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By N. Hengley. San Diego State University.

Although the major eddy currents have died out by 40 to 50 milliseconds after the TMS pulse cheap accutane 5mg online skin care jakarta timur, some longer generic accutane 30mg otc acne 8o, low-level currents are still present that cause significant image artifact (C). The averaged time domain ranges from 20 to 30 Steady State minutes for FDG PET, to 40 to 60 seconds for 15O PET Inthismodel,researchersperformTMSthroughoutanentire and perfusion SPECT, to 2 to 3 seconds for BOLD fMRI, scan and then compare results with those of another scan in to milliseconds for EEG and electromyography. The actual which all conditions are the same except for the TMS. Even TMS pulse is very brief, on the order of 300 microseconds. Moreover, because of the concerns of potentially causing a seizure with long trains of high-intensity, high-frequency TMS, only certain TMS Block Design parameters can be used constantly over the time domains of some forms of imaging. Unfortunately, some TMS ef- A different model is to scan in blocks in which periods of fects, such as speech arrest, occur only with high-intensity TMS are separated by periods of rest. To perform interleaved transcranial magnetic stimulation/magnetic resonance im- aging (TMS/fMRI), one must coordinate the TMS pulses with the MRI signal acquisition and inter- leave the two. A: An example of this process for a TMS rate of 1 to 2 Hz. B: An example of serial blood flow changes underneath the TMS coil (over left motor cortex) and in a control region. Note theincrease fromrest, r,in absolutebloodoxygenation-dependent (BOLD)activity underneaththe coil when it discharges at 1 Hz (task, T), and how it decreases afterward (post, P). With this method of scanning, images in which TMS was administered over motor cortex. This are steadily acquired at a rapid rate while the performance study showed that TMS at intensities slightly greater than of a single event is rapidly interspersed. One can image the motor threshold (110%) activates approximately the same brain activity associated with a single TMS pulse by repeat- number of pixels in the same region as does a volition move- ing the event many times and averaging the images acquired ment (Fig. This study also revealed the relative mag- at similar times after the events, much as electrophysiologists nitude of the TMS effect and the temporal relationship to have done with evoked responses (57). Applying TMS pulses to different brain regions with The method that is currently closest to the actual timing different interpulse interval times (milliseconds) may repre- of TMS and brain events is single-event fMRI, or averaged- sent a unique way of improving the temporal resolution 30: Measuring Brain Connectivity 401 A B FIGURE 30. One of the first studies in which this interleaved technique was used attempted to detect differences between volitional and transcranial magnetic stimulation (TMS)-induced movement of the thumb. In (A), the TMS device was placed over the left motor cortex of subjects, who alternately had TMS move their thumb (TMS) and then volitionally moved their thumb in response to a tone (VOL). In (B) are averaged group time series of brain activity during TMS, volition, or a noise control region (upper left). Note that for voxels that were activated in both tasks, the percentage rise in blood oxygenation-dependent (BOLD) activity does not differ from baseline. Thus, TMS produced BOLD changes that are dynamically similar to those of regular movement. In (C), the center of mass of the BOLD signal is virtually the same for both TMS and volition, within the limit of resolution of the magnetic resonance imaging scanner (2 mm). One can also use an averaged-single-trials approach of transcranial magnetic stimu- lation (TMS) and functional magnetic resonance imaging (fMRI)—that is, one can discharge a single TMS pulse and then measure the blood oxygenation-dependent (BOLD) response (top). The time series above show the BOLD response in a control region, for the auditory cortex, and in motor cortex. Note that a single pulse of TMS over motor cortex sufficient to cause the opposite thumb to move produces more blood flow changes in auditory cortex (caused by noise) than it does in the motor cortex under the coil. With further refinement, the combination of sin- sis would be that TMS increases blood flow in a manner gle-pulse and paired-pulse TMS and averaged-single-trials similar to that produced by volitional movement. Confu- fMRI will probably be of considerable interest in in vivo sion ensued when an early and still unpublished study of neurophysiology. Stimulation was REVIEW OF TRANSCRANIAL MAGNETIC performed at 1 Hz because FDG takes 20 minutes to settle STIMULATION FUNCTIONAL IMAGING into neurons and is thus a composite picture of brain activity STUDIES TO DATE over 20 minutes. This paradoxical decrease in localized Transcranial Magnetic Stimulation brain activity both under the coil and at the mirror or con- Interleaved tralateral site during TMS was surprising, but findings of decreased brain activity like this had been found in some Fluorodeoxyglucose PET electrophysiologic studies (12). The final image was a The first published combination of TMS and functional summed picture of 20 minutes of brain activity. It is likely neuroimaging in real time was performed with FDG PET that TMS has multiple different effects during that in a patient before and after rTMS treatment for refractory time—increased activity immediately with stimulation, de- depression (54). At a separate time, these investigators also creases during the rest time between TMS pulses, and dy- injected the glucose while the patient was intermittently namic changes across the 20 minutes. Peter Fox and one stimulated at 20Hz over the left prefrontal cortex for 20 of the chapter authors (MSG) (58) next sought to test this 15 minutes.

