William D. Knight

Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers

(11)Carbon-Pittsburgh compound B positron emission tomography studies have suggested early and prominent amyloid deposition in the striatum in presenilin 1 mutation carriers. This cross-sectional study examines the (11)Carbon-Pittsburgh compound B positron emission tomography imaging profiles of presymptomatic and mildly affected (mini-mental state examination ≥ 20) carriers of seven presenilin 1 mutations, comparing them with groups of controls and symptomatic sporadic Alzheimers disease cases. Parametric ratio images representing (11)Carbon-Pittsburgh compound B retention from 60 to 90 min were created using the pons as a reference region and nine regions of interest were studied. We confirmed that increased amyloid load may be detected in presymptomatic presenilin 1 mutation carriers with (11)Carbon-Pittsburgh compound B positron emission tomography and that the pattern of retention is heterogeneous. Comparison of presenilin 1 and sporadic Alzheimers disease groups revealed significantly greater thalamic retention in the presenilin 1 group and significantly greater frontotemporal retention in the sporadic Alzheimers disease group. A few individuals with presenilin 1 mutations showed increased cerebellar (11)Carbon-Pittsburgh compound B retention suggesting that this region may not be as suitable a reference region in familial Alzheimers disease.

Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series.

Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimers disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimers disease (familial Alzheimers disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Downs syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.

Acceleration of cortical thinning in familial Alzheimer's disease

BACKGROUND MRI in presymptomatic autosomal dominant Alzheimers disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls. METHODS 9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimers disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing. RESULTS An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p=0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group. DISCUSSION Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.

A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease.

We report the case of a 40 year‐old woman who, at 38 years of age, developed insidious memory loss and, subsequently, progressive dementia satisfying criteria for probable Alzheimers disease (AD) (NINCDS‐ADRDA) [Neurology 1984; 34: 939]. Analysis of the presenilin 1 gene (PSEN1) revealed a 496_498delCTT mutation at codon 166. The amnestic presentation and absence of other features contrasts with the majority of other documented deletions which have been associated with spastic paraparesis. They are, however, consistent with the reported clinical phenotype in the majority of PSEN1 exon 6 mutations so far reported.

The cultural context of visual hallucinations.

Visual hallucinations (VH) are a cardinal neuropsychiatric symptom and often have important diagnostic implications. The interpretation of VH is influenced by the patient’s social and cultural milieu, but the impact of socio-cultural factors on the interpretation, presentation and detection of VH has been little studied. When patients exhibit VH and other neuropsychiatric phenomena, appropriate sensitivity to the role of cultural factors is an important determinant of the success of the medical consultation. We discuss this issue using three illustrative cases.

Early subcortical amyloid deposition in familial Alzheimer's disease is accompanied by changes in tissue volume and diffusivity

Introduction The primary progressive aphasias (PPA) are a group of neurodegenerative language-led dementias. Three major subtypes are recognised: progressive nonfluent aphasia (PNFA) characterised by speech apraxia and agrammatism; semantic dementia (SemD), characterised by loss of vocabulary due to primary semantic memory impairment; and logopenic aphasia (LPA), characterised by word-finding pauses, anomia, and impaired phonological memory. Other subtypes have been proposed including aphasia associated with progranulin mutations (GAA). Whereas considerable progress has been made in defining profiles of cortical atrophy in PPA, information about white matter tracts connecting cortical areas remains limited. Here we addressed this issue using diffusion tensor tractography in a cohort of patients with PPA. Methods 20 consecutive patients with a clinical diagnosis of PPA (7 SemD, 6 PNFA, 5 LPA, 2 GAA) and 12 age-matched healthy controls underwent volumetric brain MRI with diffusion tensor imaging (DTI). White matter tract changes in each group and intergroup differences were assessed using Tract Based Spatial Statistics (http://www.fmrib.ox.ac.uk/fsl/tbss). Results PPA syndromic groups showed well-defined fractional anisotropy, axial and radial diffusivity changes tracking white matter pathways implicated in language processing. Compared with healthy individuals, all PPA groups showed changes in the anterior superior longitudinal fasciculus (SLF), and additional tracts were involved in particular subgroups (in SemD, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and commissural pathways; in PNFA, more posterior SLF; in LPA and GAA, ILF). Intergroup comparisons showed significantly greater involvement of ILF and UF in SD than in PNFA or GAA; and greater involvement of left ILF in GAA than PNFA. Tract alterations were restricted to the left hemisphere in GAA but bi-hemispheric in other syndromes. Discussion PPA syndromes are associated with distinctive profiles of altered white matter tract integrity and these tract changes provide substrates for the dysfunction of specific language networks in PPA.

P2-306: Patterns of atrophy in confirmed cases of sporadic and familial Alzheimer’s disease: A voxel-based morphometric study

and GF-109203X (a specific inhibitor of protein kinase C) and forskolin (a specific cAMP-dependent protein kinase A activator) into the left ventricle of rat brains to produce tau hyperphosphorylation (partially reported by us in 2003, 2004). The level of tau phosphorylation was detected by Western blot and immunohistochemistry, Morris water Maze test was carried out to evaluate the behavioral change. H MRS was performed to measure ACh level in normal controls and in the three kinds of AD-like animal model systems. Results: Wortamannin, wortmannin and GF-109203X, and forskolin all induced AD-like hyperphosphorylation of tau and spatial memory deficits. A reduction in the levels of acetylcholine in hippocampus, compared with total creatine levels, was found in the three kinds of AD-like animal model systems. We also found that the degree of spatial memory deficits increased with the reduction of Ach in these animal models. The results agree with the concept that the decrease of ACh level is an early and leading event in AD in vivo human MRS studies. Conclusions: H MRS may be served as a sensitive and noninvasive way in vivo for the diagnosis of AD-like pathology in the early stage.