Their work is based on the recent discovery of a "default network" that is ubiquitously observed in brain imaging studies of healthy, young participants (Raichle et al., 2001). Default network activity is observed during periods of rest and passive tasks that do not require targeted, effortful processing. Anticipating the work of Greicius and colleagues, it...  Read more

Their work is based on the recent discovery of a "default network" that is ubiquitously observed in brain imaging studies of healthy, young participants (Raichle et al., 2001). Default network activity is observed during periods of rest and passive tasks that do not require targeted, effortful processing. Anticipating the work of Greicius and colleagues, it is noteworthy that default network in young adults, which prominently includes regions in posterior cingulate and lateral parietal cortex, overlaps anatomically with those regions showing metabolic differences in Alzheimer's disease measured with FDG PET.

Employing a sophisticated analytic procedure that explores brain activity across networks of regions, Greicius et al. optimized the identification of the default network in elderly individuals with and without the earliest signs of Alzheimer's disease. Sensitivity and specificity of discrimination were 85 percent and 77 percent, respectively. As noted in the news story by Hakon Heimer, these numbers are promising and in the range considered clinically relevant.

Greicius and colleagues' observations are important from the perspectives of both clinical and basic science. First, the demonstrated discrimination between demented and nondemented groups using this functional MRI measure holds promise for developing a novel biomarker of Alzheimer's disease that may complement FDG PET metabolic measures. The relation between the changes in default network activity reported here and the common metabolic changes typically measured using FDG PET requires further exploration, but the possibility that the two are strongly related and that functional MRI measures may provide a complementary assessment in the early stages of dementia is intriguing.

Second, the results of their network analysis suggest a functional link to the medial temporal lobe structures that show early pathology in Alzheimer's disease. This may help to resolve the longstanding puzzle of how the pathological changes in medial temporal regions relate to the metabolic changes in parietal and posterior cingulate cortex as measured by PET. The Greicius et al. data suggest the tentative possibility that they are functionally linked and that posterior cortical changes, particularly within posterior cingulate cortex, may arise from anatomic projections between the medial temporal lobe and these regions.

In addition to the specific findings of their study, a social-scientific milestone was achieved in their paper. The data used for their discoveries were not their own. The data were downloaded from a freely available, online archive of raw functional imaging data of previously published manuscripts. The original authors who collected the data had not conceived of the form of analysis Greicius would later employ (we can speak to this point firsthand as original authors of the data). Thus, as intriguing as the results is also the process by which the discovery was made. The work of Greicius and colleagues directly illustrates the potential of open data sharing.

Reference:
Lustig C, Snyder AZ, Bhakta M, O'Brien KC, McAvoy M, Raichle ME, Morris JC, Buckner RL. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14504-9. Abstract

View all comments by Randy Buckner

Amyloid in Normal People: Quelle Surprise!
The seeming surprise that amyloid is found in normal people is a telling reflection of a field dominated by the amyloid hypothesis (Joseph et al., 2001). It is well established from autopsy studies that non-demented people have amyloid and that amyloid is only “diagnostic” [sic] for Alzheimer disease when seen in the presence of dementia (Castellani et al., 2006). To the amyloid-phile, amyloid in normal people represents incipient Alzheimer disease. To the amyloid-phobe, amyloid in both normal and Alzheimer patients represents a response to aging/disease (Smith et al., 2002). In either event, much as is the case for amyloid at autopsy, the only diagnostic value of amyloid imaging will be in the context of clinical dementia.

References:
Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006) Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol (Berl) 111(6): 503-9. Abstract

Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA (2001) Copernicus revisited: amyloid beta in Alzheimer's disease. Neurobiol Aging 22(1): 131-46. Abstract

Smith MA, Casadesus G, Joseph JA, Perry G (2002) Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med 33(9): 1194-9. Abstract

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View all comments by Xiongwei Zhu

fMRI studies further make a more significant correlation as well.

View all comments by Jacob Mack

I think Amber Dance did a fantastic job reviewing the highlights of this paper. I would like to discuss additional issues with regard to certain technical and mechanistic aspects of these findings, which could be taken into account when interpreting the data.

First, miR-659, located on chromosome 22 in humans, seems to be relatively very weakly expressed in adult brain (with cycle threshold [Ct] values of approximately 32 as measured by qRT-PCR). Therefore, whether endogenous miR-659 levels are sufficient to regulate GRN levels...  Read more

I think Amber Dance did a fantastic job reviewing the highlights of this paper. I would like to discuss additional issues with regard to certain technical and mechanistic aspects of these findings, which could be taken into account when interpreting the data.

