Current Topics in Research American Journal of Alzheimer’s Disease & Other Dementias® Volume 21 Number 6 December 2006/January 2007 439-447 Sensory Gating in Patients With © 2007 Sage Publications 10.1177/1533317506292282 http://ajadd.sagepub.com Alzheimer’s Disease and Their hosted at Biological Children http://online.sagepub.com Brandon A. Ally, PhD, Gary E. Jones, PhD, Jack A. Cole, PhD, and Andrew E. Budson, MD Research has shown that sensory gating is largely mod- potentials were recorded from 4 groups of 20 subjects ualted by acetylcholine. Diminished levels of acetyl- per group (AD, older controls, FH+, FH–). The results choline and sensory gating deficits have been reported showed that while the AD group demonstrated sensory in research involving Alzheimer’s disease (AD) patients. gating abnormalities, the FH+ group did not when However, there has been little investigation into those compared to their peers with no family history of the with a family history (FH+) of AD. The rationale of this disease (FH–). These results are discussed in relation study was to determine whether sensory gating impair- to previous findings reporting P300 abnormalities in ments could distinguish those with early AD from the FH+ group. individuals with increased risk for the disease while replicating previous findings of gating abnormalities in Keywords: Alzheimer’s disease; sensory gating; P50; AD patients. Using the paried-click paradigm, evoked at risk lzheimer’s disease (AD) is becoming highly 25 years. Finding preclinical markers and additional prevalent in the increasingly aged population risk factors of AD can prospectively lead to a more of the United States, affecting nearly 4.5 mil- accurate identification of individuals who will ulti- A 1 lion Americans annually. AD is a progressive form of mately develop the disease, allowing treatments to dementia that affects parts of the brain that control be initiated earlier and helping to reduce the near memory, language, and executive abilities, and it is $100 billion annual cost to care for patients with the most commonly diagnosed form of dementia. AD.2 Currently, treatments are being developed to Because of the devastating impact of AD on patients treat the underlying pathology of AD.3,4 Current and caregivers’ lives and on the infrastructure of the thinking is that pathology may be present 10 to 15 health care system, the clinical characteristics, pathol- years before clinical presentation or diagnosis,5 and ogy, and risk factors associated with this disease finding preclinical markers of the disease is of para- have received well-deserved attention over the past mount importance. AD is characterized by neuritic plaques, neurofib- rillary tangles, and a presynaptic deficit in acetyl- From Edith Nourse Rogers Memorial Veteran’s Hospital, GRECC, choline.6 Furthermore, it has been reported that Bedford, Massachusetts (BAA, AEB); Boston University School of Medicine, Department of Neurology, Cognitive Neuro- patients with AD show disrupted basal forebrain science Division of the Alzheimer’s Disease Center (BAA, AEB); cholinergic pathways,7 and some patients reveal Department of Psychology, Louisiana State University at associated alpha-7 receptor loss.8 This cholinergic Shreveport (GEJ); and Danville VA Medical Center, Danville, Illinois (JAC). dysfunction has been linked to behavioral distur- bances6 and cognitive deficits such as attention and Dr Budson’s work on this project was supported by National 9,10 Institute on Aging grant P30 AG13846. working memory impairments. Studies examining the efficacy of cholinesterase inhibitor therapy in Address correspondence to: Brandon A. Ally, PhD, Bedford VAMC, GRECC, Building 62, Room B31-A, 200 Springs Road, patients with AD suggest that behavioral distur- Bedford, MA 01730 (e-mail: [email protected]). bances such as distractibility, agitation, hallucinations, 439 440 American Journal of Alzheimer’s Disease & Other Dementias® / Vol. 21, No. 6, December 2006/January 2007 delusions, overactivity, and anxiety can be reduced phase subserved by the temporoparietal and pre- when taking the medication.11-13 frontal cortex and a later phase mediated by the Research examining patients in the preclinical hippocampus. and early stages of AD suggest that cytopathological In research paradigms, sensory gating is exam- changes occur in one of the brain’s largest choliner- ined using the auditory paired-click paradigm, also gic centers, the nucleus basalis.14 However, it is cur- known as the conditioning-test paradigm. P50 dif- rently unknown at what point in the disease process ferences are assessed by measuring the amplitude of this cytopathology takes place. Mesulam and col- the P50 potential to the test click (second click) as leagues14 suggest