Alison K. Godbolt

Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study

BACKGROUND Serial MRI scanning of autosomal dominant mutation carriers for Alzheimers disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimers disease progresses from the presymptomatic stage through to diagnosis. METHODS Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimers disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed. FINDINGS Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimers disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis. INTERPRETATION Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimers disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.

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 α‐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.

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.

Atrophy rates of the cingulate gyrus and hippocampus in AD and FTLD

This study explores the diagnostic utility of atrophy rates of the cingulate gyrus, its subdivisions and the hippocampus in Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD). Regions were manually outlined on MR images of a group of pathologically or genetically confirmed patients with AD (n=19), FTLD (n=8) and age-matched controls (n=11). Mean (S.D.) atrophy rates (%year(-1)) in the cingulate in controls, AD and FTLD were -0.3 (1.2), 5.9 (3.5), and 8.6 (4.1), respectively. Hippocampal atrophy rates in controls, AD and FTLD were -0.1 (0.8), 3.4 (2.2), and 5.2 (5.4), respectively. Atrophy rates were significantly higher in the cingulate and hippocampi in AD and FTLD compared with controls (p<0.01). There was evidence of a difference in trends of atrophy in the cingulate (more anterior in FTLD and more posterior in AD) between the disease groups (p=0.03). Cingulate atrophy rates discriminated perfectly between FTLD and controls. Significantly better discrimination between AD and controls was obtained by hippocampal rather than cingulate rates. In conclusion, cingulate atrophy is as significant a feature of AD and FTLD as hippocampal atrophy.

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.

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 Aβ-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.

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

Abstract.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.

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

IntroductionInherited 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).MethodsWe 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.ResultsOne 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).ConclusionIsolated 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.

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. We thank TOP and his wife for participating in this study, and the assistants of the neuropsychology department of the National Hospital of Neurology and Neurosurgery who performed the neuropsychology assessments and assisted in data collation, including Ms Susanna Cole. Mutation analysis was performed by Professor John Collinge and Mr John Beck of the MRC Prion Unit, Institute of Neurology. Funding was provided by an MRC programme grant, number G9626876. NCF holds an MRC senior clinical scientist fellowship.

Voxel-based morphometry in tau-positive and tau-negative frontotemporal lobar degenerations.

Background: The identification of specific, diagnostically useful predictors of protein dysfunction in the frontotemporal lobar degenerations (FTLD) is a problem of great clinical and biological interest. Correlations between regional patterns of tissue loss and specific proteinopathies have not been established. Objective: Specific brain imaging correlates of protein tau dysfunction were sought using voxel-based morphometry in FTLD subgroups with and without tau pathology. Methods: Seventeen patients with pathologically or genetically confirmed diagnoses of FTLD who had undergone volumetric brain magnetic resonance imaging (MRI) were identified retrospectively and tau-positive (n = 9) and tau-negative (n = 8) subgroups were defined. MRI data were compared with healthy age- and sex-matched controls using voxel-based morphometry implemented in a statistical parametric mapping software package. Results: Compared with controls, tau-positive and tau-negative subgroups had extensive common areas of regional brain atrophy predominantly affecting the frontal and anterior temporal lobes. No specific brain imaging features were identified for either subgroup. Conclusion: Patterns of frontotemporal atrophy do not predict the presence or absence of tau pathology; conversely, different immunohistochemical profiles are associated with similar patterns of regional vulnerability to neuronal loss in FTLD.