Kristy Hwang

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimers disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

Subregional hippocampal atrophy predicts Alzheimer’s dementia in the cognitively normal

Atrophic changes of the hippocampus are typically regarded as an early sign of Alzheimers dementia (AD). Using the radial distance atrophy mapping approach, we compared the longitudinal MRI data of 10 cognitively normal elderly subjects who remained normal at 3-year and 6-year follow-up (NL-NL) and 7 cognitively normal elderly subjects who were diagnosed with mild cognitive impairment (MCI) 2.8 (range 2.0-3.9) and with AD 6.8 years (range 6.1-8.2) after baseline (NL-MCI(AD)). 3D statistical maps revealed greater hippocampal atrophy in the NL-MCI(AD) relative to the NL-NL group at baseline (left p=0.05; right p=0.06) corresponding to 10-15% CA1, and 10-25% subicular atrophy, and bilateral differences at 3-year follow-up (left p=0.001, right p<0.02) corresponding to 10-30% subicular, 10-20% CA1, and 10-20% newly developed CA2-3 atrophy. This preliminary study suggests that excess CA1 and subicular atrophy is present in cognitively normal individuals predestined to decline to amnestic MCI, while progressive involvement of the CA1 and subiculum, and atrophy spreading to the CA2-3 subfield in amnestic MCI, suggests future diagnosis of AD.

Hippocampal, Caudate, and Ventricular Changes in Parkinson’s Disease with and Without Dementia

Parkinsons disease (PD) has been associated with mild cognitive impairment (PDMCI) and with dementia (PDD). Using radial distance mapping, we studied the 3D structural and volumetric differences between the hippocampi, caudates, and lateral ventricles in 20 cognitively normal elderly (NC), 12 cognitively normal PD (PDND), 8 PDMCI, and 15 PDD subjects and examined the associations between these structures and Unified Parkinsons Disease Rating Scale (UPDRS) Part III:motor subscale and Mini‐Mental State Examination (MMSE) performance. There were no hippocampal differences between the groups. 3D caudate statistical maps demonstrated significant left medial and lateral and right medial atrophy in the PDD vs. NC, and right medial and lateral caudate atrophy in PDD vs. PDND. PDMCI showed trend‐level significant left lateral caudate atrophy vs. NC. Both left and right ventricles were significantly larger in PDD relative to the NC and PDND with posterior (body/occipital horn) predominance. The magnitude of regionally significant between‐group differences in radial distance ranged between 20–30% for caudate and 5–20% for ventricles. UPDRS Part III:motor subscale score correlated with ventricular enlargement. MMSE showed significant correlation with expansion of the posterior lateral ventricles and trend‐level significant correlation with caudate head atrophy. Cognitive decline in PD is associated with anterior caudate atrophy and ventricular enlargement.

Hippocampal Atrophy and Ventricular Enlargement in Normal Aging, Mild Cognitive Impairment (MCI), and Alzheimer Disease

Alzheimer disease (AD) is the most common type of dementia worldwide. Hippocampal atrophy and ventricular enlargement have been associated with AD but also with normal aging. We analyzed 1.5-T brain magnetic resonance imaging data from 46 cognitively normal elderly individuals (NC), 33 mild cognitive impairment and 43 AD patients. Hippocampal and ventricular analyses were conducted with 2 novel semiautomated segmentation approaches followed by the radial distance mapping technique. Multiple linear regression was used to assess the effects of age and diagnosis on hippocampal and ventricular volumes and radial distance. In addition, 3-dimensional map correction for multiple comparisons was made with permutation testing. As expected, most significant hippocampal atrophy and ventricular enlargement were seen in the AD versus NC comparison. Mild cognitive impairment patients showed intermediate levels of hippocampal atrophy and ventricular enlargement. Significant effects of age on hippocampal volume and radial distance were seen in the pooled sample and in the NC and AD groups considered separately. Age-associated differences were detected in all hippocampal subfields and in the frontal and body/occipital horn portions of the lateral ventricles. Aging affects both the hippocampus and lateral ventricles independent of AD pathology, and should be included as covariate in all structural, hippocampal, and ventricular analyses when possible.

