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Johnson SA duloxetine 30mg with amex, Lampert-Etchells M discount duloxetine 40mg line, Pasinetti GM, et al. The inflammatory response system a practical method for grading the cognitive state of patients of brain: implications for therapy of Alzheimer and other neuro- for the clinician. Cytokine gene cerebral grey matter of elderly subjects. Br J Psychiatry 1968; expression as a function of the clinical progression of Alzheimer 114:797–811. Arch Intern Med 1998; of a referral population and factors associated with progression. JAMA 1997;278: implications for clinical trials and identification of subgroups. Prevalence of AD among whites: a summary nitive deterioration. Int J Ger- of apolipoprotein E allele 4 with late-onset familial Alzheimer iatr Psychopharmacol 1998;1:S7–S14. Work Group under the auspices of the Department of Health 83. Neu- prediction of dementia and the absence of dementia in healthy rology 1984;34:939–944. Memory function in taining and instrumental activities of daily living. The impact of behavioral CERAD neuropsychological measures. BUXBAUM MOLECULAR PATHOLOGY OF ALZHEIMER isoform, of which APP695 is the major isoform found in DISEASE neurons (6,7,9). The two longer forms (APP751 and APP770) contain a 56-amino-acids domain with homology Pathologic Changes to Kunitz family of serine protease inhibitors (KPI) (10). Alzheimer disease (AD) is characterized histopathologically by the intraneuronal accumulation of paired helical fila- APP Processing ments (PHFs) composed of abnormal tau proteins and ex- tracellular deposits of an amyloid peptide (A ) in plaques APP can be processed by at least three secretases: -, -, and (1). AD plaques are round, spheric structures, 15 to 20 -secretases. The site of cleavage of each of these enzymes is M in diameter, consisting of a peripheral rim of abnormal shown in Fig. In the nonamyloidogenic pathway, neuronal processes and glial cells surrounding a core of de- -secretase cleaves the amyloid precursor protein within the posited material. Several associated proteins have been iden- A domain. The cleavage within the A domain prevents tified in the plaques including heparan sulfate proteoglycans deposition of the intact amyloidogenic peptide. The site of cleavage targeted by -secretase has been identi- fied at the Lys16-Leu17 bond of the A sequence corre- Alzheimer Amyloid Precursor Protein sponding to Lys687-Leu688 peptidyl bond of APP770 (11). A is proteolytically derived from a larger integral mem- The 10- to 11-kd C-terminal product may undergo an addi- brane protein, the amyloid precursor protein (APP). Be- tional cleavage by a protease -secretase activity. This proc- cause there are mutations in APP (discussed in detail later), ess leads to the formation of p3 and its complementary that lead to AD, the molecular and cell biology of APP will product p7 (Fig. APP is a type I integral The protease termed -secretase initiates A generation membrane glycoprotein containing the A region, which by cleaving APP after methionine 671 (using APP770 num- includes 28 amino acids of the ectodomain and 12 to 14 bering), thus creating an approximately 12-kd membrane- amino acids of the adjacent transmembrane domain (1,5). This can result in the secretion precursor–like proteins 1 and 2 (APLP1 and APLP2). The of a truncated soluble APP molecule, called sAPP , into APP gene is localized on chromosome 21 at 21q21. The 12-kd fragment may then undergo - and it is encoded by 18 exons, of which exons 16 and 17 secretase cleavage within the hydrophobic transmembrane encode the A peptide domain (8). Three major splice var- domain at either valine 710, alanine 712, or threonine 713 iants of APP have been identified containing the A se- to release the 40, 42, or 43 residue A peptides (13). The quence, that is, the APP695, APP751, and the APP770 varying C-terminal of A may be a feature of crucial impor- tance because A peptides display distinct physical proper- ties and, in particular, exhibit aggregation behavior that can vary according to their length (14). Buxbaum: Department of Psychiatry, Mount Buxbaum et al. The relative importance of intracellular versus extracellular A has not yet been determined.

