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1.  A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel‐based morphometry 
Dementia is common in Parkinson's disease, but the underlying brain pathology is not yet fully understood.
To examine the changes in the brain of patients with Parkinson's disease with mild cognitive impairment (MCI) and dementia, using structural magnetic resonance imaging.
Using voxel‐based morphometry, the grey matter atrophy on brain images of patients with Parkinson's disease and dementia (PDD; n = 16) and Parkinson's disease without dementia (PDND; n = 20), and healthy elderly subjects (n = 20) was studied. In the PDND group, 12 subjects had normal cognitive status and 8 had MCI. Standardised rating scales for motor, cognitive and psychiatric symptoms were used.
Widespread areas of cortical atrophy were found in patients with PDD compared with normal controls (in both temporal and frontal lobes and in the left parietal lobe). Grey matter reductions were found in frontal, parietal, limbic and temporal lobes in patients with PDD compared with those with PDND. In patients with PDND with MCI, areas of reduced grey matter in the left frontal and both temporal lobes were found.
These findings show that dementia in Parkinson's disease is associated with structural neocortical changes in the brain, and that cognitive impairment in patients with PDND may be associated with structural changes in the brain. Further studies with larger groups of patients are needed to confirm these findings.
PMCID: PMC2117633  PMID: 17028119
2.  Grey Matter Changes in Cognitively Impaired Parkinson's Disease Patients 
PLoS ONE  2014;9(1):e85595.
Cortical changes associated with cognitive decline in Parkinson's disease (PD) are not fully explored and require investigations with established diagnostic classification criteria.
We used MRI source-based morphometry to evaluate specific differences in grey matter volume patterns across 4 groups of subjects: healthy controls (HC), PD with normal cognition (PD-NC), PD with mild cognitive impairment (MCI-PD) and PD with dementia (PDD).
We examined 151 consecutive subjects: 25 HC, 75 PD-NC, 29 MCI-PD, and 22 PDD at an Italian and Czech movement disorder centre. Operational diagnostic criteria were applied to classify MCI-PD and PDD. All structural MRI images were processed together in the Czech centre. The spatial independent component analysis was used to assess group differences of local grey matter volume.
We identified two independent patterns of grey matter volume deviations: a) Reductions in the hippocampus and temporal lobes; b) Decreases in fronto-parietal regions and increases in the midbrain/cerebellum. Both patterns differentiated PDD from all other groups and correlated with visuospatial deficits and letter verbal fluency, respectively. Only the second pattern additionally differentiated PD-NC from HC.
Grey matter changes in PDD involve areas associated with Alzheimer-like pathology while fronto-parietal abnormalities are possibly an early marker of PD cognitive decline. These findings are consistent with a non-linear cognitive progression in PD.
PMCID: PMC3897481  PMID: 24465612
3.  Gray and White Matter Degenerations in Subjective Memory Impairment: Comparisons with Normal Controls and Mild Cognitive Impairment 
Journal of Korean Medical Science  2015;30(11):1652-1658.
Subjective memory impairment (SMI) is now increasingly recognized as a risk factor of progression to dementia. This study investigated gray and white matter changes in the brains of SMI patients compared with normal controls and mild cognitive impairment (MCI) patients. We recruited 28 normal controls, 28 subjects with SMI, and 29 patients with MCI aged 60 or older. We analyzed gray and white matter changes using a voxel-based morphometry (VBM), hippocampal volumetry and regions of interest in diffusion tensor imaging (DTI). DTI parameters of corpus callosum and cingulum in SMI showed more white matter changes compared with those in normal controls, they were similar to those in MCI except in the hippocampus, which showed more degenerations in MCI. In VBM, SMI showed atrophy in the frontal, temporal, and parietal lobes compared with normal controls although it was not as extensive as that in MCI. Patients with SMI showed gray and white matter degenerations, the changes were distinct in white matter structures. SMI might be the first presenting symptom within the Alzheimer's disease continuum when combined with additional risk factors and neurodegenerative changes.
