Maria Lindau

Pittsburgh Compound-B and Alzheimer’s Disease Biomarkers in CSF, Plasma and Urine: An Exploratory Study

Background: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring β-amyloid (Aβ) load. Associations between PET PIB and cerebrospinal fluid (CSF) Aβ1–42 and apolipoprotein E Ε4 (APOE Ε4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer’s disease (AD) are less investigated. Method: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD. Results: PIB retention was constant over 1 year, inversely related to low CSF Aβ1–42 (p = 0.01) and correlated positively to the numbers of the APOE Ε4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = –0.59, p = 0.07), and plasma cystatin C (r = –0.56, p = 0.09). Conclusion: PIB retention is strongly related to CSF Aβ1–42, and to the numbers of the APOE Ε4 allele.

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the “eye of the tiger” sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

Amyloid Aβ40 Csf concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.

Clinical and Molecular Aspects of Frontotemporal Dementia

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer’s disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30–50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.

Re-Evaluation of Clinical Dementia Diagnoses with Pittsburgh Compound B Positron Emission Tomography

Objectives: There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimers disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting. Results: The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up. Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.

P3-026: Insight in frontotemporal dementia and Alzheimer's disease

Background: Loss of insight occurs in frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Since FTD is characterised by anterior cerebral neurodegeneration, and AD by posterior, insight in these disorders was hypothesised to be lost for different reasons. The aim was to compare insight in FTD and AD, and to investigate in which ways executive, emotional and cognitive aspects respectively may contribute to loss of insight. Methods: Ten FTD and ten AD patients participated. Patients were diagnosed by medical and neuropsychological examination, CT and PET scans. Insight was assessed by quantified interviews concerning diagnoses, symptoms, association of symptoms with illness, adaptation to changes, signs of living in the past, extenuation of difficulties, projections, unconcern and reduced ability to reason. The results of the interviews were compared to neuropsychological tests and CT/PET. Results: FTD patients were more unconcerned (p .03) than AD patients, whereas AD patients had taken more measures to adapt (Fig.1, p .02). In FTD awareness of cognitive problems was related to clock drawing (p .05), as was adaptation to problems (p .05). Adaptation was also correlated to the Wisconsin Card Sorting test (WCST, p .03). In AD awareness of cognitive problems and personality were associated with verbal episodic memory (p .04; p .01). Verbal episodic memory was also correlated to adaptation (p .04). Conclusions: Two types of insight emerge: In FTD loss of insight was associated with executive dysfunction (clock drawing, WCST), and with unconcern about the consequences of the disease (loss of executive insight). In AD concern about the situation may explain the higher efforts to adapt to e.g. memory problems (cognitive insight). ROI-PET analyses will yield more specific information about the localisation of deficits in insight.

P2-158: Cognitive decline and longitudinal measurements of CSF tau and AB42

The sensitivity for detection of DLB was 81% with a specificity of 71% and 70% among PDD and a combined group (AD, PDD and NDC), respectively. Conclusions: Interestingly, DLB and PDD exhibit distinct clinical temporal course of disease accompanied by distinct neurochemical phenotypes in CSF, despite their similar neuropathological appearance. Despite some overlap, especially with regard to AD and DLB, the distinct neurochemical phenotypes in CSF indicate disease-specific interactions of each ongoing neurodegenerative dementia process with APP metabolism in AD, DLB and PDD. The evaluation of CSF A peptide patterns come closest to the requirements for a biomarker candidate and may be promising for future use in multiparametric approaches towards the differential diagnosis of dementias.

Amyloid Aβ40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Aβ protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Aβ protein with 40 (Aβ40) and 42 (Aβ42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Aβ40 and Aβ42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Aβ40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = −0.77, p <0.02). Similar results have not been found in previous studies of CSF Aβ40 concentrations and atrophy in patients with AD which suggest that the role of Aβ40 differs between the pathological processes of FTD and AD.