Progressive Brain Atrophy Research Articles

Crossed Cerebellar Diaschisis after Status Epilepticus in a Young Child

We report on a 3.8-year-old girl who was born preterm. Due to a posthemorrhagic hydrocephalus she had a ventriculoperitoneal shunt. Magnetic resonance imaging (MRI) showed mild atrophy of the left cerebellum. She was found unresponsive in a febrile state. After the application of midazolam she regained consciousness. There were no epileptic discharges on electroencephalogram. MRI with diffusion-weighted sequences showed areas of hyperintensity in the right cerebrum. After the patient deteriorated again, MRI showed signs of increased intracranial pressure and high signal intensity throughout the right cerebral and left cerebellar hemispheres, suggesting crossed cerebellar diaschisis (CCD) most likely resulting from a nonconvulsive status epilepticus (SE). A follow-up MRI showed progressive brain atrophy. CCD after SE might be caused by cortical excitatory input through the cortico-pontine-cerebellar pathway. Alternatively, the cerebral edema in SE may decrease neuronal cell activity in the contralateral cerebellar hemisphere. The unilateral cerebellar atrophy before the onset of CCD might be attributed to impaired neuronal connections after peripartal cerebral injury. This case presents a young child with a combination of two CCDs, at first due to perinatal brain injury, and at second to SE. MRI with diffusion-weighted sequences can detect CCD at an early stage.

Comparison of Neuropsychological Impairment and Vocational Outcomes in Systemic Lupus Erythematosus and Multiple Sclerosis Patients

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients.

Spatiotemporal mapping of brain atrophy in mouse models of Huntington's disease using longitudinal in vivo magnetic resonance imaging

Mouse models of Huntington's disease (HD) that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q10 (CoQ10) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ10 treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.

Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats

There are an estimated 36 million dementia patients worldwide. The anticipated tripling of this number by year 2050 will negatively impact the capacity to deliver quality health care. The epidemic in diabetes is particularly troubling, because diabetes is a substantial risk factor for dementia independently of cerebrovascular disease. There is an urgent need to elucidate the pathogenesis of progressive brain atrophy, the cause of dementia, to allow rational design of new therapeutic interventions. This review summarizes recent tests of the hypothesis that the concomitant loss of insulin and insulin-like growth factors (IGFs) is the dominant cause for age-dependent, progressive brain atrophy with degeneration and cognitive decline. These tests are the first to show that insulin and IGFs regulate adult brain mass by maintaining brain protein content. Insulin and IGF levels are reduced in diabetes, and replacement of both ligands can prevent loss of total brain protein, widespread cell degeneration, and demyelination. IGF alone prevents retinal degeneration in diabetic rats. It supports synapses and is required for learning and memory. Replacement doses in diabetic rats can cross the blood-brain barrier to prevent hippocampus-dependent memory impairment. Insulin and IGFs are protective despite unabated hyperglycemia in diabetic rats, severely restricting hyperglycemia and its consequences as dominant pathogenic causes of brain atrophy and impaired cognition. These findings have important implications for late-onset alzheimer's disease (LOAD) where diabetes is a major risk factor, and concomitant decline in insulin and IGF activity suggest a similar pathogenesis for brain atrophy and dementia.

Left Anterior Temporal Lobe Sustains Naming in Alzheimers Dementia and Mild Cognitive Impairment

Cognitive decline in degenerative dementia is paralleled by progressive brain atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit. In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology, and frontotemporal dementia. Applying voxel-based morphometry using a diffeomorphic registration algorithm we contrasted GMV of patients performing within the normal range with those of patients with pathological performance. Further, differential effects of gray matter atrophy on impaired performance in AD versus MCI of AD type were investigated. Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to MCI of AD type and AD patients confirmed this relationship. While left ATL atrophy is known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and MCI of AD type.

Fulminant multiple sclerosis (MS)

Fulminant multiple sclerosis (MS) is the most malignant form of MS which usually leads to death in few weeks. Although it can be accompanied by optic neuritis (ON), but long interval between ON and the grave onset has not been reported. Fulminant MS usually occurs as the first onset and previous ON is not common. We report a rare case of 30-year-old woman with a history of ON 1 year ago. The rapid deterioration to vegetative state followed by a seizure and previous ON differentiated this case from previous reported cases. The differential diagnosis of a rapidly progressive leucoencephalopathy in this patient includes inflammatory, vascular, infectious and toxic disorders. Regarding the previous history of optic neuritis with positive brain MRI (multiple T2 hyperintense lesions in white matter) in our patient, multiple sclerosis is the most probable diagnosis. More effective treatments, such as plasmapheresis and cyclophosphamide, that influenced on the prognosis of some previous patients could be useful, but should be performed before progressive brain atrophy emerges.