PMCID: PMC4630483  PMID: 26539011
Subjective Memory Impairment; Diffusion Tensor Imaging; Voxel-based Morphometry; Mild Cognitive Impairment
4.  Spatial patterns of brain atrophy in MCI patients, identified via high-dimensional pattern classification, predict subsequent cognitive decline 
NeuroImage  2007;39(4):1731-1743.
Spatial patterns of brain atrophy in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) were measured via methods of computational neuroanatomy. These patterns were spatially complex and involved many brain regions. In addition to the hippocampus and the medial temporal lobe gray matter, a number of other regions displayed significant atrophy, including orbitofrontal and medial-prefrontal grey matter, cingulate (mainly posterior), insula, uncus, and temporal lobe white matter. Approximately 2/3 of the MCI group presented patterns of atrophy that overlapped with AD, whereas the remaining 1/3 overlapped with cognitively normal individuals, thereby indicating that some, but not all, MCI patients have significant and extensive brain atrophy in this cohort of MCI patients. Importantly, the group with AD-like patterns presented much higher rate of MMSE decline in follow-up visits; conversely, pattern classification provided relatively high classification accuracy (87%) of the individuals that presented relatively higher MMSE decline within a year from baseline. High-dimensional pattern classification, a nonlinear multivariate analysis, provided measures of structural abnormality that can potentially be useful for individual patient classification, as well as for predicting progression and examining multivariate relationships in group analyses.
PMCID: PMC2861339  PMID: 18053747
Alzheimer’s disease; early detection; mild cognitive impairment; MCI; pattern classification; structural MRI
5.  Brain Atrophy in Type 2 Diabetes 
Diabetes Care  2013;36(12):4036-4042.
Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function.
This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures.
T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume.
Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.
PMCID: PMC3836136  PMID: 23939539
6.  Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson’s disease with hallucinations 
Brain  2014;137(3):849-859.
Visual hallucinations and dementia frequently complicate advanced Parkinson's disease, but whether they have the same neurobiological basis is unknown. Goldman et al. use structural MRI to study patients with and without hallucinations, matched for cognition. Hallucinations were associated with grey matter atrophy in visuoperceptive regions rather than mesial temporal regions.
Visual hallucinations are frequent, disabling complications of advanced Parkinson’s disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson’s disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson’s disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson’s disease hallucinators to Parkinson’s disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson’s disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (±3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole-brain voxel-based morphometry techniques. Clinically, the Parkinson’s disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson’s disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral ‘what’ and dorsal ‘where’ pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson’s disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson’s disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions.
PMCID: PMC3983409  PMID: 24480486
dementia; hallucinations; magnetic resonance imaging; Parkinson’s disease; voxel-based morphometry
7.  Microstructural White Matter Changes, Not Hippocampal Atrophy, Detect Early Amnestic Mild Cognitive Impairment 
PLoS ONE  2013;8(3):e58887.
Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.
We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.
Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.
Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.
PMCID: PMC3597581  PMID: 23516569
8.  Correlating Cognitive Decline with White Matter Lesion and Brain Atrophy MRI Measurements in Alzheimer’s Disease 
Vascular risk factors are increasingly recognized as risks factors for Alzheimer’s disease (AD) and early conversion from mild cognitive impairment (MCI) to dementia. While neuroimaging research in AD has focused on brain atrophy, metabolic function or amyloid deposition, little attention has been paid to the effect of cerebrovascular disease to cognitive decline.
To investigate the correlation of brain atrophy and white matter lesions with cognitive decline in AD, MCI, and control subjects.
Patients with AD and MCI, and healthy subjects were included in this study. Subjects had a baseline MRI scan, and baseline and follow-up neuropsychological battery (CERAD). Regional volumes were measured, and white matter lesion segmentation was performed. Correlations between rate of CERAD score decline and white matter lesion load and brain structure volume were evaluated. In addition, voxel-based correlations between baseline CERAD scores and atrophy and white matter lesion measures were computed.