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Chapter 83: Molecular Genetics of Alzheimer Disease 1207 Proteins Interacting with PS is responsible for ensuring the proper folding of newly syn- thesized proteins (176 order 40 mg accutane mastercard acne 911,177) buy generic accutane 10 mg skin care 9. Presenilins have been found to interact directly with a vari- ety of proteins. Proteins interacting with presenilins include members of the catenin family (165–167). Catenins have ROLE OF APOLIPOPROTEIN E ISOFORMS IN at least two different functions in the cell. First, they are LATE-ONSET AD components of cell–cell adhesive junctions interacting with the cytoskeletal anchors of cadherin adhesion molecules. In addition to the deterministic genetic mutations found Second, there is compelling evidence that -catenin is a key in APP and presenilins, genetic factors modify the risk of effector in the Wingless/Wnt signaling cascade. The APOE gene on chromosome 19 is con- and its vertebrate counterpart Wnt signaling direct many sidered as an important risk factor for the development of crucial developmental decisions in Drosophila and verte- late-onset AD. These lipoproteins regulate plasma lipid -Catenin interact with the large loop of PS1 (165,166). Apo E has been implicated in the (15), which binds to the C-terminus of PS2. Calsenilin was transport of cholesterol and phospholipids for the repair, shown to interact with both PS1 and PS2 in cultured cells growth, and maintenance of membranes that occur during and could link presenilin function to pathways regulating development or after injury (178). Apo E is polymorphic and is encoded by three alleles Several other proteins have been identified that interact (APOE2,3,4) that differ in two amino acid positions. The with presenilins including the cytoskeletal proteins filamin most common isoform, E3, has a Cys residue at position and filamin homologue (168), -calpain (169), Rab11, a 112 and an Arg at position 158. The two variants contain small guanosine triphosphatase belonging to the p21 ras- either two Cys residues (E2) or two Arg residues (E4) at related superfamily (170), G-protein Go (171), and glyco- these positions. In general, it seems that E4 allele increases gen synthase kinase-3b (172). The presence of one or two E4 alleles is associated with earlier onset of dis- Apoptosis and Cell Death ease and an enhanced amyloid burden in brain, but it has There is increasing evidence of causal involvement of pre- little effect on the rate of progression of dementia (182). ALG3, a 103-residue C-terminal frag- Thus, homozygous E4/E4 subjects have an earlier onset ment of PS2, was isolated in death trap assay as rescuing (mean age less than 70 years) than heterozygous E4 subjects a T-cell hybridoma from T-cell receptor and Fas-induced (mean age of onset for E2/E3 is more than 90 years) (183). In PC12 cells, the down-regulation of PS2 The most obvious hypothesis is that APOE polymor- by antisense RNA protects the cells from glutamate toxicity. This hypothesis is supported by observations lation suggest that this C-terminal fragment of PS2 acts as that the subjects with one or more APOE4 alleles have a a dominant negative form of PS2. Expression of mutant higher amyloid burden than do subjects with no APOE4 alleles PS1 (L286V) in PC12 cells enhanced apoptosis on trophic (184). Second, there is evidence that both Apo E and A factor withdrawal or A toxicity (174). The alternative cas- may be cleared through the LRP receptor, and Apo E4 and pase cleavage in the C-terminal fragment of PS1 has been A peptide may compete for clearance through the LRP shown to abrogate the binding of PS1 to -catenin (167) receptor (179). Third, transgenic mice that overexpress APP and could therefore modulate the apoptotic outcome. The knock-in mutation was shown to influences the onset of AD in patients with DS and in those increase ER calcium mobilization and superoxide and mito- with APP mutations but not in families with presenilin mu- chondrial reactive oxygen species production leading to cas- tations (185–187). Evidence shows that mutant PS1 also renders cells less OTHER GENETIC RISK FACTORS IN AD efficient to respond to stress conditions in ER. Mutations in PS1 may increase vulnerability to ER stress by altering In addition to the APOE gene, which has been confirmed the unfolded protein response (UPR) signaling pathway that as a strong risk factor in various studies, polymorphisms in 1208 Neuropsychopharmacology: The Fifth Generation of Progress several other genes have been described to increase suscepti- in AD because of the very high prevalence of the APOE4 bility for AD. Most of these genetic polymorphisms are allele, even though APOE is only a risk factor for AD. These mutations in APP and PS, rare though late-onset AD and the presence of an exon 2 splice acceptor they are, give crucial insight into the molecular process un- deletion in the 2-macroglobulin (A2M) gene on the short derlying all forms of AD. Thus, the APP mutations clearly arm of chromosome 12 (188). Significantly, A2M binds to underscore critical role of APP in disease initiation. The PS a variety of proteins, including proteases (189,190) and A mutations implicate A , and particularly A 42, in disease. In addition, A2M is also present in senile A similar, crucial role for A in sporadic AD is supported plaques and can attenuate A fibrillogenesis and neurotox- by postmortem and tau studies. Moreover, A2M may, through LRP-mediated and A2M may also have their effects by interacting with endocytosis, allow the internalization and subsequent lyso- APP and A.

