Daniel F. Broderick

Mutations in the colony stimulating factor 1 receptor ( CSF1R ) gene cause hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.

Heredofamilial Brain Calcinosis Syndrome

Brain calcinosis syndrome (BCS) usually is defined as bilateral calcium accumulation in the brain parenchyma, primarily in the basal ganglia. More than 50 reported clinical conditions have been associated with BCS. We reviewed clinical, radiological, and genetic features of heredofamilial BCS accompanying all conditions associated with calcium accumulation in the brain reported in English between 1962 and 2003 in MEDLINE. The location, extent, and degree of calcification in the brain show diversity not only among the various disorders but also among patients sharing the same condition. The pathogenesis of BCS is uncertain. More complicated mechanisms may be Involved when brain calcinosis is present but calcium, phosphorus, and parathyroid hormone metabolism abnormalities are absent. We review conditions associated with heredofamilial BCS in which brain calcinosis is nearly uniformly present because such information may be Important to the clinician pursuing an investigative strategy.

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan. Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): A misdiagnosed disease entity

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.

Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids

Objective: To report a new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), including serial, presymptomatic and symptomatic, cranial MRIs from the proband. Methods: We report clinical and genealogic investigations of an HDLS family, sequential brain MRIs of the proband, and autopsy slides of brain tissue from the proband’s father. Results: We identified seven affected family members (five deceased). The mean age at symptomatic disease onset was 35 years (range: 20–57), and the mean disease duration was 16 years (range: 3–46). Five affected individuals initially manifested memory disturbance and behavioral changes, whereas two experienced a mood disorder as their presenting symptom. Our proband’s father had been diagnosed clinically with vascular dementia, but his brain autopsy was consistent with HDLS. The proband had a cranial MRI prior to symptom onset, with two subsequent MRIs performed during follow-up. These serial images reveal a progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy. Conclusions: The proband of our newly identified hereditary diffuse leukoencephalopathy with spheroids (HDLS) kindred had subtle evidence of an incipient leukoencephalopathy on a presymptomatic cranial MRI. Conceivably, MRI may facilitate identifying affected presymptomatic individuals within known HDLS kindreds, increasing the likelihood of isolating the causative genes. GLOSSARY: DLS = diffuse leukoencephalopathy with spheroids; FLAIR = fluid-attenuated inversion recovery; HDLS = hereditary diffuse leukoencephalopathy with spheroids; LENAS = leukoencephalopathy with neuroaxonal spheroids; LFB = Luxol fast blue; NAL = neuroaxonal leukodystrophy; POLD = pigmentary type of orthochromatic leukodystrophy.

MR imaging of brainstem atrophy in progressive supranuclear palsy.

BackgroundTo enhance the sensitivity and specificity of the clinical diagnosis of progressive supranuclear palsy (PSP), neuroradiological parameters established in pathologically proven cases are needed.MethodsWe examined brainstem atrophy in five pathologically confirmed PSP patients (three men, mean age at death 77 years, range 64–84 years). Time interval between symptom onset and MRI ranged from 1 to 5 years, and between MRI and death from 33 to 52 months. Only one patient had clinical diagnosis of PSP at the time of MRI. Control group consisted of 19 age- and gendermatched healthy subjects. Seventeen morphometric parameters of the midbrain and pons were measured on T1-weighted midsagittal and T2-weighted axial MRI scans with Image Analyzer. Measurements of superior cerebellar peduncle (SCP) width were performed on PSP autopsy specimens.ResultsMean SCP width on MRI in PSP (2.7 ± 0.8 mm, 95%CI: 2.1–3.3) was smaller than in controls (3.7 ± 0.5 mm, 95%CI: 3.5–3.9). Mean SCP width at autopsy was 8% smaller than mean SCP width on MRI. Midsagittal midbrain area in PSP (99.1 ± 6.9 mm2, 95%CI: 90.5–107.6) was smaller than in controls (141.0 ± 18.1 mm2, 95%CI: 132.2–149.7). Midbrain/pons area ratio in PSP was 1:5 and in controls was 1:4 (p < 0.01). Repeat MRI 17 months later in one PSP case revealed 30% decrease of SCP width.ConclusionsMR imaging with quantitative analysis may be useful in the diagnosis of early PSP and in monitoring disease course.

ACR Appropriateness Criteria Low Back Pain.

Most patients presenting with uncomplicated acute low back pain (LBP) and/or radiculopathy do not require imaging. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags raising suspicion for serious underlying conditions, such as cauda equina syndrome, malignancy, fracture, and infection. Many imaging modalities are available to clinicians and radiologists for evaluating LBP. Application of these modalities depends largely on the working diagnosis, the urgency of the clinical problem, and comorbidities of the patient. When there is concern for fracture of the lumbar spine, multidetector CT is recommended. Those deemed to be interventional candidates, with LBP lasting for > 6 weeks having completed conservative management with persistent radiculopathic symptoms, may seek MRI. Patients with severe or progressive neurologic deficit on presentation and red flags should be evaluated with MRI. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Brain Injury After Cardiopulmonary Arrest and Its Assessment With Diffusion-Weighted Magnetic Resonance Imaging

OBJECTIVE To characterize the frequency and pattern of diffusion-weighted imaging (DWI) abnormalities detected as part of brain magnetic resonance imaging (MRI) and their association with short-term neurologic outcomes in patients successfully resuscitated after cardiopulmonary arrest (CPA). PATIENTS AND METHODS We retrospectively analyzed a case series of patients who experienced CPA between May 1, 2000, and April 29, 2004, at St Lukes Hospital in Jacksonville, Fla. Eligible patients required treatment by the Code Blue team and had 1 DWI study before discharge or death. Two neuroradiologists jointly classified DWI abnormalities by anatomic location. Outcome was measured by Cerebral Performance Category score. RESULTS Resuscitation was performed 628 times during the 48-month study period. Of 514 CPA survivors, 18 (3.5%) had MRI studies. The median age was 62 years (interquartile range [IQR], 49-73), and 10 were men. Median code duration was 16 minutes (IQR, 11-19 minutes), and median code-to-scan time was 72 hours (IQR, 28-229 hours). A DWI abnormality was noted in 9 (50%) of 18 patients. Cortical areas (global and regional) were the most common sites of restricted diffusion. Diffusion-weighted imaging abnormalities were present in 7 (70%) of 10 patients with a poor neurologic outcome at discharge. CONCLUSION Magnetic resonance imaging is performed rarely after survival of CPA. In this study with limited sample size, a greater proportion of patients with normal DWI findings had a good neurologic outcome at the time of hospital discharge vs those with abnormal findings. Prospective studies of early and serial MRI (with DWI) are needed to confirm this association and to clarify the prognostic usefulness of such studies.

Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.

Familial idiopathic basal ganglia calcification: a challenging clinical–pathological correlation