Predicting Initial Changes in Brain Volume with Effective Anti-Amyloid Agents: Just Ask Alice

Changes in the rate of brain atrophy have been proposed as biomarker surrogate measures for Alzheimer's disease (AD) clinical trials. The prevailing hypothesis is that a successful therapeutic agent will slow, arrest or reverse the decline in the inexorable progression of brain atrophy associates with the disease. Numerous recent reports have put forward “power” and “sample size” calculations for hypothetical clinical trials based on hypothesized slowing of brain shrinkage in treated, compared with control subjects. On the other hand, in the clinical trials of the experimental anti-amyloid vaccine AN1792, there appeared to be an increase in the apparent rate of brain atrophy in subjects who developed significant titers of anti-amyloid antibodies in the blood, and the “acceleration” of brain atrophy appeared proportional to titer. The few subjects studied 4.5 years after the conclusion of the trial showed no greater brain tissue loss than they had at the end of the 1-year study, and autopsied brains of several persons dying after receiving AN1792 contained no amyloid deposits. Can the AN1792 observations and the expectation of decreased atrophy with successful disease-modifying AD treatment be reconciled? We identified several competing factors which might affect rates of brain volume change with anti-amyloid treatment, including 1) normal rates of age-associated brain volume loss; 2) the additional disease-related contribution to brain volume loss; 3) estimated volume of the brain occupied by amyloid deposits and its regional distribution; 4) rate of accumulation of amyloid in the brain; 5) the contribution of inflammation to brain volume and 6) the rate of brain amyloid removal or decreased rate of brain amyloid accumulation. A mathematical model was constructed, using literature-derived values for as many of the variables as possible. The model was used to predict changes in brain volume under typical clinical trial conditions. Results will be presented. Several factors contribute to the steady-state levels of amyoid deposits in the brains of AD patients. These factors, as well as the mechanism of action of the drug under study, may affect observed changes in brain volume during clinical trials.

Depression predicts progressive brain atrophy in mild cognitive impairment

Depression predicts progressive brain atrophy in mild cognitive impairment

Depression predicts progressive brain atrophy in mild cognitive impairment

Depression predicts progressive brain atrophy in mild cognitive impairment

Carotid atherosclerosis and progression of brain atrophy: The SMART‐MR Study

Atherosclerosis has been implicated in the development of brain atrophy. However, support for this association comes from cross-sectional studies. Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with symptomatic atherosclerotic disease (mean age ± standard deviation, 58 ± 10 years; 80% men), magnetic resonance imaging of the brain was performed in 1,232 patients at baseline (2001-2005) and in 663 patients at follow-up (2006-2009). Brain segmentation was used to quantify total brain volume, cortical gray matter volume, and ventricular volume as indicators of global, cortical, and subcortical atrophy. At baseline, measurements of carotid intima-media thickness (CIMT) and carotid stenosis were performed. Carotid stenosis was classified into groups 0 of 50%, 50 of 70% (moderate), and >70% (severe) and into unilateral or bilateral stenosis. Cross-sectional regression analyses showed that both increased CIMT and carotid stenosis were associated with decreased relative total brain and cortical gray matter volume. Our prospective findings showed that after a mean follow-up of 3.9 years (range, 3.0-5.8 years), CIMT and moderate stenosis were not related to progression of brain atrophy. Only severe or bilateral carotid stenosis was related to progression of global atrophy (β [95% confidence interval (CI)], -0.52% [-0.84 to -0.20%], -0.94% [-1.45 to -0.43%]), cortical atrophy (β [95% CI], -0.75% [-1.37 to -0.13%], -1.34% [-2.32 to -0.35%]), and subcortical atrophy (β [95% CI], 0.06% [-0.02 to 0.16%], 0.13% [0.01 to 0.28%]). In a study of patients with atherosclerotic disease with 4 years of follow-up, only severe or bilateral carotid stenosis, and not moderate carotid stenosis and increased CIMT, were associated with progression of brain atrophy.

