Dorene M. Rentz

Amyloid deposition is associated with impaired default network function in older persons without dementia

Alzheimers disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

Objective: To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI). Methods: Three groups of older individuals were studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individuals structural MRI, and fMRI activation was quantified within each region. Results: Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE ε4 allele than in the 16 noncarriers. Conclusions: The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimers disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.

Cerebrovascular deposition of β‐amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the β‐amyloid–binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes.

fMRI studies of associative encoding in young and elderly controls and mild Alzheimer’s disease

Objective: To examine alterations in patterns of brain activation seen in normal aging and in mild Alzheimer’s disease by functional magnetic resonance imaging (fMRI) during an associative encoding task. Methods: 10 young controls, 10 elderly controls, and seven patients with mild Alzheimer’s disease were studied using fMRI during a face–name association encoding task. The fMRI paradigm used a block design with three conditions: novel face–name pairs, repeated face–name pairs, and visual fixation. Results: The young and elderly controls differed primarily in the pattern of activation seen in prefrontal and parietal cortices: elderly controls showed significantly less activation in both superior and inferior prefrontal cortices but greater activation in parietal regions than younger controls during the encoding of novel face–name pairs. Compared with elderly controls, the Alzheimer patients showed significantly less activation in the hippocampal formation but greater activation in the medial parietal and posterior cingulate regions. Conclusions: The pattern of fMRI activation during the encoding of novel associations is differentially altered in the early stages of Alzheimer’s disease compared with normal aging.

Imaging amyloid deposition in Lewy body diseases

Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; H&Y = Hoehn and Yahr; MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

Functional Alterations in Memory Networks in Early Alzheimer’s Disease

The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimers disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face–name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions.

The A4 Study: Stopping AD Before Symptoms Begin?

A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline. A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.