Dynamics of Gray Matter Loss in Alzheimer's Disease

The gray matter deficits are correlated with a progressive decline in cognitive status (p < 0.0006).

“The shifting deficits were asymmetric (left hemisphere Ͼ right hemisphere) and correlated with progressively declining cognitive status ( p Ͻ 0.0006).”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

The gray matter deficits are asymmetric, with the left hemisphere more affected than the right.

“The shifting deficits were asymmetric (left hemisphere Ͼ right hemisphere) and correlated with progressively declining cognitive status ( p Ͻ 0.0006).”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

In patients with Alzheimer's disease, a wave of gray matter loss that spreads dynamically can be detected and mapped in the brain.

“We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD).”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

Three disease stages were effectively mapped in the new longitudinal sample, broadly corresponding to healthy aging and the transition from moderate to severe AD (MMSE scores 29, 18, and 13).

“Three disease stages were effectively mapped in this new, longitudinal sample.”

• Also stated in: § Subjects · hedged

  “These broadly correspond to healthy aging and the transition from moderate to severe AD (with MMSE scores of 29, 18, and 13, respectively).”

Transient barriers to disease progression occur at the boundaries between limbic and frontal regions.

“Transient barriers to disease progression appeared at limbic/frontal boundaries.”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

AD patients show little atrophy in primary visual, sensorimotor, and frontal areas until late in the disease.

“Patients with AD show minimal primary visual, sensorimotor, and frontal atrophy until late in the disease.”

Gray matter loss rates are faster in the left hemisphere than the right (p < 0.029).

“Local gray matter loss rates (5.3 Ϯ 2.3% per year in AD v 0.9 Ϯ 0.9% per year in controls) were faster in the left hemisphere ( p Ͻ 0.029) than the right.”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

During the study, AD subjects' MMSE scores declined from 17.7 ± 1.9 to 12.9 ± 2.5, a mean change of 5.5 ± 1.9 points (p < 0.00054, one-tailed t test).

“During the study, subjects' cognitive status declined rapidly from an initial MMSE score of 17.7 Ϯ 1.9 to 12.9 Ϯ 2.5 (mean change 5.5 Ϯ 1.9 points; p Ͻ 0.00054, one-tailed t test; maximum score 30).”

In Alzheimer's disease, central and post-central gyri showed minimal gray matter loss compared with parietal association cortices immediately posterior to them.

“A sharp division occurred in the loss maps (Fig. 6b, blue), with central and post-central gyri displaying minimal loss compared with the parietal association cortices immediately posterior to them.”

Both Alzheimer's disease patients and controls lost significant white matter over time (p < 0.035).

“although both groups lost significant white matter over time ( p Ͻ 0.035).”

Healthy controls showed a trend for diffuse gray matter loss (p < 0.08) at an annual rate of 0.91 ± 0.92% per year overall (left 1.16 ± 1.41; right 0.67 ± 1.25).

“Even the healthy controls showed a trend for diffuse gray matter loss (Fig. 4a-d) ( p Ͻ 0.08) at an annual rate of 0.91 Ϯ 0.92% per year overall (left hemisphere 1.16 Ϯ 1.41% per year; right hemisphere 0.67 Ϯ 1.25% per year).”

Whole-brain atrophic rates discriminated Alzheimer's disease patients and controls.

“Whole-brain atrophic rates (i.e., the loss rate for total cerebral volume) were found to discriminate patients and controls.”

In Alzheimer's disease, the left hemisphere lost gray matter faster than the right (0.79% per year faster; p < 0.04).

“In patients with AD, the left hemisphere lost gray matter faster than the right (0.79% per year faster) ( p Ͻ 0.04).”

White matter loss rate was not faster in Alzheimer's disease relative to controls (p = 0.41).

“We did not find a faster white matter loss rate in AD relative to controls ( p ϭ 0.41)”

A process of fast gray matter attrition occurs over the 1.5 years after the baseline scan in Alzheimer's disease.

