Alzheimer Disease: Farlow MR

Henderson VW, Paganini-Hill A, Miller BL, Elble RJ, Reyes PF, Shoupe D, McCleary CA, Klein RA, Hake AM, Farlow MR. · Department of Neurology, University of Southern California, Los Angeles 90089, USA. · Neurology. · Pubmed #10668686 No free full text.

Abstract: BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Farlow MR, Cyrus PA, Nadel A, Lahiri DK, Brashear A, Gulanski B. · Department of Neurology, Indiana University School of Medicine, Indianapolis 46202-5111, USA. · Neurology. · Pubmed #10599773 No free full text.

Abstract: OBJECTIVE: To investigate whether an interaction exists between APOE genotype and the response of AD patients to metrifonate treatment and whether APOE genotype independently affects the rate of AD progression. BACKGROUND: Metrifonate is a new acetylcholinesterase inhibitor for the treatment of AD symptoms. METHODS: Data were pooled from four prospective, randomized, double-blind, placebo-controlled clinical trials and analyzed retrospectively. A total of 959 patients who received once-daily placebo (n = 374) or metrifonate (30 to 60 mg based on weight or a 50-mg fixed dose, n = 585) for up to 26 weeks agreed to APOE genotyping. RESULTS: Metrifonate clearly improved the cognitive performance of the AD patients when compared with placebo (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], p = 0.0001). The interaction of APOE genotype and the metrifonate effect on cognitive performance were not significant (p = 0.25). Metrifonate also clearly improved the global function of the AD patients when compared with placebo (Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus], p = 0.0001). The interaction of APOE genotype with the metrifonate effect on global function also was not significant (p = 0.70). No significant three-way interactions were observed among APOE genotype, gender, and response to metrifonate treatment (ADAS-Cog, p = 0.68; CIBIC-Plus, p = 0.26). APOE genotype did not influence disease progression as evaluated by either cognitive performance (ADAS-Cog, p = 0.93) or global function (CIBIC-Plus, p = 0.64). CONCLUSIONS: The findings from these studies of up to 26 weeks' duration do not clearly support an interaction between APOE genotype and metrifonate treatment effects. They suggest that APOE genotypes do not necessarily predict an AD patient's response to metrifonate treatment and that APOE genotype may not influence the rate of disease progression for patients with mild to moderate AD.

Farlow MR. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. · J Am Geriatr Soc. · Pubmed #18808602 No free full text.

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Farlow MR, Graham SM, Alva G. · Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5111, USA. · Drug Saf. · Pubmed #18558791 No free full text.

Abstract: BACKGROUND: Memantine, a moderate-affinity, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, is the first non-cholinergic agent approved for the treatment of Alzheimer's disease (AD), and the first medication approved in the US and Europe for the treatment of moderate to severe stages of the disease. The objective of this study was to analyse safety and tolerability data from phase III memantine trials and from the open-label extensions of those trials. METHOD: We conducted an analysis of the pooled data for tolerability and safety from six double-blind, placebo-controlled, memantine trials with a minimum duration of 24 weeks (three trials in mild to moderate AD and three in moderate to severe AD; 20 mg/day; 2311 patients) and four open-label extensions of those trials (two in mild to moderate AD and two in moderate to severe AD; 20 mg/day, 1405 patients), for a total treatment period of up to 2 years. RESULTS: The analysis revealed that adverse events occurring during both short- and long-term memantine treatment were minimal, and similar in type and frequency to those reported for placebo-treated patients. The most frequently reported adverse events in placebo-controlled trials included agitation (7.5% memantine vs 12.0% placebo), falls (6.8% vs 7.1%), dizziness (6.3% vs 5.7%), accidental injury (6.0% vs 7.2%), influenza-like symptoms (6.0% vs 5.8%), headache (5.2% vs 3.7%) and diarrhoea (5.0% vs 5.6%). Discontinuations due to adverse events were similar in memantine- and placebo-treated groups (8.9% vs 9.8%, respectively). CONCLUSION: Consistent with the favourable tolerability profile of memantine observed in clinical use, this analysis of pooled safety data indicates that both short- and long-term memantine treatment of patients with AD is safe and well tolerated, with an adverse event profile similar to that of placebo.

Bekris LM, Millard SP, Galloway NM, Vuletic S, Albers JJ, Li G, Galasko DR, DeCarli C, Farlow MR, Clark CM, Quinn JF, Kaye JA, Schellenberg GD, Tsuang D, Peskind ER, Yu CE. · Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA. · J Alzheimers Dis. · Pubmed #18430993 No free full text.

Abstract: The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.

Lane R, Feldman HH, Meyer J, He Y, Ferris SH, Nordberg A, Darreh-Shori T, Soininen H, Pirttilä T, Farlow MR, Sfikas N, Ballard C, Greig NH. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA. · Pharmacogenet Genomics. · Pubmed #18334913 No free full text.

Abstract: OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Ghetti B, Spina S, Murrell JR, Huey ED, Pietrini P, Sweeney B, Wassermann EM, Keohane C, Farlow MR, Grafman J. · Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Ind. 46202, USA. · Neurodegener Dis. · Pubmed #18322394 No free full text.

Abstract: BACKGROUND: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype. OBJECTIVE: To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U. METHODS: We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings. RESULTS: FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X). CONCLUSION: Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.

Spina S, Farlow MR, Unverzagt FW, Kareken DA, Murrell JR, Fraser G, Epperson F, Crowther RA, Spillantini MG, Goedert M, Ghetti B. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Brain. · Pubmed #18065436 links to  free full text

Abstract: Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.

Lu YF, Austrom MG, Perkins SM, Bakas T, Farlow MR, He F, Jin S, Gamst A. · Indiana University School of Nursing, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #17712158 No free full text.

Abstract: This study estimates the prevalence of depressed mood in caregivers of individuals with mild cognitive impairment (MCI) and assesses whether demographics, stressors, intrapsychic strain, and gain are associated with depressed mood. A secondary analysis of baseline data from the Alzheimer's Disease Cooperative Study MCI trial was conducted using a cross-sectional, correlational design. Descriptive statistics to estimate the prevalence of caregiver depressed mood and univariate and block-wise logistic regression analyses were used. The prevalence of depressed mood in 769 caregivers was 24.6% (95% confidence interval, 21.5-27.7). The odds of being depressed were significantly higher in younger, nonspousal caregivers with less education, who cared for MCI patients with lower activities of daily living functioning, and who perceived greater relational deprivation, higher levels of self-loss, and personal gain. Controlling for relevant variables, relational deprivation and caregiver education continued to be significantly associated with depressed mood. Relational deprivation may be important for future interventions.

Gelfanova V, Higgs RE, Dean RA, Holtzman DM, Farlow MR, Siemers ER, Boodhoo A, Qian YW, He X, Jin Z, Fisher DL, Cox KL, Hale JE. · Integrative Biology Division, Lilly Research Laboratories, Greenfield, IN 46140, USA. · Brief Funct Genomic Proteomic. · Pubmed #17584762 links to  free full text

Abstract: Immunoprecipitation (IP) combined with matrix-assisted laser desorption ionization (MALDI) time of flight (Tof) mass spectrometry has been used to develop quantitative assays for amyloid-beta (Abeta) peptides in cerebrospinal fluid (CSF). Inclusion of (15)N labelled standard peptides allows for absolute quantification of multiple Abeta isoforms in individual samples. Characterization of variability associated with all steps of the assay indicated that the IP step is the single largest contributor to overall variability. Optimization of the assay resulted in overall coefficient of variation <or=8% with high agreement to an Abeta(1-40) and Abeta(1-42) ELISA assay. Application of the MALDI-Tof assay to CSF obtained from healthy volunteers and Alzheimer's disease patients indicated statistically significant 43% lower levels of Abeta(1-42) in the AD group (P = 0.0025).

Oe T, Ackermann BL, Inoue K, Berna MJ, Garner CO, Gelfanova V, Dean RA, Siemers ER, Holtzman DM, Farlow MR, Blair IA. · Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, Departments of Pharmacology and Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. · Rapid Commun Mass Spectrom. · Pubmed #17117458 No free full text.

Abstract: The 40 and 42 amino-acid residue forms of amyloid beta (Abeta(1-40) and Abeta(1-42)) in cerebrospinal fluid (CSF) have been proposed as potential biomarkers of Alzheimer's disease (AD). Quantitative analyses of Abeta peptides in CSF have relied almost exclusively on the use of immunoassay-based assays such as the enzyme-linked immunosorbent assay (ELISA) procedure. However, due to the ability of the Abeta peptides to readily self-aggregate or bind to other proteins and glassware, such analyses are extremely challenging. Analyses are further complicated by the potential of the peptides to undergo post-translational modifications and the possibilities for cross-reaction in the ELISA assays with endogenous components of the CSF. An approach based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) has now been developed which overcomes these methodological issues. The key steps in implementing this new approach involved immunoaffinity purification coupled with the use of [15N]-labeled Abeta peptides as internal standards, a basic LC mobile phase, negative ion electrospray ionization, and a basic solvent for dissolving the peptides and washing the injection needle to prevent carryover of analytes during multiple injections on the LC/MS system. The validated method had limits of quantitation of 44 fmol/mL (200 pg/mL) for Abeta(1-42) and 92 fmol/mL (400 pg/mL) for Abeta(1-40). An excellent correlation was found between the LC/MS/MS assay and an ELISA assay for Abeta(1-42) in human CSF (r2 = 0.915), although less correlation was observed for Abeta(1-40) (r2 = 0.644). Mean CSF Abeta(1-42) concentrations for samples collected 2 weeks apart from a limited number of AD patients provided additional confidence in the reproducibility of the LC/MS/MS assay. Concentrations for duplicate samples from AD patients were slightly higher than most previously reported values (mean 1.06 +/- 0.25 ng/mL; n = 7). Abeta(1-40) concentrations in duplicate samples obtained from AD patients were also reproducible but were found to be slightly lower than most previously reported values (mean 6.36 +/- 3.07 ng/mL; n = 7). Consistent with literature reports, mean Abeta(1-42) concentrations were found to be lower in AD patients compared with the normal subjects (mean 1.49 +/- 0.59 ng/mL; n = 7), whereas there was no difference in Abeta(1-40) concentrations between AD patients and normal subjects (mean 5.88 +/- 3.03 ng/mL; n = 7). The accuracy and precision of the LC/MS assay mean that it will be a useful complement to existing ELISA assays for monitoring therapeutic interventions designed to modulate CSF Abeta(1-42) concentrations in individual AD patients. Moreover, the introduction of stable isotope labeled internal standards offers the potential to achieve a more rigorous account of the influence of methodological effects related to sample collection and processing.

Sokol DK, Chen D, Farlow MR, Dunn DW, Maloney B, Zimmer JA, Lahiri DK. · Department of Neurology, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202, USA. · J Child Neurol. · Pubmed #16948926 No free full text.

Abstract: Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.

Peskind ER, Li G, Shofer J, Quinn JF, Kaye JA, Clark CM, Farlow MR, DeCarli C, Raskind MA, Schellenberg GD, Lee VM, Galasko DR. · VA Puget Sound Health Care System, Mental Illness Research, Education, and Clinical Center, Seattle, WA 98108, USA. · Arch Neurol. · Pubmed #16831961 links to  free full text

Abstract: BACKGROUND: Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease. OBJECTIVE: To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF A beta 42 concentration in adults with normal cognition across the life span. DESIGN: The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF A beta 42 and A beta 40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method.Subjects One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years. RESULTS: The CSF A beta 42, but not the A beta 40, concentration decreased significantly with age. There was a sharp decrease in CSF A beta 42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF A beta 42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele. CONCLUSION: These CSF A beta 42 findings are consistent with acceleration by the APOE*4 allele of pathogenic A beta 42 brain deposition starting in later middle age in persons with normal cognition.

Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC. · Eli Lilly and Company, Indianapolis, IN 46085, USA. · Neurology. · Pubmed #16505324 No free full text.

Abstract: LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.

Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M. · Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA. · Curr Alzheimer Res. · Pubmed #16375657 No free full text.

Abstract: CONTEXT: Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results. OBJECTIVE: To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type. DESIGN: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial. SETTING: Outpatient clinics of universities and private research centers specialized in dementia. PATIENTS: 513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug. INTERVENTION: 26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo. MAIN OUTCOMES: Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). RESULTS: There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE. CONCLUSION: The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.

Peskind ER, Riekse R, Quinn JF, Kaye J, Clark CM, Farlow MR, Decarli C, Chabal C, Vavrek D, Raskind MA, Galasko D. · VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center (MIRECC), University of Washington School of Medicine, Seattle, WA 98108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16327349 No free full text.

Abstract: Three hundred forty-two subjects underwent 428 research lumbar punctures for studies of cerebrospinal fluid (CSF) biomarkers. Subjects were 67 Alzheimer disease or mild cognitive impairment (AD/MCI) patients and 275 cognitively normal adults aged 21 to 88. Lumbar puncture was performed in the lateral decubitus or sitting position using the Sprotte 24 g atraumatic spinal needle. Up to 34 ml of cerebrospinal fluid were collected. Anxiety and pain experienced during lumbar puncture were rated on a visual analog scale. The frequency of any adverse event (11.7%), clinically significant adverse events (3.97%), and typical post-lumbar puncture headache (PLPHA) (0.93%) was low. Risk of post-lumbar puncture headache was unrelated to age, gender, position during lumbar puncture, ml of cerebrospinal fluid collected, or minutes of recumbent rest following lumbar puncture. The frequency of post-lumbar puncture headache was lower in AD/MCI (P = 0.03) than any other subject group. Anxiety and pain ratings were low. Younger subjects reported more anxiety than old (P = 0.001) and AD/MCI subjects (P = 0.008) and more pain than older normal subjects (P = 0.013). Pain ratings for women were higher than those for men (P = 0.006). Using the Sprotte 24 g spinal needle, research lumbar puncture can be performed with a very low rate of clinically significant adverse events and with good acceptability in cognitively impaired persons and cognitively normal adults of all ages.

