Lawrence S. Honig

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Seizures and Epilepsy in Alzheimer's Disease

Many studies have shown that patients with Alzheimers disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD—with reported lifetime prevalence rates of 1.5–64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.

A Pathological Perspective on the Natural History of Cerebral Atherosclerosis

Background The natural history of intracranial large artery atherosclerosis has been mainly described from lumen-based imaging studies, and much of what is reported to be known about atherosclerosis is derived from non-cerebral arteries. Aims To test the hypothesis that atherosclerosis is only partially represented by stenosis and that advanced atherosclerosis is more common that severe stenosis in noncardioembolic infarcts. Methods Cerebral large arteries from 196 autopsy cases were studied. The revised American Heart Association classification for atherosclerosis was used to determine the phenotype in each available artery. Cross-sectional lumen stenosis was obtained as defined by the Glagovs method. Results As age of cases increased, there was a progressive increment in the frequency of atherosclerotic lesions, rising from 5% of all arteries at age 20–40, to more than 40% at age 60 or older. Stenosis also increased with age: less than 3% of the arteries in those ≤50 years had >40% stenosis, while one out of five arteries in those >80 years had >40% stenosis. In most cases (80%), atherosclerosis and stenosis were directly related. However, one out of five cases with advanced atherosclerosis had <30% stenosis. In arteries supplying brain areas with noncardioembolic infarcts, the majority of segments exhibiting advanced atherosclerosis had lumen stenosis of <40%. Conclusion Although intracranial atherosclerosis is typically associated with stenosis, a substantial minority of cases shows advanced atherosclerosis in the absence of stenosis >40%. Definitions based solely on stenosis may underestimate the extent and role of intracranial large artery atherosclerosis.

Heritability of telomere length in a study of long-lived families

Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h(2)xa0= 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process.

Anti-N-methyl-d-aspartate receptor encephalitis: an emerging cause of centrally mediated sinus node dysfunction

AIMSnAnti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a recently recognized form of autoimmune encephalitis that typically affects young women, often as a paraneoplastic syndrome related to ovarian teratoma. Clinical features include psychiatric and neurological disturbances, central hypoventilation, autonomic instability, and cardiac dysrhythmias. The prevalence, nature, and outcomes of cardiac dysrhythmias in patients with NMDARE have not been well described.nnnMETHODS AND RESULTSnRecords of 10 consecutive patients with NMDARE were reviewed to obtain clinical, laboratory, echocardiographic, electrocardiographic, and radiological data. Patients were all female with an average age of 23 ± 5.5 years. Echocardiograms revealed structurally normal hearts with the exception of mild left ventricular hypertrophy in two cases. Eight patients had inappropriate sinus tachycardia. Six patients developed significant sinus bradycardia, which included periods of sinus arrest in four cases. Five patients manifested both sinus bradycardia and tachycardia. Bradycardia was often triggered by identifiable vagal stimuli. Temporary pacing was instituted in three patients, but permanent pacing was not required in any of the patients. Magnetic resonance imaging (MRI) scans revealed mesial temporal abnormalities in nine patients. In all cases, the dysrhythmias resolved with treatment of the underlying immune disorder with immunotherapy and/or teratoma resection. There was no evidence of dysrhythmia recurrence in any patient at follow-up.nnnCONCLUSIONnAnti-N-methyl-D-aspartate receptor encephalitis is a recently recognized cause of autoimmune encephalitis with a predilection to cause severe sinus node abnormalities. Temporary pacing is occasionally required, but permanent pacing appears to be unnecessary. An analysis of the clinical syndrome coupled with MRI and experimental data may offer insight into central mechanisms of heart rate regulation.

Determinants of cerebrovascular remodeling: do large brain arteries accommodate stenosis?