“A process of fast attrition occurs over the 1.5 years after the baseline scan.”

In Alzheimer's disease, asymmetry in overall gray matter quantity (including deep nuclei and cortex) increased over time (p < 0.028).

“In AD, there was also an increase in asymmetry over time ( p Ͻ 0.028) in the overall quantity of gray matter (including deep nuclei as well as cortex).”

Cortical gray matter maps discriminated Alzheimer's disease patients from controls strongly (p < 0.005 initially and p < 0.0005 at follow-up).

“Because cortical gray matter maps discriminated patients from controls so strongly (with p Ͻ 0.005 initially and p Ͻ 0.0005 at follow-up; permutation tests)”

Both left and right hemisphere maps suggested that limbic regions are more intensely impaired than frontal cortices in Alzheimer's disease.

“Both left and right hemisphere maps suggested that limbic regions are more intensely impaired than frontal cortices in AD.”

In patients with Alzheimer's disease, a highly significant gray matter deficit was observed in a broad region encompassing bilateral temporal and parietal cortices.

“In patients with AD, a highly significant gray matter deficit was observed in a broad anatomical region encompassing bilateral temporal and parietal cortices (Fig. 6a)”

In the right hemisphere medial wall, greatest impairment (>15%) was observed in temporal/entorhinal regions, parietal lobule, and adjacent occipital/visual cortices.

“(1) Greatest impairment (Ͼ15%) was observed in the temporal/entorhinal regions and the parietal lobule, and, perhaps surprisingly, the adjacent occipital/visual cortices;”

Correlations between gray matter loss and cognition were strongest in regions with greatest average loss (left cingulate and left temporal and parietal cortices).

“Correlations were strongest in regions with greatest average loss (left cingulate and left temporal and parietal cortices) (Fig. 5d).”

In Alzheimer's disease, the sensory and motor territory remained comparatively spared at follow-up despite frontal spread of deficits.

“and second, the sensory and motor territory is still comparatively spared (Fig. 6f, blue), despite the frontal spread of the deficits.”

In the deficit maps, some barriers to disease progression appear at architectonic boundaries.

“In the deficit maps, some barriers to disease progression appear at architectonic boundaries.”

Correlations between cognitive scores and gray matter deficits were observed in all brain regions with significant loss, including temporal-parietal and limbic cortices.

“These correlations were observed in all brain regions in which there was significant loss (Fig. 5a-d), including the temporalparietal and limbic cortices.”

In Alzheimer's disease, a frontal band with 0-5% loss was sharply delimited from limbic and temporoparietal regions that showed severest deficits (>15% loss).

“A frontal band (0 -5% loss) was sharply delimited (Fig. 8c) from the limbic and temporoparietal regions that showed severest deficits in AD (Ͼ15% loss).”

In controls, a prominent sensorimotor region showed 15-20% less gray matter in the left hemisphere compared with the right.

“Figure 7 shows the average gray matter asymmetry in the controls, with a prominent sensorimotor region showing 15-20% less gray matter in the left hemisphere (Fig. 7a) compared with its counterpart on the right.”

In Alzheimer's disease, frontal deficits characteristic of late disease are not found until significant cognitive decline has occurred.

“the frontal deficits characteristic of late AD are not found until significant cognitive decline has occurred (bottom).”

Loss rate patterns in Alzheimer's disease were more spatially diffuse than the deficit maps at baseline and follow-up.

“The loss rate patterns were also more spatially diffuse than the deficit maps at baseline and follow-up (Figs. 5, 6).”

In Alzheimer's disease, frontal cortices initially mildly affected (6-10% loss) became severely affected at follow-up, with deficits exceeding 15% everywhere.

“First, the frontal cortices, initially only mildly affected (with 6 -10% loss), are now severely affected (deficits exceeded 15% everywhere) (Fig. 6g)”

No correlations were found between gray matter differences in sensory and motor cortices and cognitive performance.

