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Lawrence S Honig

Publications and source records attributed to Lawrence S Honig.

15 recordsLinked to original sources
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Dementia with cerebrovascular disease.

In this case study, we review the symptoms, cognitive testing, brain imaging, and brain pathology of a woman with dementia, for whom the neuropathological findings suggest a prominent contribution of cerebrovascular disease. Vascular dementia is the term commonly used for persons with dementia resulting from strokes, either clinically evident or subclinical "silent" events. "Mixed dementia" is the term used when there is an admixture of pathological findings related to Alzheimer's disease (AD) and cerebrovascular disease, as in this situation. In some cases of mixed dementia, the pathological involvement of AD may be the principal contributory cause of the cognitive symptoms, and in others, the vascular changes may give the greater contribution.

Aged↗
PubMed2006

Essential tremor associated with pathologic changes in the cerebellum.

BACKGROUND: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. OBJECTIVE: To describe more extensive postmortem changes in the cerebellum in another ET case. DESIGN: Case report. RESULTS: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). CONCLUSIONS: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder.

Aged, 80 and over↗
PubMed2006

Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia.

OBJECTIVE: Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality. METHODS: This nested case-control study used stored leukocyte DNA from 257 individuals (mean age, 81.4 +/- 7.9 years; 64.6% female; 44.7% Hispanic, 33.5% non-Hispanic black, and 21.8% non-Hispanic white). Our assay used real-time polymerase chain reaction, with two separate reactions amplifying telomere sequence and reference single copy gene (ribosomal-protein-P0), providing a calculated telomere-to-single copy gene (T/S) ratio. RESULTS: Mean telomere length was shorter among subjects dying during follow-up than in those surviving (0.453 +/- 0.211 vs 0.525 +/- 0.226 [+/- standard deviation]; p < 0.009). It was also shorter in those with Alzheimer's disease compared with control subjects (0.458 +/- 0.207 vs 0.516 +/- 0.229; p < 0.03). For participants with Alzheimer's disease, compared with those with the longest telomeres, the mortality odds ratio (OR) was 4.8 (95% confidence interval [CI], 1.7-13.8) in those with intermediate-length telomeres and 7.3 (95% CI, 2.4-22.0) in those with the shortest telomeres. The presence of an epsilon4 allele also increased the mortality OR, with an OR of 5.8 (95% CI, 1.3-26.4) for intermediate-length telomeres and an OR of 9.0 (95% CI, 1.9-41) for the shortest telomeres. INTERPRETATION: Our findings suggest that leukocyte telomere length is related to both dementia and mortality and may be a marker of biological aging.

Aged↗
PubMed2006

Intention tremor of the head in patients with essential tremor.

Patients with essential tremor (ET) have kinetic arm tremor; this tremor can also have an intentional component. We are unaware of reports of intention tremor of the head in ET. Our aims were to describe, provide electrophysiological data and video documentation of, and estimate the prevalence of intention tremor of the head in our sample. Ten (9.0%; 95% confidence interval = 4.7%-14.3%) of 111 patients had intention tremor of the head; in 7 it involved the neck and in 3 the chin. These patients trended toward having more severe kinetic arm tremor and they had more severe intention tremor of the arms. These observations provide further support for the evolving view that the cerebellum may be involved in ET.

Aged↗
PubMed2005

Brain tumor-associated dementia.

In this case study, we describe a patient with a dementia due to a brain tumor. This unusual cause of dementia illustrates the importance of a thorough evaluation of anyone who experiences relatively sudden changes in cognitive functions. The disorder had features common to other dementias but also had some unusual attributes that made a diagnosis of neurodegenerative disease less likely. Common features included intellectual decline involving difficulties in word-finding, the occurrence of paraphasia, poor concentration, disorientation in familiar environments, problems performing routine complex tasks, and elements of social withdrawal. Unlike more common degenerative dementias, however, there was no marked memory involvement. In addition, the onset of illness was rapid and associated with headaches, incontinence, and some gait and motor dysfunction.

Aged↗
PubMed2005

Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center.

BACKGROUND: Epidemiologic studies have implicated cerebrovascular disease and its antecedents as risk factors for Alzheimer disease (AD). Cerebral atherosclerosis or strokes may increase the deposition of neuritic plaques or the formation of neurofibrillary tangles. Alternatively, they may simply hasten the age at onset of disease, or increase the severity of disease symptoms. This investigation examined the association between cerebrovascular disease and the pathologic manifestations of AD in an autopsy series. METHODS: This was a cross-sectional study using data from the United States National Alzheimer's Coordinating Center database. The primary analysis included 1,054 individuals with clinical information and semiquantitative neuropathologic measurements: 921 had AD as the primary neuropathologic diagnosis and 133 were considered neuropathologically normal. RESULTS: Overall, 9% of the individuals had clinical history of stroke during life, but 33% had evidence of cerebral infarcts at postmortem. There was no association between neuritic plaques or neurofibrillary tangles, the primary neuropathologic manifestations of AD, with either clinical history of stroke or the presence of cerebral infarcts at postmortem. The authors did find a higher frequency of neuritic plaques and neurofibrillary tangles with increased amyloid angiopathy. Neither plaques nor tangles were associated with small vessel cerebrovascular disease, arteriosclerosis. However, the presence of large-vessel cerebrovascular disease, or atherosclerosis, was strongly associated with an increased frequency of neuritic plaques. CONCLUSIONS: Atherosclerotic cerebrovascular disease may have a role in the pathogenesis of Alzheimer disease, because of a strong association with frequent neuritic plaques.

Age of Onset↗
PubMed2005

Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study.

