Matthias Riemenschneider

Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study

A high percentage of patients with mild cognitive impairment (MCI) develop clinical dementia of the Alzheimer type (AD) within 1 year. The aim of this longitudinal study was to identify characteristic patterns of cerebral metabolism at baseline in patients converting from MCI to AD, and to evaluate the changes in these patterns over time. Baseline and follow-up examinations after 1 year were performed in 22 MCI patients (12 males, 10 females, aged 69.8±5.8 years); these examinations included neuropsychological testing, structural cranial magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography (PET) evaluation of relative cerebral glucose metabolic rate (rCMRglc). Individual PET scans were stereotactically normalised with NEUROSTAT software (Univ. of Michigan, Ann Arbor, USA). Subsequently, statistical comparison of PET data with an age-matched healthy control population and between patient subgroups was performed using SPM 99 (Wellcome Dept. of Neuroimaging Sciences, London, UK). After 1 year, eight patients (36%) had developed probable AD (referred to as MCIAD), whereas 12 (55%) were still classified as having stable MCI (referred to as MCIMCI). Compared with the healthy control group, a reduced rCMRglc in AD-typical regions, including the temporoparietal and posterior cingulate cortex, was detected at baseline in patients with MCIAD. Abnormalities in the posterior cingulate cortex reached significance even in comparison with the MCIMCI group. After 1 year, MCIAD patients demonstrated an additional bilateral reduction of rCMRglc in prefrontal areas, along with a further progression of the abnormalities in the parietal and posterior cingulate cortex. No such changes were observed in the MCIMCI group. In patients with MCI, characteristic cerebral metabolic differences can be delineated at the time of initial presentation, which helps to define prognostic subgroups. A newly emerging reduction of rCMRglc in prefrontal cortical areas is associated with the transition from MCI to AD.

Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias

Early clinical symptoms of sporadic Creutzfeldt–Jakob disease (CJD) may overlap with other neurodegenerative diseases like Alzheimers disease (AD) and frontotemporal degeneration (FTD). On entering an era in which pharmaceutical treatment of CJD occurs, reliable diagnostic markers like immunodetection of 14–3–3 proteins in the cerebrospinal fluid (CSF) are required. However, false negative results in autopsy-proven, sporadic CJD cases, as well as false positive results in several other disorders including AD and FTD showing high CSF tau protein levels, limit the potential of this marker. Due to neuronal lysis the cytosolic fraction of total tau containing phosphorylated and non-phosphorylated isoforms is partially liberated into the CSF. Since hyperphosphorylation of tau may specifically occur in neurodegenerative diseases associated with neurofibrillary changes, we hypothesized that the phospho-tau (P-tau)/total tau ratio in CSF may be a useful marker to discriminate CJD from other neurodegenerative disorders. The P-tau/total tau ratio discriminated patients with CJD from all other neuro-degenerative disorders including patients with AD and FTD without any overlap. Although the results have to be confirmed in a larger sample, the preliminary data suggest that simultaneous measurement of total tau and P-tau in CSF may be useful to identify patients with CJD.

Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study

OBJECTIVE To determine the patterns of cerebral glucose metabolism in frontotemporal dementia (FTD) and semantic dementia (SD). METHODS 25 patients with mild FTD and 9 patients with mild SD as well as 15 healthy age-matched control subjects underwent 18F-FDG- positron emission tomography. Patient scans were compared with control scans using SPM-99. RESULTS As compared with healthy control subjects patients with FTD showed an extensive symmetrical hypometabolism of the frontal lobes (height threshold P <0.01) which spared the motor cortex. Patients with SD showed a hypometabolism in the whole left temporal lobe and in the right temporal pole. CONCLUSIONS In the clinical syndromes of FTD and SD two distinct patterns of cerebral metabolism were identified. FTD was associated with frontal hypometabolism, whereas in SD cerebral glucose metabolism was exclusively reduced in the temporal lobes. Our findings are consistent with the notion that FTD and SD begin as strictly lobar neuronal degenerations and that a spread of pathological changes is not seen until more advanced stages.

Tau and Aβ42 protein in CSF of patients with frontotemporal degeneration

Background CSF concentrations of tau and &bgr;-amyloid protein-42 (A&bgr;42) have been extensively studied in AD. Few data are available concerning CSF levels of both proteins in patients with frontotemporal degeneration (FTD). Methods The authors investigated CSF tau and A&bgr;42 concentrations in 34 patients with FTD, 74 patients with AD, and 40 cognitively healthy control subjects. CSF levels of tau and A&bgr;42 were measured by ELISA. With use of receiver operating characteristic–derived cutoff points and linear discrimination lines, the diagnostic sensitivity and specificity of both markers were determined. Results CSF tau concentrations were significantly higher in FTD than in control subjects but were significantly lower than in AD. CSF A&bgr;42 levels were significantly lower in FTD than in control subjects but were significantly higher than in AD. In subjects with FTD, neither tau nor A&bgr;42 levels correlated with the severity of dementia. The best discrimination between the diagnostic groups was obtained by simultaneous measurement of tau and A&bgr;42, yielding a sensitivity of 90% at a specificity of 77% (FTD vs controls) and a sensitivity of 85% at a specificity of 85% (FTD vs AD). Conclusions In FTD, CSF levels of tau are elevated and A&bgr;42 levels are decreased. With use of these markers, subjects with FTD can be distinguished from control subjects and from patients with AD with reasonable accuracy.

Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

OBJECTIVE To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). DESIGN Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies. SETTING Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. PARTICIPANTS All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls. MAIN OUTCOME MEASURES Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (now known as the Alzheimers Association). RESULTS In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120,873,131-120,886,175 base pairs [bp]; C-G-C alleles), at SNP 19 (120,953,300 bp; G allele), and at SNPs 24 through 25 (120,988,611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain. CONCLUSION This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

Decline of cerebral glucose metabolism in frontotemporal dementia: a longitudinal 18F-FDG-PET-study.

OBJECTIVE To identify the pattern of progression of decline of cerebral glucose metabolism in frontotemporal dementia (FTD, frontal variant). METHODS 22 patients with mild FTD underwent 18F-FDG-positron emission tomography at baseline and at follow-up in average 19.5 months later. Patient scans were compared with scans from 15 healthy age-matched control subjects on a voxel-by-voxel basis using SPM-99. RESULTS As compared with healthy control subjects at baseline patients with FTD showed a significant symmetrical hypometabolism of the frontal lobes sparing the motor cortex, of the caudate nuclei, insula and thalamus bilaterally. At follow-up further significant reductions in glucose metabolism were observed in the parietal and temporal cortices. CONCLUSIONS In early stages of FTD the neurodegenerative process is limited to the frontal lobes. During the progression of the disease, the pathological changes pass over the lobar borders and spread into the parietal and temporal cortices.

Examination of the current top candidate genes for AD in a genome-wide association study.

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the ‘Top Results’ list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case–control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

Cerebral glucose metabolism in patients with AD and different APOE genotypes

Objective: To examine the influence of the APOE ε4 allele on cerebral glucose metabolism in a large series of patients with Alzheimer disease (AD). Methods: Eighty-three patients (41 APOE ε4 positive and 42 ε4 negative) were selected from a pre-existing databank of patients with AD (n > 1,000). The patients were carefully matched for age, age at onset, approximate disease duration, educational level, and overall degree of cognitive impairment. Cerebral [18F]fluorodeoxyglucose PET imaging was performed in all patients by a standardized protocol. Statistical comparison of patient PET data vs a healthy control population was performed as well as an analysis of differences between groups (SPM99; Wellcome Department of Cognitive Imaging, London, UK). Results: A similar pattern of cerebral hypometabolism was detected in the ε4-positive and -negative patient groups vs healthy volunteers in regions typically affected by AD (bilateral temporal, parietal, posterior cingulate, and prefrontal cortical areas). The comparison between ε4-positive and -negative patients additionally revealed stronger abnormalities in ε4 carriers in parietal, temporal, and posterior cingulate cortical regions. Conclusions: A generally similar pattern of cerebral hypometabolism was detected in APOE ε4-positive and -negative patients with Alzheimer disease. However, in direct comparison of the two matched groups, the abnormalities in the ε4-positive group were demonstrated to be more pronounced.

Cerebrospinal protein tau is elevated in early Alzheimer's disease

Protein tau concentration was determined by an enzyme linked immunoassay (ELISA) in cerebrospinal fluid (CSF) of 22 patients with clinically diagnosed Alzheimers disease (AD), in three patients with dementia caused by other neurological disorders (OND) and in 19 cognitively healthy controls. A significantly elevated protein tau concentration was found in AD patients as compared with controls, even in 11 patients with very mild dementia. There was no correlation between protein tau and the severity of cognitive impairment as assessed with the Mini Mental State Examination (MMSE). Tau concentrations were not or only slightly elevated in OND. We conclude that protein tau in CSF might be helpful as a biological marker for the early diagnosis of AD.

A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E ε4 allele

Because of its implication in neuroprotection, formation of long lasting memories and a disturbed function in Alzheimers disease (AD), brain-derived neurotrophic factor (BDNF) may represent an appropriate candidate gene conferring risk to AD. Recently, a single nucleotide polymorphism (C-270T) within the BDNF gene has been associated with late onset AD in a Japanese population giving an odds ratio (OR) of 3.8. Because of the importance of this finding we analysed the BDNF polymorphism in a German sample consisting of 210 patients with AD and 188 cognitively healthy controls. The T-allele frequency was higher in patients with AD (11.9%) compared to controls (6.9%) (P = 0.035; OR = 2.26; 95% CI: 1.04–4.48). The risk conferred by the T-allele was stronger in patients who lack the ApoE ε4 allele giving an OR of 2.61 (1.21–5.64) P = 0.015, particularly in patients with early onset of the disease; OR 3.13 (1.32–7.43); P= 0.01. Due to the small number of patients showing both, lack of the ApoE ε4 allele and the BDNF T allele (n = 18), the result needs to be confirmed in a larger sample. The results suggest that the BDNF C-270T polymorphism is a relevant risk factor for AD particularly in patients lacking the ApoE ε4 allele in this German sample.