Diego Iacono

The Nun Study Clinically silent AD, neuronal hypertrophy, and linguistic skills in early life

Background: It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic β-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. Methods: Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. Results: A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. Conclusions: 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Neuronal hypertrophy in asymptomatic Alzheimer disease

The pathologic changes of Alzheimer disease (AD) evolve very gradually over decades before the disease becomes clinically manifest. Thus, it is not uncommon to find substantial numbers of Aβ plaques and neurofibrillary tangles in autopsy brains of older subjects with documented normal cognition, a state that we define as asymptomatic AD (ASYMAD). The goal of this study is to understand the morphometric substrate of ASYMAD subjects compared with mild cognitive impairment and definite AD cases. We used designed-based stereology to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in 4 cerebral regions: anterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex, and CA1 of hippocampus. We examined and compared autopsy brains from 4 groups (n = 15 each) of participants in the Baltimore Longitudinal Study of Aging: ASYMAD, mild cognitive impairment, AD, and age-matched controls. We found significant hypertrophy of the neuronal cell bodies, nuclei, and nucleoli of CA1 of hippocampus and anterior cingulate gyrus neurons in ASYMAD subjects compared with control and mild cognitive impairment cases. In the posterior cingulate gyrus and primary visual cortex, the hypertrophy was limited to the nuclei and nucleoli. The hypertrophy of cortical neurons and their nuclei and nucleoli in ASYMAD may represent an early reaction to the presence of neurotoxic Aβ or tau, or a compensatory mechanism that prevents the progression of the disease into dementia.

Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism

To the Editor: We read with interest the report of Onofrj et al.1 linking REM sleep behavior disorder (RBD) to the antagonist action of mirtazapine at 2-adrenoceptors. We describe a case of confirmed RBD responding to the 2-adrenoceptor agonist clonidine that supports the role of these receptors in the pathology of this disorder. A healthy 55-year-old man with no history of neurologic disorder had for 15 years suffered sleep disruption with episodes of violent behavior and accompanying dream imagery. Our clinical diagnosis of RBD was confirmed by polysomnography. He had found little benefit from prior treatments including amitriptyline, nefazodone, venlafaxine, trazodone, clonazepam and zopiclone. We prescribed clonidine, as this drug is known to reduce REM sleep time, increase sleep continuity and reduce phasic EMG activity during REM sleep in healthy volunteers.2,3 The episodes of violence were immediately reduced and sleep quality improved. Although the effects diminished after 2 weeks, they returned following a drug holiday, and we instituted a treatment plan of clonidine 100 g nocte for a week, then 200 g nocte for a week, and then a week without clonidine. The benefits have been sustained for several months and this regime has been preferable to all others tried. RBD may be caused either by disruption of the process promoting REM atonia or by excessive locomotor drive during REM sleep. Animal studies implicate pontine and medullary structures in the maintenance of REM atonia. Active inhibition of motor activity is mediated by centers in the peri-locus coeruleus region via the nucleus reticularis magnocellularis in the medulla, leading to hyperpolarization of spinal motor neurones. A condition similar to RBD was produced in cats by bilateral pontine tegmental section.4 Loss of monoaminergic brainstem nuclei was found at post mortem examination of a human case of RBD.5 The association of RBD with neurodegenerative disorders such as Progressive Supranuclear Palsy and Multiple System Atrophy suggests that the disorder could be caused by destruction or functional depression of the peri-locus coeruleus nuclei. Clonidine is a relatively selective partial agonist at central and peripheral 2-adrenoceptors. This receptor is chiefly found at presynaptic sites on noradrenaline-releasing neurones, and stimulation inhibits noradrenaline release, leading to reduced arousal and improved sleep continuity. We suggest that clonidine has a direct effect on the maintenance of REM atonia via noradrenergic transmission. Our findings, taken with those of Onofrj, strengthen the theory that central 2-adrenoceptors are involved in the pathogenesis of RBD.

In Vivo Fibrillar β-Amyloid Detected Using [11C]PiB Positron Emission Tomography and Neuropathologic Assessment in Older Adults

BACKGROUND In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of β-amyloid (Aβ). However, the extent of agreement in nondemented older adults remains unclear. OBJECTIVE To compare Aβ quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aβ in older adults. DESIGN Case series. SETTING Community-dwelling older adults who came to autopsy. PARTICIPANTS Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging. MAIN OUTCOME MEASURE Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD (CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease. RESULTS Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Aβ levels in vivo, only limited agreement was observed among those with intermediate levels of Aβ. The best overall agreement was achieved at a distribution volume ratio of 1.2. CONCLUSIONS In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Aβ using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aβ in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation.

Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons.

This study focuses on the morphometric changes of neurons in asymptomatic Alzheimers disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.

Neuropathologic Studies of the Baltimore Longitudinal Study of Aging (BLSA)

The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The BLSA is supported by the National Institute of Aging (NIA) and its mission is to learn what happens to people as they get old and how to sort out changes due to aging from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimers Disease Research Center (ADRC). Since then, 211 subjects have undergone autopsy. Here we review the key clinical neuropathological correlations from this autopsy series. The focus is on the morphological and biochemical changes that occur in normal aging, and the early neuropathological changes of neurodegenerative diseases, especially Alzheimers disease (AD). We highlight the combined clinical, pathologic, morphometric, and biochemical evidence of asymptomatic AD, a state characterized by normal clinical evaluations in subjects with abundant AD pathology. We conclude that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level (i.e., neuronal hypertrophy and synaptic plasticity) whereas a failure of compensation may culminate in disease.

Personality and resilience to Alzheimer's disease neuropathology: a prospective autopsy study

Alzheimers disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 ± 7 years) before onset of dementia and up to 30 years (mean 15 ± 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2-3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = -0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and Aβ neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.

The frequency of ApoE2 is increased in asymptomatic Alzheimer's: The Nun Study cohort

Medical Research Council, Edinburgh, United Kingdom; Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA; School of Molecular Medical Sciences, Institute of Genetics, Queen’s Medical Centre, University of Nottingham, United Kingdom; Division of Psychiatry and Neuroscience, School of Medicine and Dentistry, Queen’s University Belfast, United Kingdom; Department of Clinical Science at North Bristol, Frenchay Hospital, University of Bristol, United Kingdom; Greater Manchester Neurosciences Centre, University of Manchester, United Kingdom; OPTIMA, University Department of Physiology, Anatomy & Genetics, Oxford, United Kingdom; Memory Assessment and Research Centre, University of Southampton, United Kingdom; Division of Neuroscience, University of Birmingham, United Kingdom; Department of Psychiatry, University of Bonn, Germany; Department of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, MN, USA; Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA. Contact e-mail: belbin.olivia@ mayo.edu