“As expected, no correlations were found between gray matter differences in sensory and motor cortices and cognitive performance (Fig. 5b, blue, S/M ).”

A trend for faster gray matter loss in the left hemisphere was also observed in controls (0.50% per year faster; p < 0.057).

“A trend for faster gray matter loss in the left hemisphere was also observed in controls (0.50% per year faster; p Ͻ 0.057).”

Even late in Alzheimer's disease, some cortical regions were mostly intact, specifically frontal and sensorimotor cortices.

“Even then, some cortical regions were mostly intact (Fig. 8c, blue), specifically in the frontal and sensorimotor cortices.”

Regions with prominent 4-5% annual gray matter loss in Alzheimer's disease included right cingulate, temporal, and frontal cortices bilaterally.

“Regions with a prominent 4 -5% annual loss included the right cingulate, temporal, and frontal cortices bilaterally (Fig. 4, bottom row).”

Linkages between frontal gray matter reduction and lower MMSE scores were found only at the later time point, when frontal gray matter was in significant deficit.

“Linkages were also found between frontal gray matter reduction and lower MMSE scores, but only at the later time point, when frontal gray matter was in significant deficit (Fig. 5e).”

In Alzheimer's disease, the left hemisphere was significantly more severely impaired than the right on the medial wall at the initial scan (p < 0.029 for disease-specific asymmetry; corrected p < 0.0018 left, p < 0.014 right).

“The left hemisphere was significantly more severely impaired than the right ( p Ͻ 0.029 for disease-specific asymmetry; corrected p Ͻ 0.0018 left hemisphere, p Ͻ 0.014 right hemisphere, for the effect of diagnosis at the initial scan on the medial wall; permutation tests).”

In Alzheimer's disease, MMSE score declined from 17.7 ± 1.9 to 12.9 ± 2.5 over 1.5 years (p < 0.00054).

“after a rapid decline in MMSE score from 17.7 Ϯ 1.9 to 12.9 Ϯ 2.5 ( p Ͻ 0.00054).”

Lower cognitive scores were linked to greater gray matter deficits in Alzheimer's disease.

“Highly significant linkages were found relating lower cognitive scores to greater gray matter deficits (Fig. 5).”

In the right hemisphere medial wall, frontal regions, particularly orbitofrontal, were comparatively spared with 0-5% loss.

“(3) frontal regions, and in particular orbitofrontal regions (Fig. 8a), were comparatively spared (0 -5% loss) (Fig. 8a, blue).”

After MMSE dropped from 18 to 13, most of the cortex was engulfed in Alzheimer's disease (corrected p < 0.00015 left and right).

“After a sharp drop in MMSE score from 18 to 13, most of the cortex was engulfed (Fig. 8, bottom) (corrected p Ͻ 0.00015 left hemisphere, corrected p Ͻ 0.00015 right hemisphere, for the effect”

In the left hemisphere medial wall, the entire medial cortex was in deficit at the first scan in Alzheimer's disease.

“In the left hemisphere, the entire medial cortex was in deficit at the first scan (Fig. 8b).”

Sensorimotor cortices are relatively spared at both disease stages in Alzheimer's disease.

“Note the relative sparing of sensorimotor cortices at both disease stages (S/M ).”

Map-based measures showed vastly greater effect sizes than any measures based on volumes (e.g., p < 0.00027 at follow-up).

“Map-based measures showed vastly greater effect sizes than any measures based on volumes (e.g., p Ͻ 0.00027 at follow-up).”

Frontal deficits typical of late Alzheimer's disease do not appear until significant cognitive decline has occurred.

“Although severe temporal lobe loss ( T ) and parietal loss have already occurred at baseline (top) and subsequently continue (Fig.4), the frontal deficits characteristic of late AD are not found until significant cognitive decline has occurred (bottom).”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

Gray matter loss rates are significantly higher in Alzheimer's disease than in controls.

