Abstract Objective: To test the hypothesis that memory impairment in the oldest old has different neural substrates in those with and without Alzheimer’s pathology Background: Memory impairment is the commonest feature of dementia in the oldest old. Unlike younger age groups, non-Alzheimer’s pathologies, such as hippocampal sclerosis, are a common cause of memory impairment and dementia in the oldest old. Lack of reliable biomarkers has hampered the diagnosis of these important pathologies during life. Design/Methods: 36 participants from The 90+ Study with mild dementia (CDR-total-score=0.5) completed volumetric T1 weighted brain MRI scan and California Verbal Learning Test-Delayed Recall (CVLT-DR) (mean interval=65 days). Volumes of CA1 and CA3 hippocampal subfields and cortical thickness of temporal lobe regions were estimated using freesurfer software. A subset of 27 participants also completed florbetapir amyloid PET scans that were dichotomized (positive/negative) by visual read. Regression analysis, adjusted for age, gender, and education, assessed the association between CVLT-DR as outcome and atrophy pattern. Results: In the whole group (N=36), there was a trend of significant association between CVLT-DR and volume of CA1 subfield (estimate:0.35, p=0.08). No association was found between CVLT-DR and CA3 volume or temporal lobe cortical thicknesses. Restricting the analysis to the amyloid negative group (N=12, MMSE mean=23.4), there was a significant association between CVLT-DR and CA1 volume (estimate:0.45, p=0.04) but no association with CA3 volume or temporal lobe cortical thicknesses. In the amyloid positive group (N=15, MMSE mean=24.1), CVLT-DR was not associated with any of the hippocampal volumes. Rather, there was a positive association between CVLT-DR and cortical thickness of the left fusiform region (estimate:0.4, p=0.04). Conclusions: Our results suggest that memory impairment in the oldest old might be due to atrophy of different brain regions in those with and without Alzheimer’s pathology. This differential atrophy may serve as an imaging biomarker for non-Alzheimer’s pathologies such as hippocampal sclerosis.

Although recent developments in imaging biomarkers have revolutionized the diagnosis of Alzheimer's disease at early stages, the utility of most of these techniques in clinical setting remains unclear. The aim of this review is to provide a clear stepwise algorithm on using multitier imaging biomarkers for the diagnosis of Alzheimer's disease to be used by clinicians and radiologists for day-to-day practice. We summarized the role of most common imaging techniques and their appropriate clinical use based on current consensus guidelines and recommendations with brief sections on acquisition and analysis techniques for each imaging modality. Structural imaging, preferably MRI or alternatively high resolution CT, is the essential first tier of imaging. It improves the accuracy of clinical diagnosis and excludes other potential pathologies. When the results of clinical examination and structural imaging, assessed by dementia expert, are still inconclusive, functional imaging can be used as a more advanced option. PET with ligands such as amyloid tracers and ¹⁸F-fluorodeoxyglucose can improve the sensitivity and specificity of diagnosis particularly at the early stages of the disease. There are, however, limitations in using these techniques in wider community due to a combination of lack of facilities and expertise to interpret the findings. The role of some of the more recent imaging techniques including tau imaging, functional MRI, or diffusion tensor imaging in clinical practice, remains to be established in the ongoing and future studies.

We describe a patient with cerebral amyloid angiopathy-related inflammation (CAA-ri) presenting as Alzheimer disease (AD) with a mass lesion with symptom onset at age 59. He was found to have a nonenhancing lesion in the right temporal lobe on magnetic resonance imaging without evidence of hemorrhage. He underwent a biopsy which showed amyloid beta in blood vessel walls and a perivascular inflammatory infiltrate consistent with CAA-ri. Neurofibrillary tangles were present and a flortaucipir positron emission tomography showed bilateral signal highest in the lateral temporal and parietal cortices. A lumbar puncture showed tau, p-tau, and amyloid beta levels consistent with AD without evidence of inflammation. He was homozygous for the APOE ε4 allele. He died at age 67. A focus of CAA-ri can be present in the context of AD with a mass lesion and without evidence of hemorrhage, significant ischemic changes, or overt inflammation on cerebrospinal fluid examination.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T₁w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-β, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-β pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-β peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-β profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined.