Alzheimer Disease: Lindquist SG

Schultz K, Wiehager S, Nilsson K, Nielsen JE, Lindquist SG, Hjermind LE, Andersen BB, Wallin A, Nilsson C, Petersén A. · Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. · Neurosci Lett. · Pubmed #19356602 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimer's disease (AD). The underlying neurobiological mechanism of DLB is not fully understood and no generally accepted biomarkers are yet available for the diagnosis of DLB. In a recent MRI study, DLB patients displayed hypothalamic atrophy whereas this region was not affected in AD patients. Cocaine and amphetamine regulated transcript (CART) is a neuropeptide expressed selectively in neurons in the hypothalamus. Here, we found that CSF CART levels were significantly reduced by 30% in DLB patients (n = 12) compared to controls (n = 12) as well as to AD patients (n = 14) using radioimmunoassay. Our preliminary results suggest that reduced CSF CART is a sign of hypothalamic dysfunction in DLB and that it may serve as a biomarker for this patient group.

Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A, Stokholm J, Schwartz M, Batbayli M, Laursen H, Pardossi-Piquard R, Chen F, St George-Hyslop P, Waldemar G, Nielsen JE. · Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #18727676 No free full text.

Abstract: BACKGROUND: Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer's disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Abeta42 peptide. METHODS AND RESULTS: We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Abeta42/40 peptide ratio. The mutation was not found in 384 control individuals tested. CONCLUSIONS: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

Lindquist SG, Holm IE, Schwartz M, Law I, Stokholm J, Batbayli M, Waldemar G, Nielsen JE. · Memory Disorders Research Group, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #18284428 No free full text.

Abstract: We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre-symptomatic and affected family members underwent multidisciplinary (clinical, molecular, neuroimaging and neuropathological) examinations. Treatment with memantine in a family member with early symptoms, based on the clinical phenotype and the lack of specific treatment, appears to stabilize the disease course and increase the glucose metabolism in cortical and subcortical areas, as determined by serial [F(18)]FDG-PET scanning before and after initiation of treatment. Neuropathological examination of a second affected and mutation-positive family member showed moderate atrophy of the temporal lobes including the hippocampi. Microscopy revealed abundant numbers of tau-positive neurofibrillary tangles in all cortical areas and in some brainstem nuclei corresponding to a diagnosis of frontotemporal lobe degeneration on the basis of a MAPT mutation. The clinical and genetic heterogeneity of autosomal dominant inherited dementia must be taken into account in the genetic counselling and genetic testing of families with autosomal dominantly inherited dementia in general.

Lindquist SG, Nielsen JE, Stokholm J, Schwartz M, Batbayli M, Ballegaard M, Erdal J, Krabbe K, Waldemar G. · Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · J Neurol Sci. · Pubmed #18187157 No free full text.

Abstract: BACKGROUND: Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features. METHODS AND RESULTS: We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer's disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation). CONCLUSIONS: The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.

Lindquist SG, Waldemar G, Nielsen JE. · H:S Rigshospitalet, Neurocentret, Neurologisk Klinik, H:S Hukommelsesklinikken. · Ugeskr Laeger. · Pubmed #17032604 No free full text.

Abstract: Several prevalent, sporadic neurodegenerative disorders also occur as rare inherited variants. Mapping of the genes involved in rare variants of the disorders has contributed to elucidating pathogenetic pathways for several dementia disorders, and the increased knowledge creates a possibility for development of new molecular genetic methods for diagnostics and for the treatment of the different types of dementia. Although inherited dementia disorders are generally rare, a genetic basis should always be considered when facing a patient with a recently clinically diagnosed dementia disorder.