Farlow MR, Small GW, Quarg P, Krause A. · Indiana University School of Medicine, Indianapolis, IN 46202-5111, USA. · Dement Geriatr Cogn Disord. · Pubmed #16088144 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. METHODS: Rapidly and slowly progressing patients were identified by rates of cognitive decline [>/=4 points and <4 points, respectively, on the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0--26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26--52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. RESULTS: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p=0.029), who experienced a modest decline in cognitive symptoms at the end of the study. COMMENT: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.

Farlow MR, Lilly ML, Anonymous00300. · Department of Neurology, Indiana University, Indianapolis, Indiana, USA. · BMC Geriatr. · Pubmed #15659242 links to  free full text

Abstract: BACKGROUND: Rivastigmine, a butyl- and acetylcholinesterase inhibitor, is approved for symptomatic treatment of Alzheimer's disease (AD). Data supporting the safety and efficacy of second-generation cholinesterase inhibitors, such as rivastigmine, are available for treatment up to 1 year, with limited data up to 2 1/2 years. The purpose of this report is to present safety and effectiveness data for rivastigmine therapy in patients with mild to moderately severe AD receiving treatment for up to 5 years. METHODS: An observational approach was used to study 37 patients with originally mild to moderate AD receiving rivastigmine as a therapy for AD in an open-label extension (ENA713, B352 Study Group, 1998). RESULTS: The initial trial demonstrated rivastigmine was well-tolerated and effective in terms of cognition, global functioning and activities of daily living. In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period. Two thirds of the participants still enrolled at week 234 were in the original high-dose rivastigmine group during the double-blind phase, suggesting that early therapy may confer some benefit in delaying long-term progression of symptoms. CONCLUSIONS: Long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period. Early initiation of treatment, with titration to high-dose therapy, may have an advantage in delaying progression of the illness.

Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. · Department of Neurology, Indiana University School of Medicine, Clinical Building, Room 299, 541 Clinical Drive, Indianapolis, IN 46202-5111, USA. · Neurology. · Pubmed #15557508 No free full text.

Abstract: OBJECTIVE: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. METHODS: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. RESULTS: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. CONCLUSION: MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

Hake AM, Farlow MR. · Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, Suite 299, Indianapolis, IN 46202, USA. · Clin Geriatr Med. · Pubmed #15062492 No free full text.

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Zubenko GS, Zubenko WN, McPherson S, Spoor E, Marin DB, Farlow MR, Smith GE, Geda YE, Cummings JL, Petersen RC, Sunderland T. · Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Room E1230, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. · Am J Psychiatry. · Pubmed #12727688 links to  free full text

Abstract: OBJECTIVE: This report provides a description of the prevalence and clinical features of the major depressive syndrome of Alzheimer's disease using data derived from structured diagnostic assessments of 243 patients with probable Alzheimer's disease and 151 nondemented elderly comparison subjects. METHOD: Subjects were characterized by a consortium of four Alzheimer's disease research centers and the Geriatric Psychiatry Branch of the National Institute of Mental Health. All sites administered the Clinical Assessment of Depression in Dementia, a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize major depressive episodes in this population. RESULTS: Despite the use of a common, reliable methodology for the assessment and diagnosis of major depressive episodes, the prevalence of major depression in Alzheimer's disease ranged widely from 22.5% to 54.4% across the recruitment sites. The prevalence of major depressive episodes among Alzheimer's disease patients in the aggregate sample exceeded that for elderly comparison subjects and reached nearly 50% among the most severely demented patients. Alzheimer's disease patients with a current major depressive episode had earlier mean ages at onset, a higher mean Hamilton Depression Rating Scale score, and were more likely to be experiencing psychotic symptoms than those who had not developed a major depressive episode. Although the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects included similar numbers of depressive symptoms, patients with Alzheimer's disease were more likely to report a diminished ability to concentrate or indecisiveness and less likely to experience sleep disturbances and feelings of worthlessness or excessive guilt during their major depressive episodes. None of the clinical features of major depression differed significantly in frequency among depressed Alzheimer's disease patients with mild, moderate, or severe dementia. Concurrent psychotic symptoms progressively increased with dementia severity. CONCLUSIONS: The high rate of major depressive episodes that occur after the onset of cognitive impairment among patients with Alzheimer's disease (the majority of whom had no premorbid history of major depression), common emergence in the early stages of dementia when symptoms of cognitive impairment are least likely to contribute to the syndromal diagnosis of major depression, and differences in the clinical presentations of the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects, all support the validity of the major depressive syndrome of Alzheimer's disease. Our findings suggest that the major depressive syndrome of Alzheimer's disease may be among the most common mood disorders of older adults.

