Alzheimer Disease: Potkin SG

Lane RM, Potkin SG, Enz A. · Novartis Neuroscience, Novartis Pharmaceuticals Corporation, NJ, USA. · Int J Neuropsychopharmacol. · Pubmed #16083515 No free full text.

Abstract: The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.

Alva G, Potkin SG. · Department of Psychiatry and Human Behavior, University of California, Irvine, 101 The City Drive, Orange, CA 92868, USA. · Clin Geriatr Med. · Pubmed #15024811 No free full text.

Abstract: Dementias become more prevalent with increasing age. As the growth in the geriatric population increases, so does their incidence. Risk factor profiling, neuroimaging, and neurocognitive testing are helping provide objective evidence for determining between normal aging and cognitive deficit states. The diagnosis usually can be made, however, by a careful interview of the patient and a reliable informant and a detailed physical examination with emphasis on the neurologic and mental status examinations, followed by standard laboratory testing. Earlier therapeutic intervention can make a long-term difference in outcome. Distinguishing variants of dementias grants the clinician an opportunity of intervening based on etiology and similarities in neurotransmitter deficit states. Palliative ways of slowing progressive decline are available primarily by way of ChEIs, although no cures yet exist for the dementias. Optimizing current treatments makes sense in improving the quality of life of sufferers.

Gauthier S, Emre M, Farlow MR, Bullock R, Grossberg GT, Potkin SG. · McGill Centre for Studies in Aging, Verdun, Quebec, Canada. · Curr Med Res Opin. · Pubmed #14687441 No free full text.

Abstract: Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

Potkin SG. · Department of Psychiatry and Human Behavior, University of California at Irvine Medical Center, Orange, California 92668, USA. · Int Psychogeriatr. · Pubmed #12636178 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.

Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J. · Department of Neurosciences, University of California at San Diego, La Jolla 92093, USA. <> · Nat Med. · Pubmed #15852017 No free full text.

Abstract: Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Potkin SG, Alva G, Keator D, Carreon D, Fleming K, Fallon JH. · Department of Psychiatry and Human Behavior, Brain Imaging Center, Irvine Hall, Room 166, University of California, Irvine, Irvine, CA 92697-3960, USA. · Brain Res. · Pubmed #12231461 No free full text.

Abstract: Neotrofin, a reported inducer of CNS neurotrophic factor synthesis and release, with memory-enhancing activity and demonstrated restoration of age-induced memory deficits in animals, was tested in patients with mild to moderate Alzheimer's disease. Nineteen subjects were treated with 1 week of low-dose (150 mg per day) and 1 week of high-dose (500 or 1000 mg per day) Neotrofin. Cognitive composite scores demonstrated improvement in memory (F=9.6, P=0.0004), executive functioning (P=0.004), and attention (P=0.004). PET scanning was obtained before, after low, and after high dosing. The brain areas most affected were the cerebellum, and sensory and prefrontal cortices, where increases in GMR (Glucose Metabolic Rate) were observed. Increases and decreases were observed in the posterior superior temporal (BA 22), parahippocampal, inferior temporal (BA 37, 20), and fusiform gyri as well as the superior parietal lobule and postcentral gyrus. There were strong hemispheric differences, producing opposite metabolic effects in homologous brain regions. Subcortically, the posterior thalamic region, meso-pontine tegmentum, and tectum had increases in GMR on the left side. At the low dose, GMR was generally increased, but to a lesser degree. The brain areas subserving memory, attention and executive functions were significantly altered in GMR by Neotrofin; however, the directions of these changes were complex. There were significant correlations between improvement in memory and executive function in brain areas involved in circuits subserving these functions. Thus, Neotrofin appears to induce metabolic changes in brain regions involved in circuits underlying memory, attention, and executive functioning.

Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, Messina J, Wu JC, Hartman R, Fallon JH. · Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627-3960, USA. · Int J Neuropsychopharmacol. · Pubmed #11602028 No free full text.

Abstract: In-vivo metabolic measures with positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimer's disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo-treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non-significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients.

Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine and Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, WA 98108, USA. · Am J Geriatr Psychiatry. · Pubmed #16861375 No free full text.

Abstract: OBJECTIVE: The objective of this study was to compare the efficacy and safety of the moderate-affinity, uncompetitive N-methyl-d-aspartate receptor antagonist, memantine, versus placebo in patients with mild to moderate Alzheimer disease (AD). METHOD: This was a randomized, double-blind, placebo-controlled clinical trial conducted at 42 U.S. sites. Participants were 403 outpatients with mild to moderate AD and Mini-Mental State Examination scores of 10-22 randomized to memantine (20 mg/day; N=201) or placebo (N=202) for 24 weeks. Primary outcomes were change from baseline at 24 weeks on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a measure of cognition, and on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), a global measure. Secondary outcomes included change on the Neuropsychiatric Inventory (NPI) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL(23)), measures of behavior and function, respectively. RESULTS: Most (82.4%) participants completed the trial. Memantine resulted in significantly better outcomes than placebo on measures of cognition, global status, and behavior when based on the protocol-specified primary last observation carried forward imputation as well as a mixed-models repeated-measures approach applied to the continuous outcomes. Treatment discontinuations because of adverse events for memantine versus placebo were 19 (9.5%) and 10 (5.0%), respectively. CONCLUSIONS: These results support the safety and efficacy of memantine for the treatment of mild to moderate AD.

Fleming K, Kim SH, Doo M, Maguire G, Potkin SG. · Department of Psychiatry and Human Behavior, University of California, Irvine, California, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #14682081 No free full text.

Abstract: Although a hallmark of Alzheimer's disease (AD) is memory impairment, there is speculation that recall may be enhanced when an emotional component is associated with an event. The current study aims to assess whether patients with AD would recall emotionally laden material better than neutral stimuli. DSM-IV-diagnosed AD patients with mild to moderate dementia, as well as groups of young and elderly healthy controls, participated in this study. All subjects were administered three word lists for three trials each. The words were positive, negative, or neutral in valence and matched for concreteness, emotionality, and pleasantness. As expected, the controls performed significantly better than the AD patients. Importantly, the pattern of recall for the emotions was different, such that both control groups recalled all emotions equally, whereas the AD patients recalled significantly more negative words than positive or neutral. These findings of improved immediate memory for emotional material in AD lends support to the notion that mnemonic functions are differentially affected in the disease.

Albert KA, Hemmings HC, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE, Greengard P. · Laboratory of Molecular and Cellular Neuroscience, the Rockefeller University, New York, NY, USA. · Arch Gen Psychiatry. · Pubmed #12150646 links to  free full text

Abstract: BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Moayeri SE, Cahill L, Jin Y, Potkin SG. · Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92697-3800, USA. · Neuroreport. · Pubmed #10757495 No free full text.

Abstract: Studies suggest that emotionally influenced events enhance long-term memory. This study aimed to uncover whether this phenomenon exists in Alzheimer's Disease (AD) by comparing patients' performance with that of controls on a memory task. Overall, controls performed better than AD subjects on a delayed recognition task of a story containing emotional elements (95.8+/-2.4% vs 66.6+/-28.5%; mean +/- s.d.), respectively. Among AD subjects, there was relative sparing of emotionally influenced memory, which was not seen in controls because of a ceiling effect. Retention of the emotional phase of the story differed significantly from that of the neutral phases. These findings suggest that the influence of emotion on memory is spared, at least to some degree, in AD.