“They are significantly higher in AD and strongest in frontal and temporal regions ( g, h) at this stage of AD (as the MMSE score falls from 18 to 13).”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

In Alzheimer's disease, profound gray matter loss affects the left medial wall, exceeding 15%.

“Profound loss engulfs the left medial wall (Ͼ15%; b, d).”

On the right side, deficits in temporoparietal and entorhinal regions extend forward into the cingulate 1.5 years later, following a five-point drop in average MMSE score.

“On the right, however, the deficits in temporoparietal and entorhinal territory ( a) spread forward into the cingulate 1.5 years later ( c), after a five point drop in average MMSE score.”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

At this stage of Alzheimer's disease, when MMSE scores fall from 18 to 13, gray matter loss rates are greatest in frontal and temporal regions.

“They are significantly higher in AD and strongest in frontal and temporal regions ( g, h) at this stage of AD (as the MMSE score falls from 18 to 13).”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

Healthy controls exhibit an existing asymmetry in gray matter distribution.

“The asymmetric loss of gray matter in AD (left hemisphere faster than right) compounds an existing asymmetry in the distribution of gray matter, observed here in healthy controls (a, b).”

A period of rapid attrition occurs during the 1.5 years following the baseline scan in Alzheimer's disease.

“A process of fast attrition occurs over the 1.5 years after the baseline scan.”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

In Alzheimer's disease, gray matter loss is asymmetric, with the left hemisphere losing faster than the right.

“The asymmetric loss of gray matter in AD (left hemisphere faster than right) compounds an existing asymmetry in the distribution of gray matter, observed here in healthy controls (a, b).”

The strongest associations between gray matter reduction and cognition are found in left hemisphere medial temporoparietal areas.

“Linkages are detected most strongly in the left hemisphere medial temporoparietal zones ( d).”

In healthy controls, gray matter loss rates are below 1% per year.

“Loss rates are Ͻ1% per year in controls.”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

Gray matter variations in temporal, parietal, and eventually frontal regions are associated with cognitive status.

“Variations in temporal, parietal, and ultimately frontal ( e) tissue are linked with cognitive status.”

Sensorimotor cortices are relatively preserved at both disease stages, including late Alzheimer's disease.

“which was not in significant deficit in late AD.”

• Also stated in: § Relation to previous work · plain

  “Note the relative sparing of sensorimotor cortices at both disease stages (S/M ).”

Reduced gray matter is strongly associated with poorer cognitive performance in all regions showing prominent deficits.

“Less gray matter is strongly correlated with worse cognitive performance, in all regions with prominent deficits.”

Temporal lobe and parietal loss continue after baseline in Alzheimer's disease.

“Although severe temporal lobe loss ( T ) and parietal loss have already occurred at baseline (top) and subsequently continue (Fig.4), the frontal deficits characteristic of late AD are not found until significant cognitive decline has occurred (bottom).”

• AssumptionThe authors state this as an assumption: Gray matter loss is linear during the interval between scans.

The AD and control samples were entirely different from the AD and control groups in the authors' previous cross-sectional study.

“AD and control samples consisted of subjects who were entirely different from the group of patients with AD and controls from whom data were reported in our previous cross-sectional study (Thompson et al., 2001b).”

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The AD subjects' cognitive decline corresponds approximately to a shift from moderate to severe AD.

“This corresponds approximately to a transition from moderate to severe AD.”

After sulcal matching, image averaging creates a crisp average cortical model with gyral features in their mean anatomic locations.

“The warped color images (Fig. 2d) from many subjects are averaged together pixel by pixel and decoded; it can be shown mathematically that this image averaging creates a crisp average cortical model with gyral features in their mean anatomic locations (Fig. 2f ) (Thompson and Toga, 1997;Thompson et al., 2000a,b).”

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Specific patterns of atrophy distinguish AD from frontotemporal, semantic, and Lewy body dementias.

“Specific atrophic patterns differentiate AD from frontotemporal, semantic, and Lewy body dementias (O'Brien et al., 2001;Studholme et al., 2001).”

