Treatments and rehabilitation in the acute and chronic state of traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of acquired disability globally, and effective treatment methods are scarce. Lately, there has been increasing recognition of the devastating impact of TBI resulting from sports and other recreational activities, ranging from primarily sport-related concussions (SRC) but also more severe brain injuries requiring hospitalization. There are currently no established treatments for the underlying pathophysiology in TBI and while neuro-rehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity. In this narrative review, we highlight short- and long-term consequences of SRCs, and how the sideline management of these patients should be performed. We also cover the basic concepts of neuro-critical care management for more severely brain-injured patients with a focus on brain oedema and the necessity of improving intracranial conditions in terms of substrate delivery in order to facilitate recovery and improve outcome. Further, following the acute phase, promising new approaches to rehabilitation are covered for both patients with severe TBI and athletes suffering from SRC. These highlight the need for co-ordinated interdisciplinary rehabilitation, with a special focus on cognition, in order to promote recovery after TBI.

Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy.

INTRODUCTION: Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). METHODS: We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. RESULTS: One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). CONCLUSION: Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease.

MRS shows abnormalities before symptoms in familial Alzheimer disease.

BACKGROUND: Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset. METHODS: Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation. RESULTS: PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset. CONCLUSIONS: Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.

Short TE quantitative proton magnetic resonance spectroscopy in variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder. Clinical diagnosis is difficult in the early stages as the disease often presents with non-specific psychiatric and neurological symptoms. To investigate the diagnostic potential of quantitative short TE in vivo MRS, and the nature and anatomical distribution of biochemical abnormalities in vCJD, localised single-voxel spectra (TE/TR 30 ms/2,000 ms) were acquired from three brain regions: thalami, caudate nuclei and frontal white matter. Metabolite concentrations and ratios from three patients with definite or probable vCJD were compared with eight normal age-matched controls. Abnormal signal on T2-weighted MRI was apparent in the pulvinar region in all vCJD patients; this region also showed greatly increased myo-inositol [MI] (mean 2.5-fold, P=0.01) and decreased N-acetyl-aspartate (NAA; mean 2-fold, P=0.01). Two patients also showed increased [MI] (z=17, 11; one with decreased NAA, z=-12) in normal-appearing caudate nuclei. The magnitude of metabolite abnormalities in the thalami in moderately advanced vCJD suggests a potential role in earlier diagnosis. Short TE protocols allow the measurement of MI, which adds discriminant power to the MRS examination.

A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia.

Detailed study of the very earliest phases of Alzheimer's disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer's disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man's diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD.

Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation.

BACKGROUND: Most mutations in the amyloid precursor protein (APP) gene have been associated with familial Alzheimer disease (AD); however, some mutations within the Abeta-coding sequence have been described in families with recurrent cerebral hemorrhage. The APPAla692Gly (Flemish) mutation was reported in a family in which affected members developed hemorrhagic stroke, progressive dementia, or both. OBJECTIVE: To describe clinical, neuropathologic, and genetic features of a family of British origin with the Flemish APP mutation. METHODS: Clinical features of the proband and two affected relatives were obtained by history, examination, and medical record review. Some information on deceased affected relatives was obtained by informant interview. Neuropathologic examination was carried out on one case. DNA studies were carried out on three affected and three unaffected individuals. RESULTS: Presenile dementia was present in a pattern consistent with dominant inheritance, with the APP692 mutation being found in all affecteds and no unaffecteds. The proband also had a cerebral hemorrhage, but was the only one of five affecteds to have this complication. Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. CONCLUSIONS: This expands the number of families reported with mutations in the coding region of the amyloid precursor protein gene. Cerebral hemorrhage appears to be less frequent in this family than in the previously reported Flemish pedigree with the same mutation.

A presenilin 1 R278I mutation presenting with language impairment.

Presenilin (PSEN)1 mutations are responsible for many cases of autosomal dominant Alzheimer disease (AD), although the clinical spectrum has not been fully defined. The authors describe two members of a kindred with a novel PSEN1 mutation (R278I) presenting with language impairment and relative preservation of memory. Screening for PSEN1 mutations may be appropriate in cases of familial dementia even where the clinical phenotype is not typical of AD.

Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: broadening the clinical picture to include progressive supranuclear palsy.

The frontotemporal lobar degenerations (FTLDs) are a group of disorders in which the clinical picture is not necessarily predictive of the underlying neuropathology. The FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U) subtype is pathologically characterized by ubiquitin-positive, tau and alpha-synuclein-negative neuronal cytoplasmic inclusions in the frontotemporal cortex and hippocampal dentate fascia. When similar pathological changes are accompanied by histological features of motor neuron disease (MND), the term FTLD-MND is used. The latter pathological changes may be found in patients with or without clinical evidence of MND. We retrospectively reviewed the clinical details of three patients with a rapidly progressive, levodopa-unresponsive bradykinetic-rigid syndrome and frontal cognitive impairment. A diagnosis of progressive supranuclear palsy (PSP) had been considered in all three cases at initial presentation. Two of the cases fulfilled clinical diagnostic criteria for PSP, which was the final clinical diagnosis during life. Pathological analysis showed typical histological appearances of FTLD-MND in two cases and of FTLD-U in one case. Semi-quantitative analysis of pathological load seemed to correlate with the clinical phenotype. FTLD-U or FTLD-MND should be considered in the differential diagnosis of progressive frontal dementia with an akinetic rigid syndrome and supranuclear gaze palsy or Steele-Richardson-Olszewski disease.

Frontotemporal lobar degeneration and ubiquitin immunohistochemistry.

We set out to determine the frequency of the different pathologies underlying frontotemporal degeneration (FTD) in our brain bank series, by reviewing all cases of pathologically diagnosed FTD over the last 12 years. We identified and reviewed 29 cases of FTD and classified them using the most recent consensus criteria with further histological analysis of 6 initially unclassifiable cases. Detailed histological analysis of these 6 cases revealed variable numbers of ubiquitin-positive (tau and alpha-synuclein-negative) inclusions in 5 cases, consistent with the diagnosis of frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). As a consequence of the current re-evaluation, 18 (62%) of the 29 cases with FTD have underlying pathology consistent with FTLD-U. Therefore in our brain bank series of frontotemporal degeneration, most cases were non-tauopathies with FTLD-U accounting for 62% of all the diagnoses.

The prevalence of oligoclonal bands in the CSF of patients with primary neurodegenerative dementia.

BACKGROUND: Recent guidelines from the United States and Europe on the diagnosis and management of dementia include advice that younger patients with dementia should undergo CSF examination, which frequently includes analysis for oligoclonal bands (OCB). The presence of CNS specific OCB has traditionally been considered suggestive of an inflammatory aetiology, although the interpretation of such a finding in the presence of a normal CSF white cell count and protein is more difficult. METHODS: We reviewed retrospectively the prevalence of OCB, determined using agarose isoelectric focusing, in a series of 131 well characterised patients with a final diagnosis of a degenerative dementia who had undergone CSF examination. RESULTS: The mean age of the patients was 60.0 (SD 8.4) years. Seventy (53%) patients had Alzheimer's disease (AD), forty seven (36 %) had frontotemporal lobar degeneration (FTLD), seven (5%) had Dementia with Lewy bodies and the remaining seven (5%) patients had other rarer neurodegenerative dementias. Neuropathological examination had been performed in fifteen (11%) patients. CNS specific OCB were present in nine (7%) patients in this cohort, all of whom had normal CSF white cell counts: four AD patients (a prevalence of 6%), four FTLD patients (a prevalence of 9%), and one patient with Creutzfeldt-Jakob disease (a prevalence of 25%). Investigation of these patients, including two with neuropathologically verified AD and one with post-mortem confirmed CJD, did not reveal an alternative aetiology for their dementia. CONCLUSION: A central immune response can occur in primary neurodegenerative dementias, albeit uncommonly.

Nonsynchronized segmented heterochromia in black scalp hair.

Nonsynchronized segmented heterochromia in black scalp hair is a rarely reported entity, the only previous report being described in association with iron deficiency anaemia. A 14-year-old girl presented with a 2-year history of nonsynchronized segmented heterochromia. She was otherwise well and her serum iron, copper, zinc and protein levels were all within the normal range. She had no clinical evidence of vitiligo or alopecia areata. This patient is believed to represent the first reported case of nonsynchronized segmented heterochromia in black scalp hair as a presentation of premature greying of the hair.

Keratoacanthoma with perineural invasion: a report of 40 cases.

Keratoacanthoma is a unique clinicopathological entity, despite a recent trend to regard it as a variant of squamous cell carcinoma. The occurrence of perineural invasion is an uncommon phenomenon in keratoacanthomas, with a predilection for lesions on the face. We studied a series of 40 cases of keratoacanthoma in which perineural invasion occurred. Of the 40 cases, 27 were from the head or neck region. We found no metastasis or direct death attributable to the presence of perineural invasion in the 35 cases in our series for whom follow-up data were available. In only one case did local recurrence occur and this was not considered by the authors to be directly attributable to the presence of perineural invasion. These findings add further support to the notion that keratoacanthoma is biologically different from squamous cell carcinoma.