Deniz Erten-Lyons

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

Objective: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation. Methods: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1. Results: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003). Conclusion: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.

Factors associated with resistance to dementia despite high Alzheimer disease pathology.

Background: Autopsy series have shown that some elderly people remain with normal cognitive function during life despite having high burdens of pathologic lesions associated with Alzheimer disease (AD) at death. Understanding why these individuals show no cognitive decline, despite high AD pathologic burdens, may be key to discovery of neuroprotective mechanisms. Methods: A total of 36 subjects who on autopsy had Braak stage V or VI and moderate or frequent neuritic plaque scores based on Consortium to Establish a Registry for Alzheimers Disease (CERAD) standards were included. Twelve had normal cognitive function and 24 a diagnosis of AD before death. Demographic characteristics, clinical and pathologic data, as well as antemortem brain volumes were compared between the groups. Results: In multiple regression analysis, antemortem hippocampal and total brain volumes were significantly larger in the group with normal cognitive function after adjusting for gender, age at MRI, time from MRI to death, Braak stage, CERAD neuritic plaque score, and overall presence of vascular disease. Conclusion: Larger brain and hippocampal volumes were associated with preserved cognitive function during life despite a high burden of Alzheimer disease (AD) pathologic lesions at death. A better understanding of processes that lead to preservation of brain volume may provide important clues for the discovery of mechanisms that protect the elderly from AD. AD = Alzheimer disease; CDR = Clinical Dementia Rating Scale; CERAD = Consortium to Establish a Registry for Alzheimers Disease; CIRS = Cumulative Illness Rating Scale; ICV = intracranial volume; LB = Lewy bodies; MMSE = Mini-Mental State Examination; NCSE = Neurobehavioral Cognitive Status Examination; NFT = neurofibrillary tangle; NIA = National Institute on Aging; NP = neuritic plaques; OHSU = Oregon Health & Science University; Ref = reference; SES = socioeconomic status; UPDRS = Unified Parkinsons Disease Rating Scale.

Alzheimer Disease Pathology in Cognitively Healthy Elderly:A Genome-wide Study

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.

Trajectory of white matter hyperintensity burden preceding mild cognitive impairment

Objective: To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly. Methods: A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up. Results: During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present. Conclusions: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.

Neuropathologic Basis of Age-Associated Brain Atrophy

IMPORTANCE While brain volume changes are used as surrogate markers for Alzheimer disease neuropathology in clinical studies, the extent to which these changes are due to pathologic features of Alzheimer disease in the aging brain is not well established. This study aims to clarify the neuropathologic correlates of longitudinal brain atrophy. OBJECTIVE To examine the association between brain atrophy during life and neuropathology in an elderly population. DESIGN Autopsy study of a cohort of elderly individuals. SETTING Community-based population. PARTICIPANTS Seventy-one healthy elderly individuals were selected from participants of the Oregon Brain Aging Study for having an autopsy, more than 1 magnetic resonance imaging scan, and the last magnetic resonance imaging scan within 36 months of death. MAIN OUTCOMES AND MEASURES The associations between brain volume trajectories (ventricular, total brain, and hippocampal) and time interaction terms for neurofibrillary tangles, neuritic plaques, gross infarcts, microinfarcts, amyloid angiopathy, Lewy bodies, APOE ε4 presence, and clinical diagnosis (no cognitive impairment, mild cognitive impairment, or dementia as time-varying covariates) were examined in mixed-effects models, adjusting for duration of follow-up and age at death. RESULTS Ventricular volume trajectory was significantly associated with age, presence of infarcts, neurofibrillary tangle and neuritic plaque scores, APOE ε4 allele presence, and dementia diagnosis. Total brain volume trajectory was significantly associated with age and mild cognitive impairment diagnosis. Hippocampal volume trajectory was significantly associated with amyloid angiopathy. CONCLUSIONS AND RELEVANCE Ventricular volume trajectory is more sensitive than total brain and hippocampal volume trajectories as a marker of accruing Alzheimer disease and vascular pathology in elderly individuals. The association between brain volume trajectories and cognitive impairment (mild cognitive impairment and dementia) remained after controlling for the degree of neuropathology and other covariates. This suggests that there may be other factors not measured in this study that could be contributing to brain atrophy in those with cognitive impairment.

Aberrant detergent-insoluble excitatory amino acid transporter 2 accumulates in alzheimer disease

Alzheimer disease (AD) is characterized by deposition of amyloid-&bgr;, tau, and other specific proteins that accumulate in the brain in detergent-insoluble complexes. Alzheimer disease also involves glutamatergic neurotransmitter system disturbances. Excitatory amino acid transporter 2 (EAAT2) is the dominant glutamate transporter in cerebral cortex and hippocampus. We investigated whether accumulation of detergent-insoluble EAAT2 is related to cognitive impairment and neuropathologic changes in AD by quantifying detergent-insoluble EAAT2 levels in hippocampus and frontal cortex of cognitively normal patients, patients with clinical dementia rating of 0.5 (mildly impaired), and AD patients. Parkinson disease patients served as neurodegenerative disease controls. We found that Triton X-100-insoluble EAAT2 levels were significantly increased in patients withAD compared with controls, whereas Triton X-100-insoluble EAAT2 levels inpatients with clinical dementia rating of 0.5 were intermediately elevatedbetween control and AD subjects. Detergentinsolubility of presenilin-1, a structurally similar protein, did not differ among the groups, thus arguing that EAAT2 detergent insolubility was not causedby nonspecific cellular injury. These findings demonstrate that detergent-insoluble EAAT2 accumulation is a progressive biochemical lesion that correlates with cognitive impairment and neuropathologic changes in AD. These findings lend further support to the idea that dysregulationof the glutamatergic system may play a significant role in AD pathogenesis.

Brain volume loss in MCI predicts dementia

Rates of temporal horn volume change were significantly greater in the subjects with mild cognitive impairment who were developing dementia vs those who remained stable.

Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures.

Objective White matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify ‘WM at risk’, or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up. Methods Sixty-one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI. Results CBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time. Conclusions A CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences.

The FAS gene, brain volume, and disease progression in Alzheimer's disease

We sought to identify single‐nucleotide polymorphisms (SNPs) associated with Alzheimers disease (AD) progression and brain volume.

Relapsing polychondritis: An uncommon cause of dementia

Relapsing polychondritis (RP) is a rare disorder that is characterised by recurrent and progressive inflammation of cartilaginous structures.1 Nervous system involvement in RP has been described.1–5 We describe two cases of RP with subacute dementia. A 51-year-old lawyer was diagnosed with RP when he presented with bilateral ear swelling. He was treated with 10 mg/day of oral prednisone during this attack, with a brief taper. He continued to have flare-ups during the next several years and was treated with a short duration of prednisone ranging from 10 to 40 mg/day. Episodes of iritis and scleritis were treated with steroid eye drops. One year after the diagnosis of RP, he started to experience gradual-onset coordination problems, difficulty presenting verbal arguments, distractibility and emotional lability. He developed insomnia and nocturnal myoclonic jerks. Neuropsychological evaluation showed perseveration, prominent attention and concentration deficits. Brain MRI showed extensive periventricular and deep white matter high-signal abnormalities. There was reduced metabolic activity in bilateral temporal cortices and parietal lobes on PET scan. Electroencephalogram was normal. Cerebrospinal fluid (CSF) contained 89 mg/dL of protein, 52 mg/dL glucose, 39 white blood cells (WBCs) (65% lymphocytes) and 2 red blood cells (RBCs). CSF tau/amyloid levels and ratio were considered to …