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High-dimensional elastic matching of cortical patterns was used to associate gray matter density measures from homologous cortical regions across time and subjects.

“Given the large anatomic variability in some cortical regions, high-dimensional elastic matching of cortical patterns (Thompson et al., 2000a(Thompson et al., ,b, 2001a) was used to associate measures of gray matter density from homologous cortical regions first across time and then also across subjects (Fig. 3).”

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The order in which cortical atrophy appears during AD progression matches the order in which neurofibrillary tangles accumulate in autopsy cross-sections.

“Cortical atrophy occurred in a well defined sequence as the disease progressed, mirroring the sequence of neurofibrillary tangle accumulation observed in cross sections at autopsy.”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.
• AssumptionRests on an assumption: In early AD, neurofibrillary tangles accumulate inside neurons.

Computational matching of sulci avoids destructive cancellation of features that occurs when images are directly averaged.

“The point of this procedure is that the computational matching of sulci avoids destructive cancellation of features (Fischl et al., 1999).”

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The total suprathreshold area statistic was chosen instead of cluster extent or peak height to sensitize the permutation test to subtle but diffuse effects over large, possibly disconnected cortical regions.

“A total suprathreshold area statistic was chosen rather than a measure of cluster extent or peak height (Friston et al., 1996) to sensitize the permutation test to the detection of subtle but diffuse effects that occur over large (and possibly disconnected) regions of cortex.”

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Before symptoms appear in AD, and in people at genetic risk, gray matter loss can be detected in the anterior hippocampal/amygdala region.

“Before symptom onset in AD, and also in those at genetic risk, gray matter loss is detectable in the anterior hippocampal/amygdala region (Lehtovirta et al., 2000;Reiman et al., 2001).”

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This work is the first to provide detailed 3D quantitative maps of changes over time in cortical gray matter and the whole brain for any disease.

“It also provides the first detailed, three-dimensional (3D) quantitative maps of cortical gray matter and whole brain changes over time in any disease.”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

This work is the first to visualize cortical atrophy rates quantitatively and dynamically in both normal elderly people and those with dementia.

“This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.”

• AssumptionRests on an assumption: MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

Cortical pattern matching greatly reduces confounding from cross-subject anatomical variance, improving detection of disease effects.

“Confounding effects of cross-subject anatomical variance are greatly reduced, thereby empowering detection of disease effects.”

The p = 0.01 threshold was chosen a priori based on previous work in an independent cross-sectional sample to optimize detection of broad, diffuse effects.

“This threshold ( p ϭ 0.01) was chosen a priori on the basis of our previous work in an independent, crosssectional sample (Thompson et al., 2001b) to optimize detection of broad, diffuse effects.”

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When deficit data are visualized in 4D, a dynamic, spreading wave of loss is observed in Alzheimer's disease.

“When the deficit data are visualized in 4D, a dynamic, spreading wave of loss is observed.”

The asymmetry findings indicate faster left hemisphere cortical degeneration in Alzheimer's disease, at least during the observed interval.

“This indicates faster left hemisphere cortical degeneration in AD, at least during the time interval observed in this study.”

Metabolic scans in Alzheimer's disease show decreased metabolic activity in temporal and parietal lobes and posterior cingulate cortices.

“Decreased metabolic activity is found in temporal and parietal lobes and in the posterior cingulate cortices (Mazziotta et al., 1992;Mega et al., 1997).”

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Deficits and rates of change were coupled with declining cognitive status as quantified by MMSE scores.

“Deficits and rates of change were coupled with declining cognitive status and quantified by MMSE scores.”

Gray matter atrophy observed with MRI may be attributable to processes other than or in addition to neuronal loss, including cell shrinkage, reduced dendritic extent, and synaptic loss.

“Gray matter atrophy observed with MRI may also be attributable to a combination of processes other than, or in addition to, neuronal loss, including cell shrinkage, reduced dendritic extent, and synaptic loss (for review, see McEwen, 1997;Uylings and de Brabander, 2002).”

