Background

TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately 1/4 of subjects with pathologically confirmed Alzheimer's disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine if subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging or pathological features compared to subjects with AD without abTDP-43 immunoreactivity.

Methods

Eighty-four subjects were identified that had a pathological diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data was collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared to age and gender matched controls.

Results

Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death, and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared to controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathological predictor of abTDP-43 immunoreactivity.

Conclusions

The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.

This study tests if measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer’s Disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater hazard of progression to AD in aMCI (p=0.002). MR diffusion weighted imaging (DWI) may help identify patients with aMCI who will progress to AD as well or better than structural MRI measures of hippocampal atrophy.

Objective

To determine the 1H MR spectroscopic (MRS) findings and inter-group differences among common dementias: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD).

Methods

We consecutively recruited 206 normal elderly, 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. We evaluated the 1H MRS metabolite ratio changes in common dementias with respect to normal, and also differences among the common dementias.

Results

N-acetylaspartate/Creatine (NAA/Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with, AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD, nor between patients with DLB and VaD. NAA /Cr was lower in patients with AD and FTLD than DLB. MI /Cr was higher in patients with AD and FTLD than VaD. MI /Cr was also higher in patients with FTLD than DLB.

Conclusions

NAA/Cr levels are decreased in dementias that are characterized by neuron loss such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit such as AD and DLB.

Background

The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive-inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD).

Objective

To compare clinicopathological and MRI features of subjects with progressive aphasia and AD pathology, to subjects with aphasia and FTLD-U pathology, and subjects with typical AD.

Methods

We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathological re-analysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared to a normal control group.

Results

All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed grey matter atrophy predominantly in the temporoparietal cortices with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy.

Conclusions

A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying AD pathology rather than FTLD-U.

Background

We tested if rates of brain atrophy accelerate in individuals with amnestic mild cognitive impairment (aMCI) as they progress to typical late onset Alzheimer's Disease (AD). We included comparisons to aMCI subjects who did not progress (labeled aMCI-S) and also to cognitively normal elderly subjects (CN).

Methods

We studied 46 aMCI subjects who progressed to AD (labeled aMCI-P), 46 CN, and 23 aMCI-S. All subjects must have had three or more serial MRI scans. Rates of brain shrinkage and ventricular expansion were measured across all available serial MRI scans in each subject. Change in volumes relative to the point at which subjects progressed to a clinical diagnosis of AD (the index date) was modeled in aMCI-P. Change in volumes relative to age was modeled in all three clinical groups.

Results

In aMCI-P the change in pre to post index rate (i.e. acceleration) of ventricular expansion was 1.7 cm3/yr, and acceleration in brain shrinkage was 5.3 cm3/yr. Brain volume declined and ventricular volume increased in all three groups with age. Volume changes decelerated with increasing age in aMCI-P, and to a lesser extent aMCI-S, but were linear in the matched CN. Among all aMCI subjects, rates of atrophy were greater in apolipoprotein E ε4 carriers than non-carriers.

Conclusions

Rates of atrophy accelerate as individuals progress from aMCI to typical late onset AD. Rates of atrophy are greater in younger than older aMCI-P and aMCI-S subjects. We did not find that atrophy rates varied with age in 70 – 90 year old CN subjects.

Objective

To compare the patterns of grey matter loss in subjects with amnestic Mild Cognitive Impairment (aMCI) who progress to Alzheimer's disease within a fixed clinical follow-up time versus those who remain stable.

Methods

Twenty-one aMCI subjects were identified from the Mayo Clinic Alzheimer's research program that remained clinically stable for their entire observed clinical course (aMCI-S), where the minimum required follow-up time from MRI to last follow-up assessment was three years. These subjects were age and gender-matched to 42 aMCI subjects who progressed to AD within 18 months of the MRI (aMCI-P). Each subject was then age and gender-matched to a control subject. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI-P and aMCI-S groups compared to the control group, and compared to each other.

Results

The aMCI-P group showed bilateral loss affecting the medial and inferior temporal lobe, temporoparietal association neocortex and frontal lobes, compared to controls. The aMCI-S group showed no regions of grey matter loss when compared to controls. When the aMCI-P and aMCI-S groups were compared directly, the aMCI-P group showed greater loss in the medial and inferior temporal lobes, the temporoparietal neocortex, posterior cingulate, precuneus, anterior cingulate, and frontal lobes than the aMCI-S group.

Conclusions

The regions of loss observed in aMCI-P are typical of subjects with AD. The lack of grey matter loss in the aMCI-S subjects is consistent with the notion that patterns of atrophy on MRI at baseline map well onto the subsequent clinical course.

Objective

To test the hypothesis that magnetic resonance imaging (MRI)-based measurements of hippocampal volume were related to the risk of future conversion to Alzheimer's disease (AD) in elderly patients with a mild cognitive impairment (MCI)

Background

Persons who develop AD pass through a transitional state which can be characterized as a MCI. However, in some patients MCI is a more benign condition which may not progress to AD or may do so slowly.

Patients

Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry.

Methods

At entry into the study each patient received a MRI examination of the head from which the volumes of both hippocampi were measured. Patients were then followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical followup.

Results

Over the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk, 0.69, p = 0.015). When hippocampal volume was entered into bivariate models with age, post menopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E genotype, history of ischemic heart disease and hypertension the relative risks were not substantially different from that found univariately and the associations between hippocampal volume and crossover remained significant.

Conclusion

In elderly patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.