Sir, Familial idiopathic basal ganglia calcification (FIBGC) is characterized by brain calcium deposition and variable combinations of movement disorders, gait impairment, and neuropsychiatric symptoms [1-3, 5-7]. A locus was mapped on chromosome 14 [2], but it fails to account for disease in some families [7]. Penetrance estimates are hampered by inconsistent clinical-radiological correlation, and few detailed pathological reports are available [4, 7]. Herein, we provide clinical, radiological and pathological studies of a patient with FIBGC. We previously reported this family, including one autopsy study [4, 7]. The patient signed informed consent. A right-handed male (patient III-3 in [7]) came to our attention at age 76 with a 50-year history of trunk, upper extremities and oral abnormal movements. Motor symptoms began with writing difficulties, followed by right-predominant abnormal movements of both shoulders. At age 50, he developed progressive speech difficulties with mild memory and gait impairment. Six first-degree and three second-degree relatives had similar symptoms including generalized, oromandibular, axial, limb and cervical dystonia, chorea, postural tremor and ataxia (reported in [7]). The patient had mild recall impairment, speech-induced jaw-opening dystonia, trunk and right-predominant upper extremities chorea, right shoulder postural dystonia, and writers cramp. Genetic testing was negative for Huntingtons disease. Brain CT-scan showed calcification of the basal ganglia, subcortical white matter, thalamus, and cerebellum (Figure 1). Figure 1 Brain axial CT-scan shows third and lateral ventricles enlargement and severe calcification of the cerebellar hemispheres and vermis (a,b), striatum, globus pallidus and thalamus (b,c), and subcortical white matter and occipital cortex (a-d). Basal ganglia ... Over the next five years, the patient became severely dysarthric and unstable with falls. Upper extremities and trunk chorea and dystonia remained unchanged, whereas jaw-opening dystonia worsened. He scored 21/26 on the Mini Mental Status Examination (unable to write or draw), missing points on attention span and recall. The patient subsequently developed severe cognitive impairment and behavioral troubles with agitation and aggressiveness. He became unable to stand, chew or speak, lost 30kg over two years, and died at age 85. The fixed left hemibrain weighed 520g. There was mild frontal-predominant atrophy with enlarged lateral ventricles, and cerebellar atrophy. Brain arteries showed severe atherosclerosis. There was gray discoloration and gritty consistency of the posterior periventricular region, globus pallidus, putamen and anterior thalamus, and mild atrophy of the caudate nucleus (Figure 2a). The cerebellum had yellow-red discoloration and gritty consistency of deep white matter and dentate nucleus region. Figure 2 Macroscopic view (a) shows brown discoloration of globus pallidus (arrow), which had a gritty consistency at autopsy. On histology, von Kossa calcium staining (b) and hematoxylin-eosin staining (c-l) show widespread calcification of cerebellum deep regions ... There was striking vascular and parenchymal mineralization (Figure 2b-l) that stained positive for calcium (Figure 2b). In the cortex, small vessel calcific vasculopathy was prominent in lower cortical layers and at the grey-white junction in the depths of the sulci. Parenchymal calcification was patchy and multifocal in deep subcortical and posterior periventricular regions, putamen, globus pallidus, anterior thalamus, and in the visual cortex. There was massive cerebellar calcification in the hemispheres (cortex and white matter) and in the dentate nucleus. Even in severely affected areas, there was no significant neuronal loss. Mild Alzheimer pathology and amyloid angiopathy were present. There were ischemic changes in subcortical areas and numerous microinfarcts in the cortex and basal ganglia. Overall, the pathology was similar to that of our previous autopsied patient from the same family [4, 7]. Our observation highlights the difficulties in correlating the clinical, radiological and pathological features in FIBGC. Reasons for this include that: a) many family members have widespread calcification without symptoms [7], b) radiologic asymmetry does not always match that of symptoms, c) ataxia is rare despite common severe cerebellar involvement, and d) there is no significant neuronal loss even in severely affected areas. Although basal ganglia and subcortical/periventricular white matter involvement may explain movement disorders and cognitive impairment, the mechanism of neuronal dysfunction remains elusive. Extensive blood vessel and perivascular calcification may suggest a chronic ischemic mechanism leading to neuronal dysfunction only in susceptible brain regions/individuals. Chronic low-grade inflammation has been suggested to favor calcification, a hypothesis that gained support from the report of reactive astrocytes and microglia overexpressing inflammatory molecules around calcified areas [4]. However, using HLA-DR and GFAP immunostaining in our patient, we were unable to demonstrate activated microglia and reactive astrocytes. Alternatively, calcium deposition may alter glial cells metabolism and secondarily impair neuronal function, or only represent a by-standing phenomenon of a yet undefined patho-mechanism involving genetically-determined age-related neuronal dysfunction.