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FIGURE 8-9 (see Color Plate) M icrograph of granulom atous lesions of the renal interstitium that are observed in 15% to 40% of patients with sarcoidosis generic accutane 30mg overnight delivery acne home treatments. This figure is based on autopsy findings cheap accutane 20 mg free shipping acne before and after, which often reveal occasional granulom as of the kidney without any evidence of functional or clinical abnorm al- ity. The lower figure of 15% , or less, m ore clearly reflects diffuse infiltration of the kidneys with granulom as associated with clinical evidence of abnorm al renal function, as shown here. Generally, enlarged kidneys are noted on renal ultrasonography. Once considered rare, GRANULOM ATOUS LESIONS granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. M ost IN RENAL SARCOIDOSIS of these are seen in cases of drug hypersensitivity. The commonly implicated drugs are anti- biotics and nonsteroidal anti-inflammatory drugs. Other less common and Lesion Patients, % rather rare causes include tuberculosis, angiitis, and lupus erythematosus. In some 15% to 20% of cases, the cause of the granulomatous lesions is never established. As a rule, abnorm al renal function in patients with sarcoidosis is due to tubulointerstitial nephritis rather than granulom atous infiltration, which certainly is true in patients with progressive loss of renal function. Fibrosis m ay occur in the absence of granulom as but generally reflects the residual fibrosis of granulom atous lesions that have subsided or responded to steroid therapy. It is im portant to m onitor renal function closely in such patients and initiate proper m easures to retard the course of pro- gressive renal failure. As with all other form s of tubulointerstitial nephritis, tubular dysfunction is a com m on finding in such cases. The reduction in the glom erular filtration rate usually is m odest but can progress to end-stage renal disease. Progression to end-stage disease tends to occur in older m en who have m inim al pulm onary involvem ent. Extensive granulomatous 7 infiltration of the kidneys can result in acute renal failure as a pre- senting clinical feature of sarcoidosis in the absence of any evidence 6 of other organ involvement. As a rule, improvement in renal func- 5 tion occurs after steroid therapy (R), as shown here, in the clinical 4 course of one such patient. AprilM ay June July Time, mo FIGURE 8-13 CASE REPORT OF A PATIENT W ITH SARCOIDOSIS O bstructive nephropathy due to sarcoidosis. Acute deterioration of HAVING RETROPERITONEAL FIBROSIS renal function in sarcoidosis very rarely results from obstructive nephropathy caused by intrarenal granulom atous infiltrates or from extensive retroperitoneal lym phadenopathy or fibrosis caus- Patient profile ing obstruction of the renal vasculature or ureteral outflow [3,4]. W hereas renal involvement in sarcoidosis primarily is due to abnormalities of calcium metabolism and tubulointerstitial nephritis, rare cases of glomerulopathy have FIGURE 8-15 been associated with sarcoidosis. The detection of an abnormal urine Recurrent granulom atous sarcoid nephritis in a transplanted kid- sediment and proteinuria in a patient with sarcoidosis should always ney. In patients with sarcoidosis having renal involvem ent whose lead to consideration of glomerular disease. A variety of glomerular renal failure has progressed to end-stage renal disease, kidney lesions have been reported in patients with sarcoidosis, including transplantation can be successful. H owever, due consideration m em branous glom erulopathy, m inim al change disease, m em brano- should be given to the fact that recurrence of sarcoidosis in renal proliferative glomerulonephritis, focal glomerulosclerosis, immuno- allografts have been reported. Conversely, docum ented cases exist globulin A nephropathy, and crescentic glomerulonephritis. Of these, in which sarcoidosis was transm itted by cardiac or bone m arrow membranous glomerulopathy is more common. This observation has been taken as evidence of an represent a chance coexistence of two separate diseases; however, infectious or transm issible cause of sarcoidosis that highlights the their occurrence in a disease of altered im m unity m ay reflect a problem of transplantation in patients with sarcoidosis. M esangial deposits of C3 have been observed Shen et al.

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