Lahiri DK, Kotwal GJ, Farlow MR, Sima A, Kupsky W, Sarkar FH, Sambamurti K. · Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. · Ann N Y Acad Sci. · Pubmed #12485889 No free full text.

Abstract: Two major pathological hallmarks of Alzheimer's disease (AD) are the senile plaques that are primarily composed of amyloid beta-peptide (Abeta) and neurofibrillary tangles consisting of tau aggregates. Abeta is generated proteolytically from a family of Abeta-containing precursor proteins (APP; 695-770 amino acid) by secretase enzymes to different specific carboxyl-terminal fragments (CTFs). Herein we examined APP and its products in autopsied brain sections from 10 AD and 10 non-AD control subjects immunochemically using an antibody that was raised against APP751-770 residue (O443). The O443 antibody was initially characterized by Western blot analysis and immunoprecipitation. In this study, we used this antibody for immunohistochemical analysis to determine the distribution of APP and its CTF species. In 10 brain regions showing different levels of plaques and tangles, antibody O443 stained the perinuclear region of the nucleus, plaques, and neurites. Tangle-bearing neurons also appeared to stain with the antibody, suggesting that these dysfunctional neurons continue to synthesize APP/CTF. Alternatively, the normally short-lived APP/CTF can be stabilized and persist in these neurons. Taken together, these results suggest that, in addition to the widely believed role of Abeta, CTFs may play a key role in the pathogenesis of AD. Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD.

Gao F, Bales KR, Dodel RC, Liu J, Chen X, Hample H, Farlow MR, Paul SM, Du Y. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46285, USA. · Brain Res Mol Brain Res. · Pubmed #12399113 No free full text.

Abstract: Increasingly, inflammatory responses in localized areas of brain parenchyma in response to the extracellular deposition of the Abeta peptides are thought to play a causative role in Alzheimer's disease (AD) progression. Anti-inflammatory agents, in particular non-steroid anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been shown to be associated with a delayed onset or slowed rate of disease progression in several epidemiological studies. Activation of glial cells and the subsequent expression of a number of proteins including alpha(2)-macroglobulin (alpha(2)M) are associated with the induction of brain tissue inflammation. Additionally cytokines, such as interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are co-localized to senile plaques, a neuropathological hallmark of AD. Alpha(2)M binds various cytokines, including IL-1beta, as well as Abeta. In this study, we demonstrate that IL-1beta induces alpha(2)M synthesis/release from a human astroglial cell line (U373) via the activation of the nuclear transcription factor NF-kappaB. Our data suggest that attenuation of IL-1beta-induced alpha(2)M synthesis/release by blocking NF-kappaB activation may potentially be 'protective' against the development of late-onset AD.

Takao M, Ghetti B, Murrell JR, Unverzagt FW, Giaccone G, Tagliavini F, Bugiani O, Piccardo P, Hulette CM, Crain BJ, Farlow MR, Heyman A. · Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis 46202, USA. · J Neuropathol Exp Neurol. · Pubmed #11764087 No free full text.

Abstract: We report clinical, neuropathologic and molecular genetic data from an individual affected by a familial Alzheimer disease (AD) variant. The proband had an onset of dementia at age 29 followed by generalized seizures a year later. He died at age 40. Neuropathologically, he had severe brain atrophy and characteristic histopathologic lesions of AD. Three additional neuropathologic features need to be emphasized: 1) severe deposition of Abeta in the form of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous Abeta deposits in the subcortical white matter and in the centrum semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white maner of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the proband revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importance of this case lies in the presence of ectopic neurons in the white matter, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN1 mutation may have a causal relationship with an abnormality in neuronal development.

Morris JC, Farlow MR, Ferris SH, Kurz AF, Maelicke A, Rasmusen L, Wilkinson D, Yan B. · Department of Neurology, Washington University, St. Louis, Missouri, USA. · Clin Ther. · Pubmed #11396870 No free full text.

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