3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects

Cerebrospinal fluid (CSF) measures of Ab and tau, Pittsburgh Compound B (PIB) imaging and hippocampal atrophy are promising Alzheimers disease biomarkers yet the associations between them are not known. We applied a validated, automated hippocampal labeling method and 3D radial distance mapping to the 1.5T structural magnetic resonance imaging (MRI) data of 388 ADNI subjects with baseline CSF Ab(42), total tau (t-tau) and phosphorylated tau (p-tau(181)) and 98 subjects with positron emission tomography (PET) imaging using PIB. We used linear regression to investigate associations between hippocampal atrophy and average cortical, parietal and precuneal PIB standardized uptake value ratio (SUVR) and CSF Ab(42), t-tau, p-tau(181), t-tau/Ab(42) and p-tau(181)/Ab(42). All CSF measures showed significant associations with hippocampal volume and radial distance in the pooled sample. Strongest correlations were seen for p-tau(181), followed by p-tau(181)/Ab(42) ratio, t-tau/Ab(42) ratio, t-tau and Ab(42). p-tau(181) showed stronger correlation in ApoE4 carriers, while t-tau showed stronger correlation in ApoE4 noncarriers. Of the 3 PIB measures the precuneal SUVR showed strongest associations with hippocampal atrophy.

3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI†

We applied the hippocampal radial atrophy mapping technique to the baseline and follow‐up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimers Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA ≥ 2) hippocampal atrophy converted to Alzheimers disease (AD) during 3‐year follow‐up. MTA ≥ 2 showed a trend for greater left sided hippocampal atrophy versus MTA < 2 groups at baseline (Pcorrected = 0.08). Higher MTA scores were associated with progressive atrophy of the subiculum and the CA1‐3 subregions. The MTA < 2 group demonstrated significant bilateral atrophy progression at follow‐up (left Pcorrected = 0.008; right Pcorrected = 0.05). Relative to MTA < 2 nonconverters, MTA < 2 converters showed further involvement of the subiculum and CA1 and additional involvement of CA2‐3 at follow‐up. Right CA1 atrophy was significantly associated with conversion to dementia (for 1 mm greater right CA1 radial distance subjects had 50% reduced hazard for conversion). Greater CA1 and subicular atrophy can be demonstrated early and is predictive of future conversion to AD, whereas CA2‐3 involvement becomes more evident as the disease progresses. Hum Brain Mapp, 2010.

Automated 3D mapping of baseline and 12-month associations between three verbal memory measures and hippocampal atrophy in 490 ADNI subjects

We used a previously validated automated machine learning algorithm based on adaptive boosting to segment the hippocampi in baseline and 12-month follow-up 3D T1-weighted brain MRIs of 150 cognitively normal elderly (NC), 245 mild cognitive impairment (MCI) and 97 Dementia of the Alzheimers type (DAT) ADNI subjects. Using the radial distance mapping technique, we examined the hippocampal correlates of delayed recall performance on three well-established verbal memory tests--ADAScog delayed recall (ADAScog-DR), the Rey Auditory Verbal Learning Test -DR (AVLT-DR) and Wechsler Logical Memory II-DR (LM II-DR). We observed no significant correlations between delayed recall performance and hippocampal radial distance on any of the three verbal memory measures in NC. All three measures were associated with hippocampal volumes and radial distance in the full sample and in the MCI group at baseline and at follow-up. In DAT we observed stronger left-sided associations between hippocampal radial distance, LM II-DR and ADAScog-DR both at baseline and at follow-up. The strongest linkage between memory performance and hippocampal atrophy in the MCI sample was observed with the most challenging verbal memory test-the AVLT-DR, as opposed to the DAT sample where the least challenging test the ADAScog-DR showed strongest associations with the hippocampal structure. After controlling for baseline hippocampal atrophy, memory performance showed regionally specific associations with hippocampal radial distance in predominantly CA1 but also in subicular distribution.

Verbal memory is associated with structural hippocampal changes in newly diagnosed Parkinson's disease

Background and objective Cognitive impairment, including impairment of episodic memory, is frequently found in newly diagnosed Parkinsons disease (PD). In this longitudinal observational study we investigated whether performance in memory encoding, retention, recognition and free recall is associated with reduced hippocampal radial distance. Methods We analysed baseline T1-weighted brain MRI data from 114 PD subjects without cognitive impairment, 29 PD subjects with mild cognitive impairment and 99 normal controls from the ParkWest study. Age- and education-predicted scores for the California Verbal Learning Test 2 (CVLT-2) and tests of executive function were regressed against hippocampal radial distance while adjusting for imaging centre. Results There was no association between encoding or performance on executive tests and hippocampal atrophy in the PD group. In the full PD sample we found bilaterally significant associations between lower delayed free recall scores and hippocampal atrophy in the CA1, CA3 and subiculum area (left, p=0.0013; right, p=0.0082). CVLT-2 short delay free recall scores were associated with bilateral hippocampal CA1 and subicular atrophy in the full PD sample (left, p=0.013; right, p=0.047). CVLT-2 recognition scores showed a significant association with right-sided subicular and CA1 atrophy in the full PD sample (p=0.043). Conclusions At the time of PD diagnosis, subjects’ verbal memory performance in recall and recognition are associated with atrophy of the hippocampus, while encoding is not associated with hippocampal radial distance. We postulate that impaired recall and recognition might reflect deficient memory consolidation at least partly due to structural hippocampal changes.

Effects of ApoE4 and maternal history of dementia on hippocampal atrophy

We applied an automated hippocampal segmentation technique based on adaptive boosting (AdaBoost) to the 1.5 T magnetic resonance imaging (MRI) baseline and 1-year follow-up data of 243 subjects with mild cognitive impairment (MCI), 96 with Alzheimers disease (AD), and 145 normal controls (NC) scanned as part of the Alzheimers Disease Neuroimaging Initiative (ADNI). MCI subjects with positive maternal history of dementia had smaller hippocampal volumes at baseline and at follow-up, and greater 12-month atrophy rates than subjects with negative maternal history. Three-dimensional maps and volumetric multiple regression analyses demonstrated a significant effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD after controlling for age, ApoE4 genotype, and paternal history of dementia, respectively. ApoE4 showed an independent effect on hippocampal atrophy in MCI and AD and in the pooled sample.

Hippocampal and ventricular changes in Parkinson's disease mild cognitive impairment

We analyzed T1-weighted brain magnetic resonance imaging data of 100 cognitively normal elderly controls (NC), 127 cognitively normal Parkinsons disease (PD; PDCN) and 31 PD-associated mild cognitive impairment (PDMCI) subjects from the Norwegian ParkWest study. Using automated segmentation methods, followed by the radial distance technique and multiple linear regression we studied the effect of clinical diagnosis on hippocampal and ventricular radial distance while adjusting for age, education, and scanning site. PDCN subjects had significantly smaller bilateral hippocampal radial distance relative to NC. Nonamnestic PDMCI subjects showed smaller right hippocampal radial distance relative to NC. PDMCI subjects showed significant enlargement of all portions of the lateral ventricles relative to NC and significantly larger bilateral temporal and occipital and left frontal lateral ventricular expansion relative to PDCN subjects. Nonamnestic PDMCI subjects showed significant ventricular enlargement spanning all parts of the lateral ventricle while those with amnestic PDMCI showed changes localized to the left occipital horn. Hippocampal atrophy and lateral ventricular enlargement show promise as structural biomarkers for PD.