CERAD rate of decline was most significantly associated with lesion loads located in the fornices. Several temporal lobe ROI volumes were significantly associated with CERAD decline. Voxel-based analysis demonstrated strong correlation between baseline CERAD scores and atrophy measures in the anterior temporal lobes. Correlation of baseline CERAD scores with white matter lesion volumes achieved significance in multilobar subcortical white matter.
Both baseline and declines in CERAD scores correlate with white matter lesion load and gray matter atrophy. Results of this study highlight the dominant effect of volume loss, and underscore the importance of small vessel disease as a contributor to cognitive decline in the elderly.
PMCID: PMC4637168  PMID: 26402108
AD; MCI; cognitive decline; vascular disease; white matter lesions; atrophy
9.  Mapping Cortical Atrophy in Parkinson's Disease Patients with Dementia 
Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established.
We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01.
PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left pcorrected = 0.06, right pcorrected = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right pcorrected = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%.
Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia.
PMCID: PMC4018208  PMID: 23938313
Parkinson's disease; dementia; magnetic resonance imaging; MRI; brain atrophy; cortical atrophy; gray matter atrophy
10.  Multimodal Imaging Evidence for Axonal and Myelin Deterioration in Amnestic Mild Cognitive Impairment 
White matter (WM) microstructural declines have been demonstrated in Alzheimer’s disease and amnestic mild cognitive impairment (aMCI). However, the pattern of WM microstructural changes in aMCI after controlling for WM atrophy is unknown. Here, we address this issue through joint consideration of aMCI alterations in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, as well as macrostructural volume in WM and gray matter compartments. Participants were 18 individuals with aMCI and 24 healthy seniors. Voxelwise analyses of diffusion tensor imaging data was carried out using tract-based spatial statistics (TBSS) and voxelwise analyses of high-resolution structural data was conducted using voxel based morphometry. After controlling for WM atrophy, the main pattern of TBSS findings indicated reduced fractional anisotropy with only small alterations in mean diffusivity/radial diffusivity/axial diffusivity. These WM microstructural declines bordered and/or were connected to gray matter structures showing volumetric declines. However, none of the potential relationships between WM integrity and volume in connected gray matter structures was significant, and adding fractional anisotropy information improved the classificatory accuracy of aMCI compared to the use of hippocampal atrophy alone. These results suggest that WM microstructural declines provide unique information not captured by atrophy measures that may aid the magnetic resonance imaging contribution to aMCI detection.
PMCID: PMC3448019  PMID: 22460327
Alzheimer’s disease; atrophy; diffusion tensor imaging; mild cognitive impairment
11.  Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease 
Neurology  2009;73(12):935-940.
To investigate whether baseline CSF biomarkers are associated with hippocampal atrophy rate as a measure of disease progression in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls, controlling for baseline neuropsychological and MRI findings.
We assessed data from 31 patients with AD, 25 patients with MCI, and 19 controls (mean age 68 ± 8 years; 39 [52%] female) who visited our memory clinic and had received serial MRI scanning (scan interval 1.7 ± 0.7 years). At baseline, CSF biomarkers (amyloid β 1-42, tau, and tau phosphorylated at threonine 181 [p-tau]) were obtained, as well as neuropsychological data. Baseline MRI scans were assessed using visual rating scales for medial temporal lobe atrophy (MTA), global cortical atrophy, and white matter hyperintensities. Hippocampal atrophy rates were estimated using regional nonlinear “fluid” registration of follow-up scan to baseline scan.
Stepwise multiple linear regression, adjusted for age and sex, showed that increased CSF p-tau levels (β [standard error]: −0.79 [0.35]) at baseline was independently associated with higher subsequent hippocampal atrophy rates (p < 0.05), together with poorer memory performance (0.09 [0.04]) and more severe MTA (−0.60 [0.21]). The association of memory function with hippocampal atrophy rate was explained by the link with diagnosis, because it disappeared from the model after we additionally corrected for diagnosis.
Baseline CSF levels of tau phosphorylated at threonine 181 are independently associated with subsequent disease progression, as reflected by hippocampal atrophy rate. This effect is independent of baseline neuropsychological and MRI predictors. Our results imply that predicting disease progression can best be achieved by combining information from different modalities.
= amyloid β 1-42;
= Alzheimer disease;
= field of view;
= global cortical atrophy;
= lumbar puncture;
= mild cognitive impairment;
= Mini-Mental State Examination;
= medial temporal lobe atrophy;
= tau phosphorylated at threonine 181;
= echo time;
= inversion time;
= Trail Making Test;
= repetition time;
= Visual Association Test;
= white matter hyperintensities.
PMCID: PMC2839552  PMID: 19770469
12.  Gray matter atrophy in patients with Parkinson’s disease and those with mild cognitive impairment: a voxel-based morphometry study 
Purpose: Mild cognitive impairment is common in Parkinson’s disease, but the underlying pathological mechanism has not been fully understood. To examine the gray matter changes in patients with Parkinson’s disease and those with mild cognitive impairment (MCI) using voxel based Morphometry (VBM). Methods: Magnetic resonance images were obtained from 35 patients with PD and 20 age and sex-matched healthy control subjects. In the PD group, 14 subjects had no MCI and 21 had MCI. MRI 3D structural images were acquired and analyzed by means of the optimized VBM procedure with Statistical Parametric Mapping (SPM5). Results: Widespread areas of cortical atrophy were found in patients with PD compared with normal controls (in both temporal, occipital, parietal, frontal lobes and right limbic lobes, posterior lobes of the cerebellum and left caudate nucleus). Gray matter reductions were found in bilateral fusiform gyrus and lingual gyrus, left anterior cingulate cortex and insula, and right superior temporal gyrus, orbitofrontal cortex, central gyrus and precuneus in patients with PD with MCI compared with normal controls. Inpatients with PD with MCI, areas of reduced gray matter were found in both precentral gyrus and middle temporal gyrus, right cuneus, precuneus, and orbitofrontal cortex, and left fusiform gyrus compared with those without MCI. Conclusions: These findings suggest that PD is associated with the gray matter atrophy in the neocortical areas, and that cognitive impairment in patients with PD may be associated with gray matter changes in the parieto-occipital association cortex, right orbitofrontal cortex, and middle temporal gyrus.
PMCID: PMC4658916  PMID: 26629027
Parkinson’s disease; mild cognitive impairment; voxel-based morphometry; magnetic resonance imaging; gray matter
13.  Pattern of Regional Cortical Thinning Associated with Cognitive Deterioration in Parkinson’s Disease 
PLoS ONE  2013;8(1):e54980.
Dementia is a frequent and devastating complication in Parkinson’s disease (PD). There is an intensive search for biomarkers that may predict the progression from normal cognition (PD-NC) to dementia (PDD) in PD. Mild cognitive impairment in PD (PD-MCI) seems to represent a transitional state between PD-NC and PDD. Few studies have explored the structural changes that differentiate PD-NC from PD-MCI and PDD patients.
Objectives and Methods
We aimed to analyze changes in cortical thickness on 3.0T Magnetic Resonance Imaging (MRI) across stages of cognitive decline in a prospective sample of PD-NC (n = 26), PD-MCI (n = 26) and PDD (n = 20) patients, compared to a group of healthy subjects (HC) (n = 18). Cortical thickness measurements were made using the automatic software Freesurfer.
In a sample of 72 PD patients, a pattern of linear and progressive cortical thinning was observed between cognitive groups in cortical areas functionally specialized in declarative memory (entorhinal cortex, anterior temporal pole), semantic knowledge (parahippocampus, fusiform gyrus), and visuoperceptive integration (banks of the superior temporal sulcus, lingual gyrus, cuneus and precuneus). Positive correlation was observed between confrontation naming and thinning in the fusiform gyrus, parahippocampal gyrus and anterior temporal pole; clock copy with thinning of the precuneus, parahippocampal and lingual gyrus; and delayed memory with thinning of the bilateral anteromedial temporal cortex.