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N erve activity releases containing NA the endogenous neurotransm itter noradren- Postganglionic Nerve impulse aline (N A) and also adrenaline from the sympathetic neuron induces Sympathetic varicosities cheap duloxetine 40 mg overnight delivery. N oradrenaline and adrenaline exocytotic NA release + – C-fiber reach the postsynaptic -adrenoceptors (or Presynaptic β Presynaptic -adrenoceptors) on the cell m em brane of β-receptor α-receptor the target organ by diffusion cheap duloxetine 30 mg amex. O n receptor NA Synaptic stim ulation, a physiologic or pharm acologic cleft Varicosities effect is initiated. Presynaptic 2-adrenocep- α Effector tors on the membrane (enlarged area), when cell activated by endogenous noradrenaline as Synaptic Postsynaptic cleft well as by exogenous agonists, inhibit the α-receptor Response amount of transmitter noradrenaline released per nerve impulse. Conversely, the stimulation NA of presynaptic 2-receptors enhances nora- drenaline release from the varicosities. O nce noradrenaline has been released, it travels Target through the synaptic cleft and reaches both Postsynaptic organ - and -adrenoceptors at postsynaptic α- receptors sites, causing physiologic effects such as vasoconstriction or tachycardia. Prazosin is a lipophilic m etabolized by the liver and predom inantly excreted in the highly selective 1-adrenergic antagonist. The plasm a half-life of terazosin (approxim ately 12 hours) (approxim ately 90% ) but undergoes variable first-pass hepatic is not prolonged in patients with renal insufficiency. Doxazosin is also a water-soluble quinazoline analogue of It is extensively m etabolized by the liver and predom inantly prazosin, with about half its potency. The plasm a half-life of prazosin (2 to undergoes significant first-pass hepatic m etabolism ; bioavail- 4 hours) is not prolonged in patients with renal insufficiency. Peak concentrations occur in Terazosin is a water-soluble quinazoline analogue of prazosin 2 to 3 hours. It is extensively m etabolized by the liver and with about one third of its potency. It is com pletely absorbed prim arily elim inated in the feces. The plasm a half-life of doxa- and undergoes m inim al first-pass hepatic m etabolism. Peak zosin (approxim ately 22 hours) is not prolonged in patients plasm a concentrations occur in 1 to 2 hours. Standing 1 140 1-Adrenergic antagonists are associated with relatively few side effects [6,9]; the m ost striking is the “first-dose effect”. It 130 occurs 30 to 90 m inutes after the first dose and is dose dependent. The “first-dose effect” is exaggerated by fasting, 110 upright posture, volum e contraction, concurrent -adrenergic 100 antagonism , or excessive catecholam ine activity (eg, pheochrom o- Day 0 cytom a). It is 100 tim es m ore potent at 1-adrenergic receptors than at 2-adrenergic receptors. Phenoxybenzam ine binds covalently to -adrenergic receptors, interfering with the capacity NE of sym pathom im etic am ines to initiate action at these sites. Phenoxybenzam ine also increases the rate of turnover of norepi- nephrine (N E) owing to increased tyrosine hydroxylase activity, and it increases the am ount of norepinephrine released by each α nerve im pulse owing to blockade of presynaptic 2-adrenergic 2 NE receptors. The net physiologic effect is a decrease in peripheral resistance and increases in heart rate and cardiac output. Postural hypotension may be prominent, related to blockade of compensatory NE responses to upright posture and hypovolem ia. The degree of vasodilation is dependent on the degree of adrenergic vascular tone. NE β1 α2 α1 Vascular smooth muscle cells M ODERATELY SELECTIVE PERIPHERAL 1-ADRENERGIC ANTAGONIST Generic (trade) name First dose, mg Usual daily dose, mg Maximum of action, mg Duration of action Phenoxybenzamine (Dibenzyline) 10 20-40 bid 120 3–4 d FIGURE 7-26 M oderately selective peripheral 1-adrenergic antagonists. Phenoxybenzam ine is prim arily used in Phenoxybenzamine is the only drug in its class. Absorption is variable the m anagem ent of preoperative or inoperative pheochrom ocytom a. Peak blockade occurs in 3 to 4 Efficacy is dependent on the degree of underlying excessive -adrenergic hours. Side effects Mechanisms Nasal congestion -adrenergic receptor blockade Miosis -adrenergic receptor blockade Sedation Unknown W eakness, lassitude Impairment of compensatory vasoconstriction producing orthostatic hypotension Sexual dysfunction -adrenergic receptor blockade Inhibition of ejaculation Tachycardia