes for AD patients and mild cognitive impairment (MCI) subjects, indicating possible switch of the dementia driving mechanism. Moreover, we demonstrate that we can effectively predict changes of brain atrophy patterns with the proposed model. Our work could help understand the dynamics and origin of dementia, as well as monitor the progression of the diseases in an early stage.

EIF2B-related multisystem disorder in two sisters with atypical presentations

Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy. The index case had a history of hepatomegaly and intermittent vomiting after upper respiratory infection at 11 months of age. Her older brothers had died at an early age, one with similar symptoms and the other because of septic shock. Her older sister had similar presenting symptoms; she later suffered from both cataracts and primary amenorrhea, but showed neurological improvement. Her follow-up MRIs (at 21 years of age) revealed progressive diffuse brain atrophy with leukoencephalopathy, without cystic rarefaction. Whole-exome sequencing of the index case revealed the presence of the compound heterozygous variants, Val85Glu and Met226Lys in EIF2B2. The affected sister had the same compound heterozygous variants, and their unaffected parents were heterozygous carriers of each variant. This study expanded the clinical and genetic spectrum of VWM with EIF2B2 variants. It would be better to consider VWM as an eIF2B-related multisystem disorder, not just as a neurological disorder, on the basis that this is a family of housekeeping genes that affect multiple organs.

A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients

Background: We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing–remitting multiple sclerosis (RRMS). Methods: At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48 weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points. Results: In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, −7.5% vs −5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, −7.7% vs −6.2%, p = 0.001), and GM (d = 0.40, −7.1% vs −5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes. Conclusions: WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.

Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P = .002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P = .04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P = .004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible. In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.

Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression.

Experimental therapies for ceroid lipofuscinosis, neuronal, 2 (CLN2), a genetic disorder of childhood associated with progressive brain atrophy, are currently being developed. Because quantitative descriptions of the natural course of brain volume loss are needed to evaluate novel therapies, we performed MR imaging volumetry of patients with CLN2 to identify a suitable MR imaging marker of disease progression. Thirteen patients (8 females, 5 males) were recruited from a prospective natural disease cohort of patients with neuronal ceroid lipofuscinosis. Repeated MR imaging volumetric analysis (29 datasets) was performed by using the FreeSurfer Software Suite. Follow-up time ranged from 8 months to 5.3 years. MR imaging-segmented brain volumes were correlated to patient age and clinical scores. Segmented brain volumes correlated significantly with patient age (lateral ventricles, r = 0.606, P = .001; supratentorial cortical GM, r = -0.913, P < .001; supratentorial WM, r = -0.865, P < .001; basal ganglia/thalamus, r = -0.832, P < .001; cerebellar GM, r = -0.659, P < .001; cerebellar WM, r = -0.830, P < .001) and clinical scores (lateral ventricles, r = -0.692, P < .001; supratentorial cortical GM, r = 0.862, P < .001; supratentorial WM, r = 0.735, P < .001; basal ganglia/thalamus, r = 0.758, P < .001; cerebellar GM, r = 0.609, P = .001; cerebellar WM, r = 0.638, P < .001). Notably, supratentorial cortical GM showed a uniform decline across the patient cohort. During late stages of the disease when the clinical score was zero, segmented brain volumes still correlated with patient age; this finding suggests that MR imaging volumetry allows quantitative assessment of disease progression at stages when it cannot be detected by clinical assessment alone. Automated MR imaging volumetry, as a nonsubjective and highly sensitive tool, is feasible in CLN2 disease and provides a quantitative basis to evaluate novel experimental therapies.

Leukodystrophy with Calcifications and Central Nervous System Atrophy: Expansion of the Phenotypic Spectrum Regarding Autosomal Recessive AARS Mutations?

Background/Purpose: In a female patient developmental regression occurred in the second year of life leading to spastic tetraparesis, dysphagia, optic atrophy and epilepsy. Imaging studies showed progressive leukodystrophy, brain and spinal atrophy, cerebral and cerebellar calcifications as well as lactate peak in MR spectroscopy. Electrophysiological studies showed pathologic evoked visual and somato-sensory potentials. Extensive diagnostics did not reveal causes for acquired or known genetic leukodystrophies. Respiratory chain analysis in muscle tissue showed diminished activities for complexes I, II/III and IV.

Progression of Brain Atrophy and Cognitive Impairment in Hereditary Frontotemporal Lobar Degeneration (P6.247)

Progression of Brain Atrophy and Cognitive Impairment in Hereditary Frontotemporal Lobar Degeneration (P6.247)

Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells.