The pattern of regional decreased cortical thickness that relates to cognitive deterioration is present in PD-MCI patients, involving areas that play a central role in the storage of prior experiences, integration of external perceptions, and semantic processing.
PMCID: PMC3554657  PMID: 23359616
14.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI 
Neurology  2006;67(5):834-842.
To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI).
Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis.
The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level.
Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.
PMCID: PMC3488276  PMID: 16966547
15.  Asymmetrical extra‐hippocampal grey matter loss related to hippocampal atrophy in patients with medial temporal lobe epilepsy 
Structural neuroimaging studies have consistently shown a pattern of extra‐hippocampal atrophy in patients with left and right drug‐refractory medial temporal lobe epilepsy (MTLE). However, it is not yet completely understood how extra‐hippocampal atrophy is related to hippocampal atrophy. Moreover, patients with left MTLE often exhibit more intense cognitive impairment, and subtle brain asymmetries have been reported in patients with left MTLE versus right MTLE but have not been explored in a controlled study.
To investigate the association between extra‐hippocampal and hippocampal atrophy in patients with MTLE, and the effect of side of hippocampal atrophy on extra‐hippocampal atrophy.
Voxel‐based morphometry analyses of magnetic resonance images of the brain were performed to determine the correlation between regional extra‐hippocampal grey matter volume and hippocampal grey matter volume. The results from 36 patients with right and left MTLE were compared, and results from the two groups were compared with those from 49 healthy controls.
Compared with controls, patients with MTLE showed a more intense correlation between hippocampal grey matter volume and regional grey matter volume in locations such as the contralateral hippocampus, bilateral parahippocampal gyri and frontal and parietal areas. Compared with right MTLE, patients with left MTLE exhibited a wider area of atrophy related to hippocampal grey matter loss, encompassing both the contralateral and ipsilateral hemispheres, particularly affecting the contralateral hippocampus.
Our results suggest that left hippocampal atrophy is associated with a larger degree of extra‐hippocampal atrophy. This may help to explain the more intense cognitive impairment usually observed in these patients.
PMCID: PMC2117646  PMID: 17012334
16.  Tensor-Based Morphometry as a Neuroimaging Biomarker for Alzheimer’s Disease: An MRI Study of 676 AD, MCI, and Normal Subjects 
NeuroImage  2008;43(3):458-469.
In one of the largest brain MRI studies to date, we used tensor-based morphometry (TBM) to create 3D maps of structural atrophy in 676 subjects with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and healthy elderly controls, scanned as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Using inverse-consistent 3D non-linear elastic image registration, we warped 676 individual brain MRI volumes to a population mean geometric template. Jacobian determinant maps were created, revealing the 3D profile of local volumetric expansion and compression. We compared the anatomical distribution of atrophy in 165 AD patients (age: 75.6 ± 7.6 years), 330 MCI subjects (74.8 ± 7.5), and 181 controls (75.9 ± 5.1). Brain atrophy in selected regions-of-interest was correlated with clinical measurements - the sum-of-boxes clinical dementia rating (CDR-SB), mini-mental state examination (MMSE), and the logical memory test scores - at voxel level followed by correction for multiple comparisons. Baseline temporal lobe atrophy correlated with current cognitive performance, future cognitive decline, and conversion from MCI to AD over the following year; it predicted future decline even in healthy subjects. Over half of the AD and MCI subjects carried the ApoE4 (apolipoprotein E4) gene, which increases risk for AD; they showed greater hippocampal and temporal lobe deficits than non-carriers. ApoE2 gene carriers - 1/6 of the normal group - showed reduced ventricular expansion, suggesting a protective effect. As an automated image analysis technique, TBM reveals 3D correlations between neuroimaging markers, genes, and future clinical changes, and is highly efficient for large-scale MRI studies.
