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Diffusion imaging changes in grey matter in Alzheimer's disease: a potential marker of early neurodegeneration.

Weston PS, Simpson IJ, Ryan NS, Ourselin S, Fox NC - Alzheimers Res Ther (2015)

Bottom Line: Although use of the technique is still at a relatively early stage, results so far have been promising.The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues.Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes.

View Article: PubMed Central - PubMed

Affiliation: Dementia Research Centre, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Box 16, Queen Square, London, WC1N 3BG UK.

ABSTRACT
Alzheimer's disease (AD) is recognized to have a long presymptomatic period, during which there is progressive accumulation of molecular pathology, followed by inexorable neuronal damage. The ability to identify presymptomatic individuals with evidence of neurodegenerative change, to stage their disease, and to track progressive changes will be important for early diagnosis and for prevention trials. Despite recent advances, particularly in magnetic resonance imaging, our ability to identify early neurodegenerative changes reliably is limited. The development of diffusion-weighted magnetic resonance imaging, which is sensitive to microstructural changes not visible with conventional volumetric techniques, has led to a number of diffusion imaging studies in AD; these have largely focused on white matter changes. However, in AD cerebral grey matter is affected very early, with pathological studies suggesting that grey matter changes predate those in white matter. In this article we review the growing number of studies that assess grey matter diffusivity changes in AD. Although use of the technique is still at a relatively early stage, results so far have been promising. Initial studies identified changes in diffusion measures in the hippocampi of patients with mild cognitive impairment, which predated macroscopic volume loss, with positive predictive value for progression to AD dementia. More recent studies have identified abnormalities in multiple neocortical areas (particularly the posterior cingulate) at various stages of disease progression. Studies of patients who carry genetic mutations predisposing to autosomal dominant familial AD have shown cortical and subcortical grey matter diffusivity changes several years before the expected onset of the first clinical symptoms. The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues. Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes. This imaging technique may also be useful in comparing and contrasting subtle variations in different disease subgroups, and as a sensitive outcome measure for presymptomatic clinical trials in AD and other neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

A simplified schematic representation of molecular diffusion in and around neurons, and how this may change over time in Alzheimer’s disease (AD). a In the early presymptomatic stage water molecules are able to diffuse normally, with the mean diffusivity (MD) being the same as a normal healthy individual. b Evidence from familial AD studies suggests that in the period shortly before symptom onset the MD falls, implying that diffusion is restricted. This restriction may be a result of cellular hypertrophy and/or inflammation, in response to amyloid deposition in the presymptomatic phase. c During the symptomatic phase, progressive cellular atrophy results in a breakdown in the usual barriers to diffusion, with studies showing an increase in MD compared with normal controls. The effects in (c) are likely to progressively outweigh the effects in (b) as the disease progresses
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Fig3: A simplified schematic representation of molecular diffusion in and around neurons, and how this may change over time in Alzheimer’s disease (AD). a In the early presymptomatic stage water molecules are able to diffuse normally, with the mean diffusivity (MD) being the same as a normal healthy individual. b Evidence from familial AD studies suggests that in the period shortly before symptom onset the MD falls, implying that diffusion is restricted. This restriction may be a result of cellular hypertrophy and/or inflammation, in response to amyloid deposition in the presymptomatic phase. c During the symptomatic phase, progressive cellular atrophy results in a breakdown in the usual barriers to diffusion, with studies showing an increase in MD compared with normal controls. The effects in (c) are likely to progressively outweigh the effects in (b) as the disease progresses

Mentions: The above studies detected in vivo presymptomatic microstructural grey matter changes in limbic cortex, neocortex and subcortical grey matter structures. However, one key finding, consistent across all of these anatomical structures, was that the presymptomatic change in MD was not in the direction one would have expected, in that it was decreased rather than increased compared with controls. This is opposite to the direction of change observed in symptomatic AD (both familial and sporadic). This reduction in presymptomatic MD was also associated with marginally increased cortical thickness. Although unexpected, and requiring further replication in larger studies, the finding of a presymptomatic fall in MD is very interesting. It may suggest the presence of more than one pathological process affecting diffusion imaging changes: the presymptomatic reduction in MD may indicate an inflammatory response to amyloid accumulation (Fig. 3), occurring prior to (or coincident with and obscuring) the onset of microstructural breakdown and macrostructural atrophy [38, 39]. A summary of research studies assessing grey matter diffusivity in AD is given in Table 1.Fig. 3


Diffusion imaging changes in grey matter in Alzheimer's disease: a potential marker of early neurodegeneration.