OBJECTIVEnIt is hypothesized that outward remodeling in systemic arteries is a compensatory mechanism for lumen area preservation in the face of increasing arterial stenosis. Large brain arteries have also been studied, but it remains unproven if all assumptions about arterial remodeling can be replicated in the cerebral circulation.nnnMETHODSnThe sample included 196 autopsied subjects with a mean age of 55 years; 63 % were men, and 74 % non-Hispanic whites. From each of 1396 dissected cadaveric large arteries of the circle of Willis, the areas of the lumen, intima, media, and adventitia were measured. Internal elastic lamina (IEL) area was defined as the area encircled by this layer. Stenosis was calculated by dividing the plaque area by the IEL area and multiplying by 100.nnnRESULTSnPlotting stenosis against lumen area or stratified by arterial size showed no preservation of the lumen in the setting of growing stenosis. We could not find an association between greater IEL proportion and stenosis (Bxa0=xa00.44, Pxa0=xa00.86). Stratifying arteries by their size, we found that smaller arteries have greater lumen reduction at any degree of stenosis (Bxa0=xa0-23.65, Pxa0≤xa00.0001), and although larger arteries show a positive association between IEL proportion and stenosis, this was no longer significant after adjusting for covariates (Bxa0=xa06.0, Pxa0=xa00.13).nnnCONCLUSIONSnWe cannot confirm the hypothesis that large brain arteries undergo outward remodeling as an adaptive response to increasing degrees of stenosis. We found that the lumen decreases proportionally to the degree of stenosis.

Frequency of GBA Variants in Autopsy‐proven Multiple System Atrophy

Multiple system atrophy (MSA) is marked by abnormal inclusions of α‐synuclein in oligodendrogliocytes, and its etiology remains unknown. Variants in the glucocerebrosidase (GBA) gene have been associated with the other synucleinopathies, dementia with Lewy bodies, and Parkinsons disease. It is unclear whether glucocerebrosidase variants are associated with MSA. The objective of this study was to analyze the frequency of GBA variants among patients who had autopsy‐proven MSA at a brain bank in New York City.

Treatment of Alzheimer’s Disease: Current Management and Experimental Therapeutics

Alzheimer’s disease (AD) is a major cause of morbidity in the elderly. AD affects over 5 million persons in the United States, but because it increases in incidence in the elderly, and because of the “graying” of the population, AD is projected to increase in prevalence by many-fold over the coming decades. AD causes progressive mental impairment, resulting in the inability of persons to care for themselves. As a consequence, AD results in enormous costs to society due to both lost productivity, and required care. Thus, improved management and treatment is essential. In this review we will briefly review current understanding of the disease, including roles of beta-amyloid and tau proteins. We will then discuss current therapies in use, including the evidence for treatments with supplements, established drugs, and investigational therapeutic strategies, recently completed and ongoing.

Telomere length is longer in women with late maternal age.

Objective: Maternal age at birth of last child has been associated with maternal longevity. The aim of this study was to determine whether older women with a history of late maternal age at last childbirth had a longer leukocyte telomere length than those with maternal age at last childbirth of 29 years or less. Methods: A nested case control study was conducted using data from the Long Life Family Study. Three hundred eighty-seven women who gave birth to at least one child and lived to the top fifth percentile of their birth cohort, or died before the top fifth percentile of their birth cohort died, but were at least 70 years old, were studied. Logistic regression models using generalized estimating equations were used to determine the association between tertiles of telomere length and maternal age at last childbirth, adjusting for covariates. Results: Age at birth of the last child was significantly associated with leukocyte telomere length. Compared with women who gave birth to their last child before the age of 29, women who were past the age of 33 when they had their last child were two to three times more likely to have leukocyte telomere length in the second and third tertiles than in the first tertile. Conclusions: These findings show an association between longer leukocyte telomere length and a later maternal age at birth of last child, suggesting that extended maternal age at last childbirth may be a marker for longevity.

Subacute Imbalance in a Renal Transplant Patient

ily history was notable for her father having died of lung cancer and her mother had heart disease and DM. Social history did not reveal any unusual exposures. Physical examination results showed a transplant surgical scar and onychomycosis. Neurologic findings revealed reasonably preserved mental status, with bedside examination revealing normal attention, language, and orientation but mild memory deficits for short-term recall (2 of 3 words recalled at a 5-minute delay) and long-term fund of knowledge. Cranial nerve, motor, sensory, and reflex examination results were significant only for gait ataxia, with an inability to perform tandem gait. Blood test results were consistent with DM. Findings from cerebrospinal fluid (CSF) examination included a white blood cell count of 9/μL, with differential examination showing 84% lymphocytes, 13% monocytes, and 3% neutrophils; red blood cell count of 1080/μL; protein level, 180 mg/dL; and glucoselevel,87mg/dL.FlowcytometryrevealedBandTlymphocytesbutnomonoclonalpopu