Alzheimer Disease: Pihlajamäki M

Jauhiainen AM, Pihlajamäki M, Tervo S, Niskanen E, Tanila H, Hänninen T, Vanninen RL, Soininen H. · Institute of Clinical Medicine, Unit of Neurology, University of Kuopio, Kuopio, Finland. · Hippocampus. · Pubmed #18777563 No free full text.

Abstract: We investigated structural and functional changes in the medial temporal lobe (MTL) using magnetic resonance imaging (MRI) and compared the discriminative power of these measures with neuropsychological testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Functional MRI (fMRI) was performed in 21 elderly controls, 14 MCI subjects, and 15 mild AD patients during encoding and cued retrieval of word-picture pairs. A region-of-interest-based approach in SPM2 was used to extract the extent of hippocampal activation. The volumes of the hippocampus and entorhinal cortex (EC) were manually outlined from anatomical MR images. Discriminant analyses were conducted to assess the ability of hippocampal fMRI, MTL volumetry, and neuropsychological measures to classify subjects into clinical groups. Entorhinal but not hippocampal volumes differed significantly between the control and MCI subjects. Both entorhinal and hippocampal volumes differed between MCI and AD patients. There were no significant differences in the extent of hippocampal fMRI activation during encoding or retrieval between the groups. Entorhinal volume was the best discriminator with a discriminating accuracy of 85.7% between controls and MCI, 86.2% between MCI and AD, and 97.2% between controls and AD. Delayed recall of a wordlist classified the subjects, second best, with a discriminating accuracy of 81.8% between controls and MCI, 75% between MCI and AD and 93.5% between controls and AD. The accuracy of hippocampal volumetry ranged from 42.9 to 69.4%, and hippocampal fMRI activation during encoding and retrieval had a classification accuracy of only 41.4-57.7% between the groups. Our results suggest that evaluation of entorhinal atrophy, in addition to the prevailing diagnostic criteria, seems promising in the identification of prodromal AD. Future technical improvements may improve the utilization of hippocampal fMRI for early diagnostic purposes.

Pihlajamäki M, DePeau KM, Blacker D, Sperling RA. · Memory Disorders Unit, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Am J Geriatr Psychiatry. · Pubmed #18378553 links to  free full text

Abstract: OBJECTIVES: Neural networks supporting encoding of new information are affected early in the course of Alzheimer disease (AD). Functional magnetic resonance imaging (fMRI) studies in AD have reported decreased medial temporal lobe (MTL) activation when comparing novel versus repeated stimuli. It is, however, unclear whether this finding is related to a failure of normal suppression of MTL activity to repeated stimuli in AD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Twenty-nine healthy older subjects comprising a comparison group (OC) and 15 mild AD patients underwent fMRI during an associative memory paradigm in an academic medical center. The task consisted of blocks of Novel and Repeated face-name pairs and visual Fixation. To reveal neural correlates of processing repeatedly presented stimuli, Repeated blocks were contrasted to Fixation. RESULTS: AD patients demonstrated greater activation during Repeated stimuli in the MTL and in prefrontal and superior parietal cortices, compared with OC. In contrast, OC showed greater parietal task-induced deactivation than AD. Increased MTL activity during Repeated was correlated with more impaired parietal deactivation and poorer performance of the postscan recognition memory test of encoding the face-name pairs. CONCLUSION: Reduction of MTL activity to repeated stimuli, which become highly familiarized to healthy OC, was impaired in AD. This abnormal increased MTL activation was related to disrupted parietal deactivation and to poor recognition memory performance. These preliminary results suggest that the typical episodic memory impairment seen in mild AD may manifest as a failure of normal repetition suppression and loss of "beneficial" deactivation in the MTL-parietal memory networks.

Diamond EL, Miller S, Dickerson BC, Atri A, DePeau K, Fenstermacher E, Pihlajamäki M, Celone K, Salisbury S, Gregas M, Rentz D, Sperling RA. · Department of Neurology, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115, USA. · Neurology. · Pubmed #17893294 No free full text.

Abstract: BACKGROUND: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. OBJECTIVE: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. METHODS: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects' high-resolution structural images. RESULTS: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = -0.51) and left prefrontal (p = 0.00001; r = -0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. CONCLUSIONS: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. .

Pihlajamäki M, Tanila H, Hänninen T, Könönen M, Laakso M, Partanen K, Soininen H, Aronen HJ. · Department of Neuroscience and Neurology, University of Kuopio, Finland. · Ann Neurol. · Pubmed #10762158 No free full text.

Abstract: Verbal fluency tests (VFTs) are suggested to assess frontal lobe function. This view is supported by functional imaging studies that report left frontal activation during VFTs. VFTs require retrieval of semantically associated words from long-term memory storage. The neural networks that participate in this process, however, are largely unknown. These neural networks are of interest, given that patients with early Alzheimer's disease, typically without frontal pathology, are often impaired in VFTs. In the present study, functional magnetic resonance imaging was performed to determine brain activation areas during VFTs in young subjects. In the activation task, category fluency was contrasted with orderly listing of numbers. As judged from using this comparison, there was activation in the left medial temporal lobe, in the inferior frontal and retrosplenial cortices bilaterally, and in the left superior parietal lobule. Left medial temporal lobe activation was present in 13 of the 14 study subjects either in the hippocampal formation (11 of 14) or in the posterior parahippocampal gyrus (12 of 14). These results suggest that the medial temporal lobe is required for the process of retrieval by category. Functional magnetic resonance imaging combined with a category fluency task may provide a new method to study patients with early Alzheimer's disease.

Geroldi C, Pihlajamäki M, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB. · IRCCS San Giovanni di Dio-FBF, Brescia, Italy. · Neurology. · Pubmed #10563634 No free full text.

Abstract: OBJECTIVE: To test the hypothesis that the e4 allele of APOE is associated with a region-specific pattern of brain atrophy in AD. METHODS: Volumes of the hippocampi, entorhinal cortices, and anterior temporal and frontal lobes were measured in 28 mild to moderate AD patients and 30 controls using MRI. Within the AD group, 14 patients were noncarriers (-/-), 9 were heterozygous (e4/-), and 5 were homozygous (e4/4) for the e4 allele. Dementia severity was similar across the three AD groups. RESULTS: Smaller volumes were found with increasing dose of the e4 allele in the hippocampus, entorhinal cortex, and anterior temporal lobes in AD patients. When compared with controls, the volume loss in the right and left temporal regions ranged from -15.3 to -22.7% in the -/- AD group, from -26.2 to -36.0% in the e4/- group, and from -24.0 to -48.0% in the e4/4 group (p < 0.0005). In contrast, larger volumes were found in the frontal lobes with increasing e4 gene dose. When compared with controls, volume differences of the right frontal lobe were -11.8% in the -/- AD group, -8.5 in the e4/- group, and -1.4% in the e4/4 group (p = 0.03). CONCLUSIONS: We found smaller volumes in the temporal lobe regions but larger volumes in the frontal lobes with increasing APOE-e4 gene dose in AD patients. These data suggest a region-specific biological effect of the e4 allele in the brains of AD patients.