PMCID: PMC3197851  PMID: 18691658
17.  A Comparative White Matter Study with Parkinson's disease, Parkinson's Disease with Dementia and Alzheimer's Disease 
Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common neurodegenerative disorders affecting older populations. AD is characterized by impaired memory and cognitive decline while the primary symptoms of PD include resting tremor, bradykinesia and rigidity. In PD, mild cognitive changes are frequently present, which could progress to dementia (PD dementia (PDD)). PDD and AD dementias are different in pathology although the difference in microstructural changes remains unknown. To further understand these diseases, it is essential to understand the distinct mechanism of their microstructural changes. We used diffusion tensor imaging (DTI) to investigate white matter tract differences between early stage individuals with AD (n=14), PD (n=12), PDD (n=9), and healthy non-demented controls (CON) (n=13). We used whole brain tract based spatial statistics (TBSS) and a region of interest (ROI) analysis focused on the substantia nigra (SN). We found that individuals with PDD had more widespread white matter degeneration compared to PD, AD, and CON. Individuals with AD had few regional abnormalities in the anterior and posterior projections of the corpus callosum while PD and CON did not appear to have significant white matter degeneration when compared to other groups. ROI analyses showed that PDD had the highest diffusivity in the SN and were significantly different from CON. There were no significant ROI differences between CON, PD, or AD. In conclusion, global white matter microstructural deterioration is evident in individuals with PDD, and DTI may provide a means with which to tease out pathological differences between AD and PD dementias.
PMCID: PMC3979316  PMID: 24724042
Neurodegenerative disorders; Dementia; Corticospinal tract; Corpus callosum; Cingulum
18.  Hippocampal atrophy rates in Alzheimer disease 
Neurology  2009;72(11):999-1007.
To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls.
We included 64 patients with AD (67 ± 9 years; F/M 38/26), 44 patients with MCI (71 ± 6 years; 21/23), and 34 controls (67 ± 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 ± 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools.
All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5–22.2]), hippocampal atrophy rate (5.2 [1.9–14.3]), and whole brain atrophy rate (2.8 [1.1–7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1–606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression.
Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD.
= Alzheimer disease;
= brain extraction tool;
= confidence interval;
= degrees of freedom;
= frontotemporal lobar degeneration;
= hazard ratio;
= mild cognitive impairment;
= Mini-Mental State Examination;
= normalized brain volume;
= percentage brain volume change;
= region of interest;
= vascular dementia;
= visual association test.
PMCID: PMC2821835  PMID: 19289740
19.  Semantic memory activation in amnestic mild cognitive impairment 
Brain  2009;132(8):2068-2078.
Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65–85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE ε4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame—Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.
PMCID: PMC2714062  PMID: 19515831
Area under the curve (AUC); fMRI; semantic memory; mild cognitive impairment; APOE ε4
20.  Late-life depression, mild cognitive impairment and hippocampal functional network architecture☆ 
NeuroImage : Clinical  2013;3:311-320.