Huntington's disease (HD) is a neurodegenerative condition characterized by pathology in the brain and peripheral tissues. Hyperactivity of the innate immune system, due in part to NFκB pathway dysregulation, is an early and active component of HD. Evidence suggests targeting immune disruption may slow disease progression. Laquinimod is an orally active immunomodulator that down‐regulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain down‐regulates astrocytic and microglial activation by modulating NFκB signalling. Laquinimod had beneficial effects on inflammation, brain atrophy and disease progression in multiple sclerosis (MS) in two phase III clinical trials. This study investigated the effects of laquinimod on hyperactive proinflammatory cytokine release and NFκB signalling in HD patient myeloid cell cultures. Monocytes from manifest (manHD) and pre‐manifest (preHD) HD gene carriers and healthy volunteers (HV) were treated with laquinimod and stimulated with lipopolysaccharide. After 24 h pre‐treatment with 5 μM laquinimod, manHD monocytes released lower levels of IL‐1β, IL‐5, IL‐8, IL‐10, IL‐13 and TNFα in response to stimulation. PreHD monocytes released lower levels of IL‐8, IL‐10 and IL‐13, with no reduction observed in HV monocytes. The effects of laquinimod on dysfunctional NFκB signalling in HD was assessed by inhibitor of kappa B (IκB) degradation kinetics, nuclear translocation of NFκB and interactions between IκB kinase (IKK) and HTT, in HD myeloid cells. No differences were observed between laquinimod‐treated and untreated conditions. These results provide evidence that laquinimod dampens hyper‐reactive cytokine release from manHD and preHD monocytes, with a much reduced effect on HV monocytes. Evidence suggests targeting CNS and peripheral immune disruption may slow Huntington's disease (HD) neurodegenerative processes. The effects of laquinimod, an orally active immunomodulator, on hyperactive cytokine release and dysfunctional NFκB signalling in stimulated myeloid cell cultures from pre‐manifest and manifest HD gene carriers and healthy volunteers were investigated. Laquinimod dampened cytokine release but did not impact NFκB signalling.Read the Editorial Highlight for this article on page 670.

Effect of natalizumab on brain atrophy and disability progression in multiple sclerosis patients over 5 years.

The long-term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years. This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006-2007. At the 5-year follow-up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted P = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. At the follow-up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow-up. There was another case of non-fatal PML over the follow-up. In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk-benefit therapeutic assessment is mandatory.

Severe Progressive Brain Atrophy in Pediatric Multiple Sclerosis

Background Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Progressive brain atrophy is a known marker of patient disability and cognitive impairment in MS patient, but limited information is available about the clinical and cognitive consequences in the pediatric population. Case Report We present a case of aggressive pediatric-onset MS with severe rapidly progressive brain atrophy, neurological disability, and cognitive deterioration. Serial brain magnetic resonance imaging studies demonstrate ongoing cerebral atrophy correlating with severe deficits on serial neuropsychological testing. Conclusion A subset of pediatric MS patient may be vulnerable to severe cognitive deterioration associated with marked brain atrophy.

Laquinimod in the treatment of multiple sclerosis: a review of the data so far.

Laquinimod (ABR-215062) is a new orally available carboxamide derivative, which is currently developed for relapsing remitting (RR) and chronic progressive (CP) forms of multiple sclerosis (MS; RRMS or CPMS) as well as neurodegenerative diseases. Its mechanism of action may comprise immunomodulatory effects on T-cells, monocytes, and dendritic cells as well as neuroprotective effects with prominent actions on astrocytes. Laquinimod was tested in Phase II and III clinical trials in RRMS at different dosages ranging from 0.1 to 0.6 mg/day. The compound was well tolerated, yet at the dosages tested only led to moderate effects on the reduction of relapse rates as primary study endpoint in Phase III trials. In contrast, significant effects on brain atrophy and disease progression were observed. While there were no significant safety signals in the clinical trials, the Committee for Medicinal Products for Human Use (CHMP) refused marketing authorization for RRMS based on the assessment of the risk–benefit ratio with regard to data from animal studies. At present, the compound is further tested in RRMS as well as CPMS and Huntington’s disease at different concentrations. Results from these trials will further inform about the clinical benefit of laquinimod in patient cohorts with a persisting, but still insufficiently met need for safe and at the same time effective oral compounds with neuroprotective effects.

3D shape analysis of the brain's third ventricle using a midplane encoded symmetric template model