Uninhibited effects of epinephrine, norepinephrine and direct or reflex sympathetic nerve stimulation on the heart Peripheral Indicates blockade FIGURE 7-28 adrenergic Peripheral adrenergic neuronal blocking agents. Peripheral adrenergic nerve ending neuronal blocking agents are selectively concentrated in the adren- ergic nerve term inal by an active transport m echanism , or “norepi- nephrine pum p” [6,9]. They act by interfering with the release of norepinephrine (NE) from neuronal storage sites in response to nerve NE stimulation and by depleting norepinephrine from nerve endings. Acutely, cardiac output is reduced, caused by dim inished venous return and by blockade of sym pathetic -adrenergic effects on the heart; peripheral resistance is unchanged. Following chronic therapy, peripheral resistance is decreased, along with m odest decreases in heart rate and cardiac output. By adm inistering loading doses of the prototype peripheral adrenergic neuronal blocking agent. The drug patients with severe renal insufficiency, drug excretion is decreased; rapidly leaves the plasma for extravascular storage sites, including dose reduction is required. Guanethidine is elim inated with a plasma Guanadrel is a guanethidine derivative with a short therapeutic half-life of 4 to 8 days, a time course that corresponds with its anti- half-life.

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Although extensive analysis by Braak and Braak has suggested that neurofibrillary changes of Braak and Braak stage I/II in elderly people may represent early stages of AD pathology (68) generic 60mg duloxetine free shipping, this has yet to be proven in studies of sub- TABLE 94 duloxetine 40mg otc. DISEASES WITH TAU-POSITIVE jects who have been subjected to longitudinal cognitive test- NEUROFIBRILLARY LESIONS ing up until the time of death. Coexistence of tau and Argyrophilic grain dementia Corticobasal degeneration amyloid pathologies in some diseases suggests an interaction Diffuse neurofibrillary tangles with calcification between tau and amyloid in mechanisms of brain degenera- Frontotemporal dementia with parkinsonism linked to tion. Chapter 94: Tau Protein and Tauopathy 1341 Ultrastructure of Filamentous Tau normal physiologic conditions (83,84), whereas the neurofi- Lesions brillary lesions in AD accumulate in the neuronal perikarya, axons, and dendrites. In contrast to the axon-specific distri- According to transmission electron microscopic (EM) and bution of tau in normal states, MAP2 has somatodendritic immuno-EM analyses of tau filaments in various neurofi- localization (85,86). Although it is likely that the compart- brillary lesions, the filamentous lesions consist of three types ment specificity of normal tau and MAP2 in neurons may of morphologies. Approximately 95% of the neurofibrillary subserve functional differences such as organization of neu- components in AD NFTs are paired helical filaments ronal polarity and spacing of intermicrotubule distances, or (PHFs), and the rest consists of straight filaments (SFs) (69, other aspects of axonal and somatodendritic MT distribu- 70). PHFs have a helical structure consisting of two ribbon- tion and architecture (87–91), there is no direct evidence like strands that are paired together in filaments that have for these different roles for tau and MAP2. Lower expression a diameter of 8 to 20 nm and a stereotypical periodicity of tau mRNA and less abundant tau protein have been of 80 nm (70,71). In Down syndrome, ALS/PDC, prion observed in astrocytes as well as in oligodendrocytes (92,93), diseases with tangles, dementia with tangles only, Nieman- and this suggests that the formation of glial tau inclusions Pick disease type C, and the Seattle family A FTDP-17 in several neurodegenerative tauopathies results from the kindred with the V337M tau gene mutation, the filamen- aggregation of tau proteins produced in glial cells them- tous tau pathology is composed of fibrils that are ultrastruc- selves. Moreover, PSP and Pick disease show laboratories that tau proteins play a major role in regulating tangles composed of numerous SFs and smaller numbers neuronal MT assembly and stability (94–96). For example, of twisted tau filaments similar to PHFs (63,74). Twisted tau proteins promote the polymerization of tubulin into ribbon-like tau filaments that are morphologically different MTs (97), and tau bound to MTs help stabilize these struc- from AD PHFs and SFs are found in the tangles of the tures in the polymerized state (98). Moreover, developing familial MSTD