that although the number of cholin- compared to the conditioning click (first click) of a ergic neurons in the nucleus basalis of patients with paired-click paradigm. Researchers then typically mild cognitive impairment (MCI) is not reduced produce a ratio called the sensory gating ratio by when compared to age-matched controls, these neu- dividing the test click amplitude by the conditioning rons are at pretangle stages of cytopathology and are click amplitude (click 2/click 1).22 Responses to the unlikely to function normally. Mesulam et al further conditioning click can also be compared to ensure suggest that early neurofibrillary tangle formations that any deficit in sensory gating is not due to some have been shown to interfere with protein synthesis nonspecific changes in the brain that affect sensory- and energy metabolism and that normal whole-brain evoked responses. In effect, the conditioning click acetylcholine levels do not ensure the integrity of can act as an internal control measure for between- cholinergic innervation of the cortex. Because the group comparisons. nucleus basalis is known to be the main source of Data suggest that P50 sensory gating heavily acetylcholine to the cortex, cytopathology in a single involves the cholinergic system.16,21,23,24 Leonard et al24 nucleus basalis neuron may have widespread conse- proposed that interneurons and pyramidal neurons quences on cortical cholinergic innervation.14 There receive cholinergic input from the septum (which is has been recent evidence supporting the idea that connected to important structures involved in AD cholinergic cells are dysfunctional in MCI and early such as the hippocampus and fornix) and that the stages of the disease. A positron emission tomo- blockade of the septal cholinergic input removes graphy (PET) study completed by Herholz et al15 the inhibitory effect of the interneurons, allowing showed a significant reduction in cerebral acetyl- pyramidal cells to fire in response to irrelevant cholinesterase in the brains of patients with MCI. repetitive stimuli. Freedman et al25 support this find- Neurophysiologists have studied cholinergic func- ing by reporting that the cholinergic agonist nicotine tion using the exogenously evoked auditory P50 improves gating in individuals who exhibit the P50 component.16 P50 has been used to examine the gating deficit, whereas antagonists of the α-7 nico- ability of the brain to inhibit irrelevant sensory input tinic receptor block P50 inhibition, impairing gat- in a wide range of healthy and neurologically impaired ing. Furthermore, several studies have examined the populations.17 The term sensory gating, commonly direct link between P50 and scopolamine, which associated with the P50 component, refers to the temporarily blocks muscarinic cholinergic receptors inhibition of a stimulus-related neuronal response if in the brain. Results of these studies also suggest the stimulus is preceded by a warning stimulus.18 that these cholinergic receptors modulate P50, and Studies have demonstrated that the habituation of they have reported that cholinergic contribution to repetitive, irrelevant sensory stimuli is an essential preattentive auditory processing underlies stimulus- function of the human brain that keeps higher cor- change detection.16,23,26,27 tical centers from being flooded with this sensory Studies investigating the P50 component in the information.17 Disruption in this sensory gating process AD/MCI process have found a diminished ability to could impair the brain’s ability to select, process, gate irrelevant repetitive stimuli. Most research and store important information or stimuli.19 Animal examining patients with AD has found disrupted studies20 and postmortem studies of patients with sensory gating.18,26,28,29 Jessen and colleagues18 con- schizophrenia21 reveal that sensory gating may be cluded that disturbed sensory gating in patients with mediated by the α-7 subunit of the cholinergic nico- AD results from cholinergic dysfunction and possi- tinic receptor. Grunwald et al17 identified the neural bly from α-7 nicotinic receptor loss. One study, correlates of the gating process, reporting that sen- however, found no significant differences in P50 sory gating may be a multistep process, with an early ratios between patients with AD and an age-matched Sensory Gating and Alzheimer’s Disease / Ally et al 441 control group.30 Investigations into the early stages services, contained individuals with a National of cognitive impairment linked to AD have also found Institute of Neurological and Communicative Diseases– sensory gating deficits in patients with MCI.31,32 Alzheimer’s Disease and Related Disorders Association Irimajiri et al32 suggest that changes in the cholinergic diagnosis