BackgroundStructural changes of the brain's third ventricle have been acknowledged as an indicative measure of the brain atrophy progression in neurodegenerative and endocrinal diseases. To investigate the ventricular enlargement in relation to the atrophy of the surrounding structures, shape analysis is a promising approach. However, there are hurdles in modeling the third ventricle shape. First, it has topological variations across individuals due to the inter-thalamic adhesion. In addition, as an interhemispheric structure, it needs to be aligned to the midsagittal plane to assess its asymmetric and regional deformation. MethodTo address these issues, we propose a model-based shape assessment. Our template model of the third ventricle consists of a midplane and a symmetric mesh of generic shape. By mapping the template's midplane to the individuals’ brain midsagittal plane, we align the symmetric mesh on the midline of the brain before quantifying the third ventricle shape. To build the vertex-wise correspondence between the individual third ventricle and the template mesh, we employ a minimal-distortion surface deformation framework. In addition, to account for topological variations, we implement geometric constraints guiding the template mesh to have zero width where the inter-thalamic adhesion passes through, preventing vertices crossing between left and right walls of the third ventricle. The individual shapes are compared using a vertex-wise deformity from the symmetric template. ResultsExperiments on imaging and demographic data from a study of aging showed that our model was sensitive in assessing morphological differences between individuals in relation to brain volume (i.e. proxy for general brain atrophy), gender and the fluid intelligence at age 72. It also revealed that the proposed method can detect the regional and asymmetrical deformation unlike the conventional measures: volume (median 1.95ml, IQR 0.96ml) and width of the third ventricle. Similarity measures between binary masks and the shape model showed that the latter reconstructed shape details with high accuracy (Dice coefficient ≥0.9, mean distance 0.5mm and Hausdorff distance 2.7mm). ConclusionsWe have demonstrated that our approach is suitable to morphometrical analyses of the third ventricle, providing high accuracy and inter-subject consistency in the shape quantification. This shape modeling method with geometric constraints based on anatomical landmarks could be extended to other brain structures which require a consistent measurement basis in the morphometry.

Changes in brain atrophy indices in patients with relapsing-remitting multiple sclerosis treated with natalizumab.

To evaluate the effect of natalizumab on progression of brain atrophy in multiple sclerosis (MS) patients and to search for a clinical or radiological marker of progression of brain atrophy. We retrospectively recorded demographic and clinical data, as well as the corpus callosum index (CCI) using MRI, in MS patients treated with natalizumab for 1-4 years. In the study population (n = 29), baseline mean CCI was 0.37 ± 0.04 and final CCI 0.36 ± 0.04. 17 patients did not develop brain atrophy during follow-up. There was no statistically significant relationship between progression of atrophy and clinical and radiological parameters. Natalizumab may have a neuroprotective effect.

Posterior cortical atrophy as a variant of progressive local brain atrophy

Posterior cortical atrophy (PCA) is a rare disease that manifests mainly as disturbance of cortical visual function, agnosia. Balint’s syndrome (optic ataxia) is one of the clearest clinical markers of the disease. The disease is caused by progressive atrophy of the visual cortex. Many researchers define PCA as an independent disease, while others suggest that it is a “posterior” variant of Alzheimer’s disease, corticobasal degeneration, etc. Morphological studies of brain tissues support the neurodegenerative nature of the disease.

Hypertensive Target Organ Damage and Longitudinal Changes in Brain Structure and Function: The Second Manifestations of Arterial Disease-Magnetic Resonance Study.

Hypertension has been related to structural and functional brain changes. In high-risk populations, hypertensive target organ damage might better represent exposure to high blood pressure than the blood pressure measurement itself. We examined the association of hypertensive target organ damage with longitudinal changes in brain structure and function within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study. Renal function, albuminuria, and left ventricular hypertrophy on electrocardiography were measured in 663 patients with manifest arterial disease (mean age, 57±9 years; 81% men). Automated brain segmentation was used to quantify progression of global brain atrophy (change in brain parenchymal fraction) and progression of cerebral small vessel disease on 1.5T magnetic resonance imaging, and memory and executive functioning were assessed at baseline and after on average 3.9 years of follow-up. Regression analyses showed that an increasing number of signs of target organ damage was associated with more progression of global brain atrophy and more rapid decline in memory performance. Compared with no target organ damage, mean differences in change in brain parenchymal fraction (95% confidence interval) for 1 and ≥2 signs of organ damage were -0.12 (-0.30; 0.06) and -0.41 (-0.77; -0.05) % intracranial volume, and mean (95% confidence interval) differences in change in memory performance (z score) were -0.15 (-0.29; -0.00) and -0.27 (-0.54; -0.01). Results were independent of blood pressure, antihypertensive treatment, and other confounders. Hypertension target organ damage was not associated with progression of cerebral small vessel disease or change in executive functioning. Routinely assessed signs of hypertensive target organ damage, and in particular impaired renal function, could be used to identify patients at the highest risk of cognitive decline.

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b.

Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status. Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

Is amyloid-β harmful to the brain? Insights from human imaging studies.

Although the amyloid-β protein associated with the Alzheimer's disease plaque has been detectable in living people for over a decade, its importance in the pathogenesis of Alzheimer's disease is still debated. The frequent presence of amyloid-β in the brains of cognitively healthy older people has been interpreted as evidence against a causative role. If amyloid-β is crucial to the development of Alzheimer's disease, it should be associated with other Alzheimer's disease-like neurological changes. This review examines whether amyloid-β is associated with other biomarkers indicative of early Alzheimer's disease in normal older people. The preponderance of evidence links amyloid-β to functional change, progressive brain atrophy, and cognitive decline. Individuals at greatest risk of decline seem to be those with evidence of both amyloid-β and findings suggestive of neurodegeneration. The crucial question is thus how amyloid-β is related to brain degeneration and how these two processes interact to cause cognitive decline and dementia.