Late-life depression (LLD) and amnestic mild cognitive impairment (aMCI) are associated with medial temporal lobe structural abnormalities. However, the hippocampal functional connectivity (HFC) similarities and differences related to these syndromes when they occur alone or coexist are unclear. Resting-state functional connectivity MRI (R-fMRI) technique was used to measure left and right HFC in 72 elderly participants (LLD [n = 18], aMCI [n = 17], LLD with comorbid aMCI [n = 12], and healthy controls [n = 25]). The main and interactive relationships of LLD and aMCI on the HFC networks were determined, after controlling for age, gender, education and gray matter volumes. The effects of depressive symptoms and episodic memory deficits on the hippocampal functional connections also were assessed. While increased and decreased left and right HFC with several cortical and subcortical structures involved in mood regulation were related to LLD, aMCI was associated with globally diminished connectivity. Significant LLD–aMCI interactions on the right HFC networks were seen in the brain regions critical for emotion processing and higher-order cognitive functions. In the interactive brain regions, LLD and aMCI were associated with diminished hippocampal functional connections, whereas the comorbid group demonstrated enhanced connectivity. Main and interactive effects of depressive symptoms and episodic memory performance were also associated with bilateral HFC network abnormalities. In conclusion, these findings indicate that discrete hippocampal functional network abnormalities are associated with LLD and aMCI when they occur alone. However, when these conditions coexist, more pronounced vulnerabilities of the hippocampal networks occur, which may be a marker of disease severity and impending cognitive decline. By utilizing R-fMRI technique, this study provides novel insights into the neural mechanisms underlying LLD and aMCI in the functional network level.
•Effects of late-life depression and MCI on hippocampal memory network using R-fMRI•Distinct hippocampal functional network correlates in late-life depression and MCI.•Late-life depression and MCI interact on hippocampal functional network level.•Hippocampal functional network correlates with neuropsychological measures.•Novel insights into functional network vulnerability underlying depression and MCI
PMCID: PMC3814948  PMID: 24273715
Depression; Mild cognitive impairment; Hippocampus; Functional connectivity; MRI; Episodic memory; Depressive symptoms; Elderly
21.  Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease 
PLoS ONE  2014;9(8):e106062.
Mild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.
In this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.
Retrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.
At baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.
Our results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.
PMCID: PMC4143363  PMID: 25153085
22.  3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD 
Brain : a journal of neurology  2007;130(Pt 7):1777-1786.
Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI.
PMCID: PMC2752411  PMID: 17533169
Alzheimer's disease; mild cognitive impairment; longitudinal; magnetic resonance imaging; voxel-based morphometry
23.  Abnormal Cortical Networks in Mild Cognitive Impairment and Alzheimer's Disease 
PLoS Computational Biology  2010;6(11):e1001006.
Recently, many researchers have used graph theory to study the aberrant brain structures in Alzheimer's disease (AD) and have made great progress. However, the characteristics of the cortical network in Mild Cognitive Impairment (MCI) are still largely unexplored. In this study, the gray matter volumes obtained from magnetic resonance imaging (MRI) for all brain regions except the cerebellum were parcellated into 90 areas using the automated anatomical labeling (AAL) template to construct cortical networks for 98 normal controls (NCs), 113 MCIs and 91 ADs. The measurements of the network properties were calculated for each of the three groups respectively. We found that all three cortical networks exhibited small-world properties and those strong interhemispheric correlations existed between bilaterally homologous regions. Among the three cortical networks, we found the greatest clustering coefficient and the longest absolute path length in AD, which might indicate that the organization of the cortical network was the least optimal in AD. The small-world measures of the MCI network exhibited intermediate values. This finding is logical given that MCI is considered to be the transitional stage between normal aging and AD. Out of all the between-group differences in the clustering coefficient and absolute path length, only the differences between the AD and normal control groups were statistically significant. Compared with the normal controls, the MCI and AD groups retained their hub regions in the frontal lobe but showed a loss of hub regions in the temporal lobe. In addition, altered interregional correlations were detected in the parahippocampus gyrus, medial temporal lobe, cingulum, fusiform, medial frontal lobe, and orbital frontal gyrus in groups with MCI and AD. Similar to previous studies of functional connectivity, we also revealed increased interregional correlations within the local brain lobes and disrupted long distance interregional correlations in groups with MCI and AD.