Writing Error May Be a Predictive Sign for Impending Brain Atrophy Progression in Amyotrophic Lateral Sclerosis: A Preliminary Study Using X-Ray Computed Tomography

Aim: To investigate whether writing errors are predictive of longitudinal brain atrophy progression in patients with amyotrophic lateral sclerosis (ALS). Methods: The frequency of writing errors in 6 ALS patients without dementia was compared with longitudinal changes in lateral ventricular areas of the bilateral anterior and inferior horns on X-ray computed tomography scans. The increase in area per month for the anterior and inferior horns was used as a measure of longitudinal brain atrophy progression, and was calculated as: (area on the initial scan – area on the follow-up scan)/scan interval (month). Results: The longitudinal rate of increase in the area of the anterior horns showed significant associations with the rates of total writing errors (r = 0.886, p = 0.0152), kana errors (r = 0.887, p = 0.0148) and kana omission (r = 0.856, p = 0.0268), whereas that for the inferior horns size showed no significant association with any writing errors. Conclusion: The increased area of the anterior horns indicates frontal-lobar atrophy, and writing errors may be a predictive sign for impending brain atrophy progression in the frontal lobes, which reflects the development of anterior-type dementia.

Cardiorespiratory fitness is associated with atrophy in Alzheimer's and aging over 2 years

We sought to describe change in cardiorespiratory (CR) fitness over 2 years in those with early-stage Alzheimer's disease (AD) and nondemented aging and assess the relationship of CR fitness with cognitive decline, brain atrophy, and dementia progression. Individuals with early-stage AD (n = 37) and without dementia (n = 53) attended clinical evaluations, cognitive and exercise tests, and magnetic resonance imaging (MRI) at baseline and 2 years later. CR fitness was lower in those with AD over the study period. Lower baseline CR fitness was associated with progression of dementia severity in AD. Declining CR fitness over 2 years was associated with brain atrophy in AD, especially in the parahippocampus. In nondemented participants, there was a trend for lower baseline fitness to be related to cognitive decline. Both lower baseline CR fitness and declining CR fitness over 2 years were associated with regional brain atrophy. We conclude that CR fitness is chronically reduced in those with AD. Further, in those with AD, CR fitness is associated with progression of dementia severity and brain atrophy in AD, suggesting a link between progression of dementia severity and cardiorespiratory health.

MRI predictors of cognitive outcome in early multiple sclerosis

To determine MRI predictors for cognitive outcome in patients with early relapsing-remitting multiple sclerosis (MS). Forty-four patients recently diagnosed with clinically definite MS were followed up with clinical and cognitive evaluations at 1, 2, 5, and 7 years and underwent brain MRI including magnetization transfer (MT) imaging at baseline and 2 years. Cognitive evaluation was also performed in 56 matched healthy subjects at baseline. Cognitive testing included the Brief Repeatable Battery. Imaging parameters included lesion load, brain parenchymal fraction (BPF), ventricular fraction (VF), and mean MT ratio (MTR) of lesion and normal-appearing brain tissue (NABT) masks. At baseline, patients presented deficits of memory, attention, and information processing speed (IPS). Over 2 years, all magnetic resonance parameters deteriorated significantly. Over 7 years, Expanded Disability Status Scale score deteriorated significantly. Fifty percent of patients deteriorated on memory cognitive domain and 22.7%of patients on IPS domain. Seven-year change of memory scores was significantly associated with baseline diffuse brain damage (NABT MTR). IPS z score change over 7 years was correlated with baseline global atrophy (BPF), baseline diffuse brain damage, and central brain atrophy (VF) change over 2 years. The main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis.

Parry-Romberg Syndrome and Rasmussen Encephalitis: Possible Association. Clinical and Neuroimaging Features

Parry-Romberg syndrome (PRS) is a sporadic disease of unknown etiology with typical onset in childhood or in young adults. It is characterized by a slow and progressive atrophy affecting one side of the face, the skin, the subcutaneous tissue, the muscles, the cartilages, and the underlying bony structures. The neurological symptoms usually include focal epilepsy, migraine, and unilateral brain lesions on the same side as the atrophy. A common neuroimaging finding of the syndrome is white matter high signal intensity on brain magnetic resonance (MR) imaging. Rasmussen encephalitis (RE) is a rare and chronic inflammatory disease of the brain that begins in the first decade of life and more rarely in adolescents and adults. It usually involves one hemisphere with focal cortical inflammation. Neurologic symptoms are intractable seizures and progressive hemiplegia. Both PRS and RE are often associated with other inflammatory or autoimmune disorders and only 1 case of both syndromes has been reported in literature. We report the clinical and neuroradiological findings in a 6-year-old boy, presenting with focal hemifacial and arm motor seizures and progressive facial hemiatrophy. Serial MR imaging studies revealed progressive brain hemispheric signal alterations and atrophy. This would thus suggest acoexistence of PRS and RE.

Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington's disease mouse model

Huntington's disease (HD) displays progressive striatal atrophy that occurs long before the onset of clinical motor symptoms. As there is no treatment for the disease once overt symptoms appear, it has been suggested that neuroprotective therapy given during this presymptomatic period might slow progression of the disease. This requires biomarkers that can reliably detect early changes and are sensitive to treatment response. In mouse models of HD, structural MRI measures have been shown to detect disease onset. To determine whether such measures could also be suitable biomarkers for following responses to treatment, we used T2-weighted MR imaging combined with automated morphological analyses and characterized changes in regional brain volumes longitudinally in the N171-82Q HD mouse model in a preclinical trial. We report here that N171-82Q HD mice exhibit adult-onset and progressive brain atrophy in the striatum and neocortex as well as in whole brain; the progressive atrophy in striatum and neocortex is positively correlated with motor deficits. Most notably, MRI also detected neuroprotective effects of sertraline treatment, a neuroprotective agent confirmed in our previous studies. Our present studies provide the first evidence that longitudinal structural MRI measures can detect the therapeutic effect in HD mice, suggesting that such measures in brain could be valuable biomarkers in HD clinical trials.

Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia

Nonketotic hyperglycinemia (NKH), or glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme system. In neonatal-onset NKH, patients manifest lethargy, hypotonia, apnea, and intractable epileptic seizures that are not specific to this disease. We experienced a 6-year-old girl with spastic quadriplegia, intractable epilepsy, and mental retardation, all initially regarded as sequelae of neonatal meningitis. The seizure frequency was transiently increased when valproate was started. Head MRI revealed progressive brain atrophy and white matter loss with high intensity signals on T2 -weighted and diffusion -weighted images, which prompted us to conduct further metabolic workups. High glycine levels led us to suspect NKH, and we confirmed this diagnosis by the non-invasive, 13C-glycine breath test. DNA sequencing revealed novel Leu885Pro/Trp897Cys mutations in the glycine decarboxylase gene that were transmitted from both parents. Sodium benzoate and dextromethorphan dramatically decreased her hypertonicity. Our case shows that paradoxical increases in seizure frequency following valproate can be a clue for a diagnosis of NKH, and that a correct diagnosis of NKH can greatly alter the quality of life in such patients.

Cranial Magnetic Resonance Imaging Findings in Children With Nonsyndromic Mitochondrial Diseases

Cranial magnetic resonance imaging findings suggestive of specific mitochondrial syndromes are reported. However, cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases are rarely described. From January 1992-September 2009, data from 33 patients with nonsyndromic mitochondrial diseases were collected. We investigated cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases, and identified potential diagnostic characteristics. Eleven of 33 patients (33.3%) demonstrated normal findings, and 22 (66.7%) demonstrated abnormal findings. The most common abnormal finding was cerebral atrophy, with or without other lesion sites (15/33; 45.5%). The second most common was bilateral basal ganglia involvement (6/33; 18.2%). Follow-up imaging was performed in 20 patients. Ten of these 20 (50.0%) demonstrated evolutionary changes, in which progressive global brain atrophy was evident. Three patients with normal results and one patient with cerebral atrophy on initial imaging demonstrated prominent signal changes over the basal ganglia, brainstem, gray matter, white matter, and bilateral cerebellar hemispheres on follow-up imaging. Imaging in children with nonsyndromic mitochondrial diseases may produce variable findings. Normal results and cerebral atrophy on the initial cranial magnetic resonance imaging are commonly evident in this patient group.

A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

A wide spectrum of clinical and brain MRI findings in patients with SLC19A3mutations

BackgroundSLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernicke's-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases.MethodsWe conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions.ResultsGenome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient.ConclusionOur cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.