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Some phylogenetically older brain systems, such as sensorimotor cortices, are spared late in Alzheimer's disease.

“(3) some phylogenetically older brain systems are spared late in the disease (e.g., sensorimotor cortices).”

The observed medial wall deficit pattern is consistent with the hypothesis that Alzheimer's disease pathology spreads centrifugally from limbic/paralimbic to higher-order association cortices.

“This pattern is consistent with the hypothesis that AD pathology spreads centrifugally from limbic/paralimbic to higher-order association cortices (Mesulam, 2000).”

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In the right hemisphere, sharp boundaries appeared in deficit patterns at the cingulate/frontal border on the medial wall, indicating differential susceptibility, at least transiently, in mild to moderate Alzheimer's disease.

“In the right hemisphere, sharp boundaries appeared in the deficit patterns at the cingulate/frontal border on the medial wall (Fig. 8c), indicating differential susceptibility, at least transiently, in mild to moderate AD.”

The correlation maps support the idea that structure/cognition effects are regionally specific in Alzheimer's disease, at least initially.

“These maps support the idea that structure/cognition effects are regionally specific in AD, at least initially (Fig. 5b).”

The deficit sequence matches the trajectory of neurofibrillary tangle distribution observed postmortem in patients with increasing dementia severity at death.

“The deficit sequence also matches the trajectory of NFT distribution observed postmortem in patients with increasing dementia severity at death (Braak andBraak, 1991, 1997).”

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The vulnerability of neocortical association areas may relate to their degree of functional connectivity with limbic structures, where pathology begins.

“The vulnerability of neocortical association areas may relate to their degree of functional connectivity with limbic structures, in which pathology begins (Arriagada, 1992).”

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Later cell loss in association areas may result from cortical remodeling attributable to impaired input activity in limbic-paralimbic neurons that innervate them.

“Later cell loss in association areas may result from cortical remodeling attributable to impaired input activity in limbic-paralimbic neurons that innervate them.”

The anterior and ventromedial temporal lobes may be especially susceptible to Alzheimer's disease pathology.

“The anterior and ventromedial temporal lobes may be especially susceptible to AD pathology.”

The leading edge of the region with significant deficits spreads somewhat centrifugally from medial temporal/limbic to frontal regions.

“In summary, the leading edge of the region with significant deficits spreads somewhat centrifugally (from medial temporal/limbic to frontal regions).”

The spread of neurofibrillary tangle pathology may originate in limbic regions because of their high levels of baseline plasticity.

“The spread of NFT pathology (Hof and Morrison, 1994;Morrison and Hof, 2002) may originate in limbic regions because of their high levels of baseline plasticity.”

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Increased power may result from restricting the search space for disease effects to the cortical sheet.

“Increased power may result from restricting the search space for disease effects to the cortical sheet.”

The study's design included only two scans per participant, which required assuming that gray matter loss was linear between the scans.

“A limitation of our current study is our use of only two time points per subject, which forces us to assume linear loss during the interscan interval.”

The asymmetric gray matter loss in Alzheimer's disease builds upon an existing asymmetry in gray matter distribution seen in healthy controls.

“The asymmetric loss of gray matter in AD (left hemisphere faster than right) compounds an existing asymmetry in the distribution of gray matter, observed here in healthy controls (a, b).”

The dynamic maps indicate that structural changes in Alzheimer's disease, measured in living patients, align with earlier cross-sectional metabolic and pathological findings.

“In summary, the dynamic maps presented here suggest that dynamic structural changes in AD, mapped in living patients, are congruent with earlier cross-sectional metabolic and pathologic changes.”

The severe gray matter deficits found in this study support the temporal lobe as a site of early and progressive change in Alzheimer's disease.

“The profound deficits observed here further support the focus on temporal lobe as a site of early and progressive change in AD (Murphy et al., 1993;Kaye et al., 1997;Jack et al., 1998;Laakso et al., 2000).”

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