Author Summary
Understanding the progression of Alzheimer's disease (AD) is essential. We investigated networks of cortical connectivity along a continuum from normal to AD. Mild Cognitive Impairment (MCI) has been implicated as transitional between normal aging and AD. By investigating the characteristics of cortical networks in these three stages (normal, MCI and AD), we found that all three networks exhibited small-world properties. These properties indicate efficient information transfer in the human brain. We also found that the small-world measures of the MCI network were intermediate to those of the normal controls and the patients with AD. This supports the opinion that MCI is a transitional stage between normal aging and AD. Additionally, we found altered interregional correlations in patients with MCI and AD, which may indicate that a compensatory system interacts with cerebral atrophy. The presence of compensatory mechanisms in patients with MCI and AD may enable them to use additional cognitive resources to function on a more nearly normal level. In future, we need to integrate the multi-level network features obtained with various functional and anatomical brain imaging technologies on different scales to understand the pathophysiological mechanism of MCI and AD. We propose brainnetome to represent such integration framework.
PMCID: PMC2987916  PMID: 21124954
24.  Longitudinal pattern of regional brain volume change differentiates normal aging from MCI 
Neurology  2009;72(22):1906-1913.
Neuroimaging measures have potential as surrogate markers of disease through identification of consistent features that occur prior to clinical symptoms. Despite numerous investigations, especially in relation to the transition to clinical impairment, the regional pattern of brain changes in clinically normal older adults has not been established. We predict that the regions that show early pathologic changes in association with Alzheimer disease will show accelerated volume loss in mild cognitive impairment (MCI) compared to normal aging.
Through the Baltimore Longitudinal Study of Aging, we prospectively evaluated 138 nondemented individuals (age 64–86 years) annually for up to 10 consecutive years. Eighteen participants were diagnosed with MCI over the course of the study. Mixed-effects regression was used to compare regional brain volume trajectories of clinically normal individuals to those with MCI based on a total of 1,017 observations.
All investigated volumes declined with normal aging (p < 0.05). Accelerated change with age was observed for ventricular CSF (vCSF), frontal gray matter, superior, middle, and medial frontal, and superior parietal regions (p ≤ 0.04). The MCI group showed accelerated changes compared to normal controls in whole brain volume, vCSF, temporal gray matter, and orbitofrontal and temporal association cortices, including the hippocampus (p ≤ 0.04).
Although age-related regional volume loss is apparent and widespread in nondemented individuals, mild cognitive impairment is associated with a unique pattern of structural vulnerability reflected in differential volume loss in specific regions. Early identification of patterns of abnormality is of fundamental importance for detecting disease onset and tracking progression.
= Alzheimer disease;
= Blessed Information Memory Concentration Scale;
= Baltimore Longitudinal Study of Aging;
= gray matter;
= intracranial volume;
= mild cognitive impairment;
= Mini-Mental State Examination;
= ventricular CSF;
= white matter.
PMCID: PMC2690968  PMID: 19487648
25.  Accelerating regional atrophy rates in the progression from normal aging to Alzheimer’s disease 
European Radiology  2009;19(12):2826-2833.
We investigated progression of atrophy in vivo, in Alzheimer’s disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 ± 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate atrophy rates in six regions: frontal, medial temporal, temporal (extramedial), parietal, occipital lobes and insular cortex. In MCI, the highest atrophy rate was observed in the medial temporal lobe, comparable with AD. AD patients showed even higher atrophy rates in the extramedial temporal lobe. Additionally, atrophy rates in frontal, parietal and occipital lobes were increased. Cox proportional hazard models showed that all regional atrophy rates predicted conversion to AD. Hazard ratios varied between 2.6 (95% confidence interval (CI) = 1.1–6.2) for occipital atrophy and 15.8 (95% CI = 3.5–71.8) for medial temporal lobe atrophy. In conclusion, atrophy spreads through the brain with development of AD. MCI is marked by temporal lobe atrophy. In AD, atrophy rate in the extramedial temporal lobe was even higher. Moreover, atrophy rates also accelerated in parietal, frontal, insular and occipital lobes. Finally, in nondemented elderly, medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the involvement of this region in the development of AD.
PMCID: PMC2778773  PMID: 19618189
Alzheimer’s disease; Magnetic resonance imaging; Atrophy; Image processing; Computer-assisted

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