BACKGROUND: Essential tremor is one of the most common neurological diseases. Its links with Parkinson disease (PD) are often debated. There have been few published postmortem studies. OBJECTIVE: To study our first case of essential tremor through the recently established Essential Tremor Centralized Brain Repository. DESIGN: Report of a case of a patient with a diagnosis of severe essential tremor for 46 years who exhibited no signs of parkinsonism. RESULTS: On postmortem examination, gross brain sections showed no abnormalities. Results of microscopic examination of hematoxylin-eosin-stained sections revealed that the locus coeruleus contained multiple Lewy bodies (LBs), although none were found in the substantia nigra, dorsal vagal nuclei, thalamus, substantia innominata, inferior olivary nucleus, or cerebellum. Immunochemical staining using antibodies directed against alpha-synuclein confirmed the presence of many LBs in the locus ceruleus and showed rare LBs in the substantia innominata and dorsal vagal nuclei. There were no LBs in the substantia nigra. CONCLUSIONS: Our patient had a very focal presence of LBs in the locus ceruleus, an anatomically restricted form of LB disease. This study provides support for the link between essential tremor and LB disease and raises the question as to what proportion of patients with essential tremor might have unusual forms of LB disease.

Aged↗
PubMed2004

Cognitive reserve-mediated modulation of positron emission tomographic activations during memory tasks in Alzheimer disease.

BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.

Aged↗
PubMed2004

Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

Aged↗
PubMed2004

Three-word recall in normal aging.

Three-word recall tasks are widely used as brief measures of verbal memory function, although interpretation of performance is complicated by variations in test instructions and procedures. The purpose of this study was to examine 3-word recall performance in samples of healthy subjects aged 5275 (M age = 70) and age 7692 (M age = 82) compared to patients with Alzheimer's Disease (AD) when explicit prompts to remember the words were given. Those in the younger aging group remembered significantly more words than those in the older sample after a brief delay (M= 2.8 and 2.3, respectively). However, the majority of control subjects recalled 2 or 3 words after the delay, with only 3% of the 5075 year old group and 17% of the 76+ year old group recalling 0 or 1 word on delayed recall. This is in stark contrast to the 87% of individuals with AD who recalled 0 or 1 word. Even though 3-word recall performance decreases with age, good recall (2 or 3 words) can be expected in most cases of normal aging.

Aged↗
PubMed2003

Frontotemporal dementia.

In this case study, we describe the symptoms, neuropsychological testing, and brain pathology of a man with frontotemporal dementia (FTD). FTD most often presents with either a change in personality or behavior, such as social withdrawal, increased gregariousness, disinhibition, or obsessive behaviors; or with impairment of language function. Memory difficulties are common, but usually are less prominent than these other symptoms in the early stages of the disease. Frequently, psychiatric diagnoses are initially the primary consideration. Cases may be either familial or sporadic. In this familial case, an autopsy was ultimately performed and revealed findings characteristic of FTD, with grossly evident focal brain degeneration in the frontal and temporal regions, microscopic signs of gliosis, and cellular abnormalities of the intracellular microtubule-associated protein tau.

Age of Onset↗
PubMed2003

Stroke and the risk of Alzheimer disease.

BACKGROUND: Alzheimer disease (AD) and stroke are common in elderly individuals, but the relation between these 2 disorders remains uncertain. OBJECTIVE: To investigate the association between a clinical history of stroke and subsequent risk of AD. DESIGN: A cohort of 1766 Medicare recipients without dementia participated in a longitudinal follow-up study from 1992 through 1999 in upper Manhattan, New York, NY. History of stroke and presence of cardiovascular risk factors were ascertained at the onset of the study. Incidence rates for AD among those with and without stroke were calculated; proportional hazards ratios were computed using age at onset of the disease as the time-to-event variable. RESULTS: The annual incidence for AD was 5.2% among individuals with stroke vs 4% for those without stroke. The hazards ratio for AD among those with a history of stroke was 1.6 (95% confidence interval, 1.0-2.4) compared with those without stroke. Of the vascular risk factors, hypertension, diabetes, and heart disease, only diabetes related to risk of AD in the absence of stroke. Stroke remained weakly associated with AD in the absence of these factors, but risk significantly increased with the additional factors of hypertension (relative risk, 2.3; 95% confidence interval, 1.4-3.6), diabetes (relative risk, 4.6; 95% confidence interval, 2.2-9.5), or heart disease (relative risk, 2.0; 95% confidence interval, 1.2-3.2). CONCLUSIONS: Stroke is associated with AD among elderly individuals. The relation is strongest in the presence of known vascular risk factors. The observed association between stroke and AD might relate to an underlying systemic vascular disease process, or alternatively, to the additive effects of stroke and AD pathologic features, leading to an earlier age at onset of disease.

Aged↗
PubMed2003

Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration.

Radial glial cells play at least two crucial roles in cortical development: neuronal production in the ventricular zone (VZ) and the subsequent guidance of neuronal migration. There is evidence that radial glia-like cells are present not only during development but in the adult mammalian brain as well. In addition, radial glial cells appear to be neurogenic in the central nervous system of a number of vertebrate species. We demonstrate here that most dividing progenitor cells in the embryonic human VZ express radial glial proteins. Furthermore, we provide evidence that radial glial cells maintain a vimentin-positive radial fiber throughout each stage of cell division. Asymmetric inheritance of this fiber may be an important factor in determining how neuronal progeny will migrate into the developing cortical plate. Although radial glial cells have traditionally been characterized by their role in guiding migration, their role as neuronal progenitors may represent their defining characteristic throughout the vertebrate CNS.

Adaptation, Physiological↗