Karen Putnam

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia.

Objective: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). Methods: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. Results: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. Conclusions: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.

Cerebrospinal fluid β-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele

Background Cerebrospinal fluid (CSF) measures of β-amyloid 1–42 and tau are linked with the known neuropathology of Alzheimers disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE e4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE e4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. Methods We assessed the levels of β-amyloid 1–42 and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. Results When divided according to the absence or presence of the APOE e4 allele, the control subjects with at least one e4 allele had significantly lower CSF β-amyloid 1–42 but not tau levels than control subjects without an APOE e4 allele ( p 1–42 and higher CSF tau levels than the normal control group ( p Conclusions The association of APOE e4 allele and lower, more AD-like levels of CSF β-amyloid 1–42 in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with e4 carriers and suggests that CSF β-amyloid 1–42 decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Testosterone Suppression of CRH-Stimulated Cortisol in Men

Despite observations of age-dependent sexual dimorphisms in hypothalamic–pituitary–adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18–45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.

Biomarkers in the diagnosis of Alzheimer's disease: are we ready?

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer’s disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer’s disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer’s disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions. (J Geriatr Psychiatry Neurol 2006;19:172-179)

Context-specific memory and apolipoprotein E (ApoE) [varepsilon]4: Cognitive evidence from the NIMH prospective study of risk for Alzheimer's disease

The aim of the study was to determine whether the epsilon 4 allele of the apolipoprotein E (ApoE) gene was associated primarily with context-specific memory among individuals at genetic risk for developing Alzheimers disease. The effect of ApoE status on comprehensive neuropsychological results was examined in 176 healthy adults during baseline cognitive testing in the NIMH Prospective Study of Biomarkers for Older Controls at Risk for Alzheimers Disease (NIMH Prospective BIOCARD Study). The presence of the epsilon 4 allele was associated with significantly lower total scores on the Logical Memory II subtest of the Wechsler Memory Scale-Revised and percent of information retained after delay. Further analysis indicated the prose recall and retention effect was partially explained by a small subgroup of epsilon 4 homozygotes, suggesting a gradually progressive process that may be presaged with specific cognitive measures. The current results may represent an epsilon 4-associated breakdown between gist-related information and context-bound veridical recall. This relative disconnection may be understood in light of putative epsilon 4-related preclinical accumulation of Alzheimer pathology (tangles and plaques) in the entorhinal cortex (EC) and among frontal networks, as well as the possibility of less-efficient compensatory strategies.

Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age : Results from the NIMH BIOCARD study

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimers disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.

Effects of Previous Major Depressive Illness on Cognition in Alzheimer Disease Patients

OBJECTIVE Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored. METHODS Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment. RESULTS After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD. CONCLUSIONS Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.

Stability of CSF β-Amyloid1–42 and Tau Levels by APOE Genotype in Alzheimer Patients

Background: Cerebrospinal fluid (CSF) measures of β-amyloid1–42 and tau differ between patients with Alzheimer’s Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. Methods: We assessed CSF β-amyloid1–42 and tau in 20 mild-to-moderate AD patients, 11 APOE Ε4+ and 9 APOE Ε4–, over a mean time of 3.8 years (range 1–11.1 years). Results: Over the period measured, CSF β-amyloid1–42 levels were lower in APOE Ε4+ compared to APOE Ε4– patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. Conclusions: While this is a limited clinical sample, the further decrease in CSF β-amyloid1–42 (i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that β-amyloid1–42 and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF β-amyloid1–42 and tau are used as measures of treatment response.

Fine-needle, negative-pressure lumbar puncture: A safe technique for collecting CSF

Analysis of CSF is an important component of clinical and research studies involving illnesses such as AD. In fact, longitudinal analysis of CSF may be vital to identify and track potential biological markers in people at risk for developing AD. However, recruiting initial and long-term participation of research subjects in lumbar puncture (LP)-based studies can be challenging, especially because the incidence of post-LP headaches (post-LPHAs) with traditional methods often exceeds 30%.1 Reduction of post-LPHAs through the use of small-diameter spinal needles is well documented,2 presumably due to reduced leakage of CSF from the smaller hole produced when the spinal needle traverses the dura.3-5⇓⇓ There is relatively little experience obtaining large quantities of fluid from small-diameter Whitacre spinal needles compared with the traditional 20-guage, Quincke needles. Therefore, we sought to determine whether research quantities of CSF could be withdrawn using small, atraumatic needles and negative pressure techniques without causing a significant increase in the rate of …

Proteomic approaches in drug discovery and development.

Publisher Summary This chapter describes the proteomic approaches in drug discovery and development. Proteomics represents the effort to establish the identities, quantities, structures, and biochemical and cellular functions of all proteins in an organism, organ, or organelle and how these properties vary in space, time, or physiological state. The proteome is more complex than the genome, because the inherent biochemical nature of proteins depends on more complicated building blocks. Intracellular localization, proteolytic processing, post-translational modification, and protein-protein interactions add greatly to protein complexity. The chapter provides an overview of the existing technologies, and presents a case study that shows how two-dimensional gel electrophoresis (2DE)-mass spectroscopy (MS) profiling approaches can be applied to one type of issue central to drug discovery and development. From a drug discovery and development perspective, the greatest challenge is translating the information garnered from proteomic initiatives into quantitative, sensitive, and specific assays capable of delivering information about a drugs effect on the target, and if the drug can effectively alter the disease in a clinically beneficial manner. Although proteomics may provide information about new targets, one of the major hurdles in early drug discovery is to demonstrate that the drug has bound specifically to target and produced a biological, meaningful activity both in vitro and in vivo . Despite the existing challenges, proteomic technologies offer powerful tools for difficult scientific questions, and are certainly a path to the future for more efficient drug discovery and development.