FTDP-17 syndrome caused byaGtoA neurons treated with antisense oligonucleotides to tau mutation in the intron following exon 10 of the tau gene mRNA to block expression of tau fail to extend axon-like (64), Dutch family 1FTDP-17 syndrome owing to the processes, suggesting that tau protein also functions in, or is P301L mutation in exon 10 of the tau gene (75), and CBD required for, the establishment of neuronal polarity during (76). Unlike AD PHFs, these filaments have an irregular development (99,100). However, mice lacking tau protein periodicity of 90 to 130 nm (64). Tau is likely to phorylated tau proteins, and possess the same tau epitopes play an essential role in the development of neurons and (77–82), although the relative abundance of different even glial cells, but it is also probable that other proteins pathologic tau isoforms may vary in these tauopathies, as such as MAP1A can be upregulated to partially compensate discussed in the following. Currently, there seems to be no for the loss of tau at least early in life, as indicated in the association between ultrastructural diversity and biochemi- preceding tau-knockout mouse study (101,102). Observation of hy- brid filaments suggests a transition from PHF to SF. Expression of Multiple Tau Isoforms As a consequence of alternative mRNA splicing, the single BIOCHEMICAL FEATURES OF TAU tau gene on the long arm of chromosome 17 gives rise to PROTEINS IN NORMAL AND PATHOLOGIC six brain tau proteins that are normally expressed in the CONDITIONS adult human CNS (77,103–105) (Fig. The differ- ences among these six brain tau isoforms result from the Localization and Function of Tau Protein presence of three (3R tau) or four (4R tau) imperfect MT Tau is a low molecular weight component of cytoskeletal binding repeats of 31or 32 amino acids in the carboxy- structures and is known as one of the microtubule-associ- terminal half of each of two sets of these proteins, as well ated proteins (MAPs). Neuronal MAPs consisting of tau as from the presence of inserts of 29 or 58 amino acids or and MAP2 regulate the assembly of microtubules (MTs). The Although tau and MAP2 are thought to have similar func- tandem repeats in the carboxy-terminal half are encoded by tions, intracellular localization of tau largely differs from exons 9, 10, 11, and 12, and the alternative splicing of exon that of MAP2. The mRNAs encoding tau proteins are ex- 10 (E10) results in the generation of E10 4R tau and pressed predominantly in neurons, where these tau proteins E10 3R tau mRNAs and their corresponding 4R and 3R are localized mostly to axons of the CNS and PNS under tau isoforms, respectively. This consecutive repeat region 1342 Neuropsychopharmacology: The Fifth Generation of Progress FIGURE 94. Six human CNS tau iso- forms produced by alternative splicing of thetau gene. Thedifferences among the six isoforms are the number of MT- binding repeat domains (black boxes) and the number of amino-terminal in- serts. The alternatively spliced exons, exons 2 (E2), 3 (E3), and 10 (E10) are indicated with gray boxes, and hatched boxes indicate the inter-repeat se- quences. The recombinant tau proteins run as six bands on SDS-PAGE (left). In each domain, binding affinity to MTs is pro- AD Brains vided by a binding element that consists of 18 amino acids Tau is a phosphoprotein, and tau isolated from the develop- (107), but the remainder of this motif, known as the interre- ing and adult brain is phosphorylated at multiple sites. Indeed, the interrepeat sequence between MT-bind- bands (approximately 60, 64, and 68 kDa) and one minor ing repeats 1and 2, which is included only in 4R tau iso- band (approximately 72 kDa) in SDS-PAGE. Enzymatic forms, has a binding affinity for MTs that is more than dephosphorylation of PHF-tau in vitro using alkaline phos- twofold higher than any MT-binding repeat (108). This phatase changes the electrophoretic mobility of these three may suggests that 4R tau plays a much greater role in regu- bands to generate six bands that are identical to the six tau lating the MT-binding than 3R tau, and it is possible that isoforms extracted from normal human brain after dephos- 3R and 4R tau have different MT-binding sites on MTs. The function of the amino-terminal region remains unset- This suggests that PHF-tau in AD is composed of all six tled, but this region is supposed to affect inter-MT distances tau isoforms that are abnormally phosphorylated. Indeed, by forming a bridge between two adjacent MTs.

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