First, miR-659, located on chromosome 22 in humans, seems to be relatively very weakly expressed in adult brain (with cycle threshold [Ct] values of approximately 32 as measured by qRT-PCR). Therefore, whether endogenous miR-659 levels are sufficient to regulate GRN levels in vivo remains speculative. Mechanistically, one must envisage that regulation of GRN mRNA by miR-659 occurs in a cell-autonomous fashion. One possibility, not shown here, is that miR-659 is expressed in specific cell types, such as the granular cell layer of the cerebellum where GRN protein is decreased (it should be noted that the qRT-PCR for miR-659 was performed on whole tissues). In my opinion, this would strongly strengthen the biological significance of the proposed mode of regulation.

Here, the authors use basic, but widely accepted in vitro systems to validate their hypothesis. First, artificial overexpression of miR-659 (at a concentration of 12 nM) in human M17 neuroblastoma cells leads to decreased expression of endogenous GRN protein levels (note that inverse experiments using antisense oligonucleotides to block endogenous miR-659 was not performed, possibly due to the extremely low levels of this microRNA in these cells). Whether GRN mRNA levels are affected in these conditions is not shown. Then, additional studies were conducted in mouse Neuro2A cells using luciferase-based constructs containing the GRN 3’UTR. In these latter experiments, functional effects on GRN expression are seen with the mutant TT construct at concentrations starting at 5 pM of exogenous miR-659. Again from a mechanistic point of view, it would be interesting to see whether the “increased” binding (i.e., increased sequence complementarity) of miR-659 to the mutant TT allele causes an siRNA effect (thus degradation of mRNA). It should be noted, however, that, in affected patients, GRN mRNA (from total tissue sections) is not affected.

Interestingly, the predicted target site (more particularly the “seed” sequence) for miR-659 in the GRN 3’UTR is only conserved in humans, and is not found in other mammals including mouse and dog (e.g., see www.targetscan.org). Similarly, miR-659 is, at least for now, only found in humans. Interestingly, the GRN 3’UTR is quite short (approximately 300 bp in length). In comparison, the BACE1 and APP 3’UTRs, which equally have functional microRNA target sites, are approximately 4,000 bp and 2,000 bp in length, respectively.

Overall, these findings provide novel and important clues into the development of FTLD-U. In addition, this study contributes to the potential role of microRNA pathways in the development of neurodegenerative disorders in human. I agree that relatively few patients were analyzed here to make definitive conclusions with regard to the biological relevance of these findings.

View all comments by Sebastien S. Hebert

The first one is contemporary to the initiation of AD; I have seen it (Foncin, 1974; Foncin et al., 1985) in a cortical biopsy of a 42-year-old woman who died demented aged 51; she was the index case of FAD4 (Sherrington et al., 1995); congophilic angiopathy is seen prominently in AD with lobar hemorrhages. On the opposite, dysoric angiopathy is probably secondary.

My conclusion is what is called AD really is the result of the lumping together of various conditions with various pathogenies, and inferences for AD...  Read more

The first one is contemporary to the initiation of AD; I have seen it (Foncin, 1974; Foncin et al., 1985) in a cortical biopsy of a 42-year-old woman who died demented aged 51; she was the index case of FAD4 (Sherrington et al., 1995); congophilic angiopathy is seen prominently in AD with lobar hemorrhages. On the opposite, dysoric angiopathy is probably secondary.

My conclusion is what is called AD really is the result of the lumping together of various conditions with various pathogenies, and inferences for AD therapy in general drawn from any particular mouse model are hazardous at best.

References:
FONCIN J.-F. (1974): Angiopathie amyloïde et maladie d'Alzheimer familiale. In "Biologie et pathologie des parois artérielles et artériolo-capillaires" Lyon, ACEML, pp. 49-50.

Foncin JF, Salmon D, Supino-Viterbo V, Feldman RG, Macchi G, Mariotti P, Scoppetta C, Caruso G, Bruni AC. Démence présénile d'Alzheimer transmise dans une famille étendue. Rev Neurol (Paris). 1985;141(3):194-202. Abstract

Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. Abstract

View all comments by Jean-François FONCIN

Cavallaro RA, Fuso A, D'Anselmi F, Seminara L, Scarpa S. The effect of S-adenosylmethionine on CNS gene expression studied by cDNA microarray analysis. J Alzheimers Dis. 2006 Aug;9(4):415-9. Abstract

View all comments by Sigfrido Scarpa

Her Alzheimer's appeared to be stable during the months she took the trial medication. It appears to have deteriorated markedly during the few weeks since she stopped the medication.

Has anyone observed a developing weakness possibly related to LY-450139?

View all comments by Paul Murray

These findings are important. But like all other retrospective studies, this study has several limitations, including the difficulty to find appropriate controls, as described in the manuscript. Therefore, the findings from this study and other post-operative cognitive dysfunction studies strongly suggest that there is a need to perform an adequately powered, multicenter human study to further define post-operative cognitive dysfunction.

View all comments by Zhongcong Xie