Alzheimer Disease: Boeve B

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Lowe VJ, Kemp BJ, Jack CR, Senjem M, Weigand S, Shiung M, Smith G, Knopman D, Boeve B, Mullan B, Petersen RC. · Department of Radiology, Mayo Clinic, Rochester, Minnesota 55905, USA. · J Nucl Med. · Pubmed #19443597 No free full text.

Abstract: The purpose of this study was to compare the diagnostic accuracy of glucose metabolism and amyloid deposition as demonstrated by (18)F-FDG and Pittsburg Compound B (PiB) PET to evaluate subjects with cognitive impairment. METHODS: Subjects were selected from existing participants in the Mayo Alzheimer's Disease Research Center or Alzheimer's Disease Patient Registry programs. A total of 20 healthy controls and 17 amnestic mild cognitive impairment (aMCI), 6 nonamnestic mild cognitive impairment (naMCI), and 13 Alzheimer disease (AD) subjects were imaged with both PiB and (18)F-FDG PET between March 2006 and August 2007. Global measures for PiB and (18)F-FDG PET uptake, normalized to cerebellum for PiB and pons for (18)F-FDG, were compared. Partial-volume correction, standardized uptake value (SUV), and cortical ratio methods of image analysis were also evaluated in an attempt to optimize the analysis for each test. RESULTS: Significant discrimination (P < 0.05) between controls and AD, naMCI and aMCI, naMCI and AD, and aMCI and AD by PiB PET measurements was observed. The paired groupwise comparisons of the global measures demonstrated that PiB PET versus (18)F-FDG PET showed similar significant group separation, with only PiB showing significant separation of naMCI and aMCI subjects. CONCLUSION: PiB PET and (18)F-FDG PET have similar diagnostic accuracy in early cognitive impairment. However, significantly better group discrimination in naMCI and aMCI subjects by PiB, compared with (18)F-FDG, was seen and may suggest early amyloid deposition before cerebral metabolic disruption in this group.

Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R. · Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Brain. · Pubmed #19158106 links to  free full text

Abstract: Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Lancet Neurol. · Pubmed #17826340 No free full text.

Abstract: BACKGROUND: The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS: We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS: Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION: Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

Testa JA, Ivnik RJ, Boeve B, Petersen RC, Pankratz VS, Knopman D, Tangalos E, Smith GE. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota 55901, USA. · J Int Neuropsychol Soc. · Pubmed #15327729 No free full text.

Abstract: As the incidence of dementia increases, there is a growing need to determine the diagnostic utility of specific neuropsychological tests in the early diagnosis of Alzheimer's disease (AD). In this study, the relative utility of Boston Naming Test (BNT) in the diagnosis of AD was examined and compared to the diagnostic utility of other neuropsychological measures commonly used in the evaluation of AD. Individuals with AD (n = 306), Mild Cognitive Impairment (MCI; n = 67), and cognitively normal subjects (n = 409) with at least 2 annual evaluations were included. Logistic regression analysis suggested that initial BNT impairment is associated with increased risk of subsequent AD diagnosis. However, this risk is significantly less than that imparted by measures of delayed recall impairments. A multivariate Cox proportional hazards regression analysis suggested that BNT impairment imparted no additional risk for subsequent AD diagnosis after delayed recall impairments were included in the model. Although BNT impairment occurred in all severity groups, it was ubiquitous only in moderate to severe dementia. Collectively these results suggest that although BNT impairments become more common as AD progresses, they are neither necessary for the diagnosis of AD nor particularly useful in identifying early AD.

Baker M, Graff-Radford D, Wavrant DeVrièze F, Graff-Radford N, Petersen RC, Kokmen E, Boeve B, Myllykangas L, Polvikoski T, Sulkava R, Verkoniemmi A, Tienari P, Haltia M, Hardy J, Hutton M, Perez-Tur J. · Neurogenetics Laboratories and Neurology Department, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA. · Neurosci Lett. · Pubmed #10793248 No free full text.

Abstract: We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.