Weston PS, Simpson IJ, Ryan NS, Ourselin S, Fox NC - Alzheimers Res Ther (2015)

A simplified schematic representation of molecular diffusion in and around neurons, and how this may change over time in Alzheimer’s disease (AD). a In the early presymptomatic stage water molecules are able to diffuse normally, with the mean diffusivity (MD) being the same as a normal healthy individual. b Evidence from familial AD studies suggests that in the period shortly before symptom onset the MD falls, implying that diffusion is restricted. This restriction may be a result of cellular hypertrophy and/or inflammation, in response to amyloid deposition in the presymptomatic phase. c During the symptomatic phase, progressive cellular atrophy results in a breakdown in the usual barriers to diffusion, with studies showing an increase in MD compared with normal controls. The effects in (c) are likely to progressively outweigh the effects in (b) as the disease progresses
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487800&req=5

Fig3: A simplified schematic representation of molecular diffusion in and around neurons, and how this may change over time in Alzheimer’s disease (AD). a In the early presymptomatic stage water molecules are able to diffuse normally, with the mean diffusivity (MD) being the same as a normal healthy individual. b Evidence from familial AD studies suggests that in the period shortly before symptom onset the MD falls, implying that diffusion is restricted. This restriction may be a result of cellular hypertrophy and/or inflammation, in response to amyloid deposition in the presymptomatic phase. c During the symptomatic phase, progressive cellular atrophy results in a breakdown in the usual barriers to diffusion, with studies showing an increase in MD compared with normal controls. The effects in (c) are likely to progressively outweigh the effects in (b) as the disease progresses
Mentions: The above studies detected in vivo presymptomatic microstructural grey matter changes in limbic cortex, neocortex and subcortical grey matter structures. However, one key finding, consistent across all of these anatomical structures, was that the presymptomatic change in MD was not in the direction one would have expected, in that it was decreased rather than increased compared with controls. This is opposite to the direction of change observed in symptomatic AD (both familial and sporadic). This reduction in presymptomatic MD was also associated with marginally increased cortical thickness. Although unexpected, and requiring further replication in larger studies, the finding of a presymptomatic fall in MD is very interesting. It may suggest the presence of more than one pathological process affecting diffusion imaging changes: the presymptomatic reduction in MD may indicate an inflammatory response to amyloid accumulation (Fig. 3), occurring prior to (or coincident with and obscuring) the onset of microstructural breakdown and macrostructural atrophy [38, 39]. A summary of research studies assessing grey matter diffusivity in AD is given in Table 1.Fig. 3

Bottom Line: Although use of the technique is still at a relatively early stage, results so far have been promising.The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues.Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes.

View Article: PubMed Central - PubMed

Affiliation: Dementia Research Centre, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Box 16, Queen Square, London, WC1N 3BG UK.

ABSTRACT
Alzheimer's disease (AD) is recognized to have a long presymptomatic period, during which there is progressive accumulation of molecular pathology, followed by inexorable neuronal damage. The ability to identify presymptomatic individuals with evidence of neurodegenerative change, to stage their disease, and to track progressive changes will be important for early diagnosis and for prevention trials. Despite recent advances, particularly in magnetic resonance imaging, our ability to identify early neurodegenerative changes reliably is limited. The development of diffusion-weighted magnetic resonance imaging, which is sensitive to microstructural changes not visible with conventional volumetric techniques, has led to a number of diffusion imaging studies in AD; these have largely focused on white matter changes. However, in AD cerebral grey matter is affected very early, with pathological studies suggesting that grey matter changes predate those in white matter. In this article we review the growing number of studies that assess grey matter diffusivity changes in AD. Although use of the technique is still at a relatively early stage, results so far have been promising. Initial studies identified changes in diffusion measures in the hippocampi of patients with mild cognitive impairment, which predated macroscopic volume loss, with positive predictive value for progression to AD dementia. More recent studies have identified abnormalities in multiple neocortical areas (particularly the posterior cingulate) at various stages of disease progression. Studies of patients who carry genetic mutations predisposing to autosomal dominant familial AD have shown cortical and subcortical grey matter diffusivity changes several years before the expected onset of the first clinical symptoms. The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues. Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes. This imaging technique may also be useful in comparing and contrasting subtle variations in different disease subgroups, and as a sensitive outcome measure for presymptomatic clinical trials in AD and other neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus