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WO2010042603A1 - Amyloïde et dépression - Google Patents

Amyloïde et dépression Download PDF

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WO2010042603A1
WO2010042603A1 PCT/US2009/059819 US2009059819W WO2010042603A1 WO 2010042603 A1 WO2010042603 A1 WO 2010042603A1 US 2009059819 W US2009059819 W US 2009059819W WO 2010042603 A1 WO2010042603 A1 WO 2010042603A1
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depression
neuron
layer
layers
cases
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Brent Vogt
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CINGULATE NEURO THERAPEUTICS LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a method of treating a depressive disorder that prevents the accumulation of an amyloid beta protein in the brain.
  • Hippocrates (460-357 BC) was the first to describe melancholia ("black bile”); Aretaeus of Cappadocia (ca. 150 AD) described manic-depression (bipolar disorder), and
  • DSM-IV and ICD-10 Current classification systems (DSM-IV and ICD-10; WHO, 1993, APA, 1994) classify mood disorders into unipolar (major depression and dysthymia) and bipolar (bipolar disorder includes the alternation of depressive and manic, hypomanic, or mixed episodes, and cyclothymia).
  • the clinical picture includes also vegetative and psychomotor disorders, and there is a great overlap with anxiety disorders (mainly with generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social phobia; Ahrens et al., 1995).
  • the current concept of mood disorders includes many conditions previously diagnosed as schizophrenia, personality disorder, or neurosis.
  • 'mood' which refers to the internal tone was chosen today as more suitable in comparison to 'affective,' which refers to the external expression or 'emotion' that is the transient present state. It should be stressed that whereas depression has traditionally been considered a benign episodic disorder, recent observations suggest that many patients are only partial responders to therapy or become chronic. Thus, the presence of structural abnormalities is possible.
  • the Object Loss model refers to traumatic separation from significant objects of attachment, while the Loss of Self-Esteem model suggests depression originates from the narcissistic injury because of the ego's inability to give up unattainable goals.
  • the Cognitive model incorporated negative thinking about self, the environment and the future, while the Learned Helplessness model viewed depression as learned from past situations in which the person was unable to terminate undesirable situations.
  • the Reinforcement model viewed depression as associated with the lack of appropriate rewards and non-contingent rewards.
  • Depression- Vulnerable Network Early efforts to synthesize theories and empirical data suggested that psychological and biological etiological factors converge in deficits in the diencephalic substrates of pleasure and reward (Akiskal and McKinney, 1973). As discussed in the previous chapter, neuroimaging observations also emphasize a pivotal role of sACC. One level of involvement is in the contribution of cingulate cortex to distributed network functions; as opposed to unique intracingulate information processing.
  • the integrative model shown in Figure 25.1 links the central chemistry and physiology of structures that generate mood, episodic memory storage and retrieval, motor response programs and reward mechanisms with behavioral impairments of depression.
  • the amygdala and the cingulate cortex together play a key role in this model, hi this simplified neurobiological model 'mood' derives from the processes in the broader limbic network including the amygdala, insula, ACC and orbitofrontal cortex. Each of these sites is also involved in generating emotion and external affective responses, while the effortful regulation of movement likely implicates area 24' in midcingulate cortex (MCC) and the dorsolateral prefrontal cortex; between these regions it appears that 'affect' is generated at least partially (Phillips et al., 2003a, b).
  • MCC midcingulate cortex
  • the sACC also has direct projections to autonomic brainstem nuclei and is likely responsible for much or all of the final common autonomic output generated in the frontocingulate circuit. The details of this circuitry are considered in Chapter 5.
  • Figure 25.1 provides an overview of part of the network that is involved in depression and the "levels" of organization of the system from gene to cingulate cortex outputs.
  • the short allele of the 5HT transporter (5HTT) is associated with altered serotonin (5HT) uptake and volumetric reductions in the ACC and amygdala (Pezawas et al., 2005).
  • the short allele generates transporter mRNA and transporter protein that is ineffective in transporting 5HT into the cell is reviewed by Caneli and Lesch (2007) in the context of emotion regulation and anxiety.
  • the actions of this ineffective transporter are mediated by the axon terminals of the dorsal raphe nuclei that project throughout much of the rostral limbic system including ACC.
  • Mood may be generated by the aggregate activity in this 5HT-regulated network and forms an endophenotype for depression. Emotion as an acute and internal response to various environmental cues and contexts is generated directly in cingulate cortex and may be modified by mood.
  • One aspect of cingulate-mediated depression etiology could be the disruption of valence-coded sensory information that flows through PCC as discussed in detail in Chapter 13 and the final common pathway of emotional expression is mediated by autonomic activity via sACC and skeletomotor outputs from the cingulate premotor areas.
  • amygdala has been implicated in fear and anxiety and contributes in a profound way to this network function. For this reason the projections of the amygdala are shown in Figure 25.1B and two important points are emphasized.
  • the major amygdala projections terminate in ACC, although there is a small extension in anterior MCC (aMCC).
  • aMCC anterior MCC
  • the greatest termination in ACC is to inner layer I and layer II. Since layer III pyramidal neurons have apical dendrites and tufts in layers I and II, they are likely relevant to this interaction as well and this plays an important part in histopathological hypotheses discussed below and the case review that follows.
  • the present invention relates to a method of treating a depressive disorder comprising inhibiting or preventing the accumulation of an amyloid beta protein in the brain.
  • Figure 25.1 Cingulate morphological substrates of depression.
  • A. Network organization from 5HTT gene to behavioral output.
  • B. Amygdalocingulate connections (Vogt and Pandya, 1987) that support the layer II/IIIab hypothesis
  • C. Plots of cingulate atrophy (dotted line) and correlated atrophy with that in the amygdala (red; Pezawas et al., 2005) plotted onto the medial surface of a control case. The most significant volumetric reduction is shown in black and the subregion borders have arrows.
  • ANS autonomic nervous system
  • AB accessory basal
  • Lat lateral
  • LB laterobasal
  • M medial.
  • FIG.2 Structure of area s24b in two control cases stained with thionin (T) and NeuN (N). Layer Va is densely packed with large neurons and, although layer Vb is relatively neuron spare; note large pyramids in this layer magnified for Case 3. Layer III is particularly thin in subgenual areas.
  • Figure 25.3. Intraneuronal A ⁇ 42 in area s24b of Case 7 at two magnifications (A. and
  • Case 13 is unique among 9 because this individual had both intraneuronal A ⁇ 42 in ACC and diffuse plaques in PCC.
  • the dense deposition on the ventral bank of the cingulate sulcus can be seen at low magnification (dPCC) and it is not matched on the gyral surface where two higher magnification photographs show the composition of a large diffuse plaque (bottom of two photographs) and the architecture of smaller plaques in between the latter and the dorsal bank of the cingulate gyrus (top of two).
  • dPCC low magnification
  • two higher magnification photographs show the composition of a large diffuse plaque (bottom of two photographs) and the architecture of smaller plaques in between the latter and the dorsal bank of the cingulate gyrus (top of two).
  • the large pyramidal neuron that is heavily decorated with granular deposits of A ⁇ 42 at the asterisk suggesting a potential seeding site of diffuse plaques.
  • FIG. 25.6 Comparison of ACC control case thionin (2, 4) with young (B. Case 7) and old (D. Case 9) BD cases including the A ⁇ 42 of which none were in controls. Some A ⁇ 42-positive neurons in Case 7 are emphasized with asterisks and the details shown in Figure 25.4. The second pattern of A ⁇ 42 is shown for Case 9 with diffuse plaques extending throughout layers I-V. Neither BD case appears to have normal cytoarchitecture. Some areas of neuron sparcity are emphasized with arrows.
  • Figure 25.7 Comparison of A ⁇ 42 deposition in ACC and PCC in two BD (9, 10) and two MD (14, 15) cases. The only case with higher ACC plaques is #9 who was 75 at death.
  • FIG.11 Thionin-stained, deep layers of ACC in MD and a control. Greatest overall neuron loss is in layer Vb with no case appearing intact. Layer VI is severely involved in Cases 11, 12, 14 and 15; only Case 13 appears approximately normal. Layer Va is severely involved in Cases 12, 14 and 15 and to a lesser extent in Cases 11 and 13.
  • FIG.12 Thionin-stained sections of dPCC in two control (2, 5) and three BD and MD cases selected a priori as detailed in the text.
  • the arrows are points with greatest overall neuron loss in each layer as assessed at 500X with each cortical strip between the control cases. Extensive laminar neurodegeneration is most pronounced in MD and this subgroup experiences profound losses in layer IV that do not appear in BD.
  • FIG.13 Neuron shrinkage occurs in every case and is most apparent at those sites that have significant neuron loss. Arrows point to examples of neuron shrinkage in each case. Cases 2 and 5 are controls, 7-9 BD, and 12-15 MD. Figure 25.14. Neuron shrinkage and active neuropil in BD. Young (6) and old (9)
  • Receptor distributions of ACC targets that are effective in treating depressive symptoms.
  • a selective vulnerability of neurons in particular layers in vulnerable regions are also important with layer II receiving amygdala afferents and layer V projecting to the striatum and other brainstem motor areas. These layers could be important to mood and internal activation and motor drive that are altered in depression.
  • Neuron shrinkage has been widely reported as occurring in cingulate cortex and these changes could be associated with volumetric changes reported in the functional imaging literature but it is not clear to what extent these changes are related to neuron loss. Changes in neuron size, number and glial proliferation associated with inflammatory changes could all occur simultaneously and are assessed in the present case review.
  • Carriers of the short allele of a functional 5' promoter polymorphism of the 5HTT gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression.
  • morphometric analyses showed reduced gray matter volume in short-allele carriers in the areas 24, a24' and 32 of the ACC and in the amygdala (Pezawas et al., 2005).
  • Figure 25.1C shows the distribution of volumetrically reduced cortex from this very important study (within dotted lines coregistered to a control postmortem case; most significant reductions shown in solid black). This study showed correlations between volumetric changes in the amygdala and cingulate cortex and the two sites with a significant correlation in structural changes are shown in red in the figure and are located mainly in aMCC and pACC.
  • BD patients during the early stages of the disease may show volume changes of the sACC.
  • Reduction in cortex volume was replicated in three of four studies in patients with familial BD (Hajek et al., 2005).
  • Hirayasu et al. (1999) reported a 25% reduction in the volume of the left sACC in patients with familial BD during their first psychotic episode.
  • Kaur et al. (2005) added the finding of a significantly smaller PCC bilaterally.
  • Drevets et al. (1997) reported a higher grey matter reduction of 39% in the same area.
  • Drevets et al. (1997) reported a decreased metabolism in the sACC bilaterally during depression and maybe increased during mania, thus suggesting that the sACC metabolism is state dependent in BD patients. Also, there was a decreased metabolism in the left sACC only in familial BD and familial MD, which could at least partly be explained by a corresponding reduction in cortical volume with magnetic resonance imaging (MRI) with a 39% reduction in mean grey matter volume in same area.
  • MRI magnetic resonance imaging
  • Laminar cortical thicknesses and pyramidal neuron densities were significantly decreased in area p24 and s24 in BD patients.
  • the major changes were in layers III, V, and VI of area s24, whereas patients with major depression were comparable to controls.
  • Ong ⁇ r et al. (2003) state that area 32ac is agranular and provided no supporting histological evidence for this claim, although Brodmann stated it is granular. Indeed, we have shown this area is dysgranular not agranular (Vogt et al., 1995; 2004; Palomero-Gallagher et al., 2008). To the extent that area "32pl" of Ongiir et al. is agranular, they have observed a second division of area 25 rather than a division of area 32. The Ong ⁇ r study did not identify an area 33 and the designation of area 32 as agranular led them to identify part of area 32 as area 10m.
  • Figure 25.2 shows examples of subgenual area 24b (s24b) stained with both thionin and neuron-specific nuclear binding protein (NeuN).
  • This area has a thinner layer III than its dorsal counterpart in pACC and it is not differentiated with only medium-sized pyramids (Palomero-Gallagher et al., 2008a).
  • Layer Va is dense as is true for all cingulate areas, while a neuron-dense layer VI makes differentiation of layer Vb possible; although there are many large neurons in layer Vb itself as shown with the higher magnification in Figure 25.2.
  • Cingulate Tissues Five postmortem cases for control, BD, and MD were used to analyze cingulate cortex.
  • Section thickness and sampling strategies are pivotal to the outcomes. As a rule, published studies use sections 5- ⁇ m to 10- ⁇ m thick. However, the thinner the section is the more difficult it is to visually assess laminar changes in neuron densities. Indeed, below 20 ⁇ m and even at 30- ⁇ m thickness it is difficult to reliably identify laminar architecture in the human cortex. This makes it quite difficult to define precise regions of interest when a layer is the target. If there is a focus of pathology in only one or two layers, a stereology sampling strategy that does not define the region of interest in terms of laminae can easily conclude there is no change in neuron or glial density because what changes have occurred in a single layer are lost in counts of many layers.
  • One-cm-thick blocks were taken from all sACC and dPCC. These blocks, including those from control cases, were all cut at a thickness of 50 ⁇ m to begin a qualitative review of the laminar architecture in samples from each subregion. Interestingly, there are no pictures in the literature showing the laminar changes in neuron density in depression compared with control cases. What does the ACC look like in BD where there is a 41% reduction in glial numbers but no changes in neuron density as reported by Ongur et al. (1998)? The glial analysis in the latter study was performed independent of layers and no photographic documentation was provided.
  • a ⁇ 42 was observed in 9 of 10 depression cases (5 with BD and 4 of 5 with MD; no evidence of it in Case 12). 2. A ⁇ 42 was deposited in two patterns. In the youngest cases A ⁇ 42 was entirely intraneuronal, mainly in large neurons in layer V but also with significant but variable staining in outer layer III and layer II. In older cases, regardless of diagnosis, dense extracellular plaques were in layers I- Va with no evidence of intraneuronal deposition in any layers including layers III and V.
  • Case #13 was a 74 year-old male who had a transitional pattern; i.e., light intraneuronal deposition in ACC and the first signs of diffuse amyloid plaques in PCC. This is an important case as it confirms that these two patterns are topographically dissociable even in the same cases and it shows an approximate age at which the transition to diffuse amyloid plaques occurs. 3) As there was no expression of phosphorylated tau (AT8 antibody) or ⁇ -synuclein, these cases do not represent typical forms of diseases associated with aging such as Alzheimer's and diffuse Lewy body diseases.
  • phosphorylated tau AT8 antibody
  • ⁇ -synuclein these cases do not represent typical forms of diseases associated with aging such as Alzheimer's and diffuse Lewy body diseases.
  • Figure 25.3 presents the laminar distribution of intraneuronal A ⁇ 42 for Case 7 (63 year old; BD).
  • the adjacent thionin-stained section was coregistered to the A ⁇ 42 section and it shows that A ⁇ 42-expressing neurons in layer Vb are large and form aggregates as noted at the asterisks at two levels of magnification (A. and B.).
  • Expression in upper layer III is in small pyramidal neurons that are irregularly dispersed throughout this layer; sometimes extending into layer II but not usually. This suggests that layers II-III and layer V are vulnerable to neuron loss and this can be assessed by comparing thionin-stained sections in control and depression cases as done below for all cases. It is an interesting fact that the youngest Case 6 (32 suicide death) had intraneuronal A ⁇ 42 throughout her entire cingulate cortex
  • Case 13 is of special note because both patterns are present therein and the patient died at age 74. It appears that the early 70s is the key point of transition between the two patterns.
  • Figure 25.5 shows the features of A ⁇ 42 deposition. Light staining in layer V neurons suggests this is a late stage of the intraneuronal pattern.
  • the posterior cingulate gyrus has dispersed-diffuse plaques on the gyral surface and a substantial increase in them on the ventral bank of the cingulate sulcus.
  • a ⁇ 42 had a severe perisomatic build-up of A ⁇ 42 and might be interpreted as seeding diffuse plaques; although other mechanisms are possible and likely based on the low number of these profiles and high number of diffuse plaques observed.
  • the life cycle of A ⁇ 42 appears to involve a reduction in the intraneuronal build-up with seeding and subsequent deposition of diffuse extraneuronal plaques.
  • the diffuse plaques often condense into mature plaques with a central core.
  • a second pattern of A ⁇ 42 staining is the formation of plaques in individuals that died at or over 75 years of age. These plaques were either diffuse in the 70s or also mature and containing a dense core when the patient was in their 80s.
  • Figure 25.6 shows coregistrations of thionin and A ⁇ 42 for Case 9; BD aged 75 at death.
  • the diffuse plaques are labeled throughout layers I- V without preference and it is often in a perivascular location.
  • a comparison with neuron densities is provided by coregistration with adjacent thionin-stained sections to initiate a consideration of the role that A ⁇ 42 may play in neurodegeneration in depression.
  • patches of neuron losses can be seen in layers III and V and these are layers that contain intraneuronal A ⁇ 42 suggesting a possible link to neuron death.
  • layer VI also shows profound neuron losses and no intraneuronal A ⁇ 42 has been observed in this layer suggesting death associated with another mechanism at this stage of the disease.
  • Case 9 in Figure 25.6 has extensive neuron loss in layer H-V; the layers with heavy diffuse plaques. Although this neuron loss could be generated by extracellular A ⁇ 42, there is also extensive neurodegeneration in layer VI where virtually no plaques occur except for a few mature ones. It is possible in this instance that extracellular A ⁇ 42 is toxic to layer VI neurons as they frequently have apical dendrites that project through layer V.
  • the laminar co-distribution of intraneuronal and extracellular plaques provides one or more sources of neuron death. It is also possible that the shift in the pattern of A ⁇ 42 deposition is associated with additional mechanisms of neurodegeneration. According to this model, neuron losses may build progressively as the pattern of A ⁇ 42 shifts.
  • Figure 25.7 provides a comparison of ACC and PCC for the two oldest cases with BD and MD. If one expects that sACC is a diagnostic region for depression as might be concluded from the extensive literature on the subject, the likely hypothesis is that the aggregate density of diffuse and mature plaques would be greatest in ACC as shown for Case 9. Surprisingly this is the only case for which that occurred. Cases 10, 14, and 15 all had richer deposits of plaques in dPCC than in ACC. The possible reason for this is that Case 9 was only 75 at death, while the other three cases were in their eighth decade. This would suggest that plaques in ACC are at a later stage as demonstrated with a higher density of mature/dense core plaques. This is indeed true. In each instance there is very little diffuse plaque in ACC suggesting that in the eighth decade, depressed patients experience a terminal aggregation of A ⁇ 42 into dense core plaques.
  • Case 10 dPCC (Fig. 25.7, low magnification insert) shows an enhanced deposition in the dorsal bank of the cingulate gyrus, suggesting once again as with Case 13, that the earliest diffuse plaque formation has a regional selectivity in PCC.
  • the hypothesis that plaque deposition begins in ACC and progresses to PCC is confirmed by the forms and densities of A ⁇ 42 plaques.
  • Amyloid- ⁇ peptides are critical for neuron viability (Plant et al., 2003) and A ⁇ 42 is made and retained in an insoluble form in the endoplasmic reticulum and it is packaged for secretion in the trans-Golgi network (Greenfield et al., 1999).
  • human cortex that is vulnerable to Alzheimer's disease, i.e., mild cognitive impairment, accumulates intraneuronal A ⁇ 42 (Gouras et al., 2000). It is not yet known why neurons in adult cases of depression sequester intraneuronal A ⁇ 42 as reported here but it may also contribute to neuron death as also shown in Alzheimer's disease (Sheng et al., 1998; Parvathy et al., 2001).
  • a ⁇ 42 deposition can be used as landmarks to assess laminar patterns in neurodegeneration; even though they are not diagnostic of a particular clinical subgroup. Indeed, their presence in both BD and MD at similar ages suggests an underlying age-linked phenomenon that may indicate common stages of disease progression.
  • the keys to this progression include a full cingulate deposition of intraneuronal A ⁇ 42 during early adulthood which continues until the neurons are quite dark with the A ⁇ 42 antibody reaction.
  • the first extracellular, diffuse plaques appear in sACC and the intraneuronal deposits lighten/are reduced. Aggressive extrusion of A ⁇ 42 by some pyramidal neurons could lead to seeding of diffuse plaques. Indeed, it has been proposed that GMl ganglioside-bound A ⁇ may initiate A ⁇ aggregation by seeding fibril formation and could lead to plaque deposition (Hayashi et al., 2004). As diffuse plaques build up in dorsal PCC those in ACC are forming mature plaques with cores and the diffuse plaques disappear. During the eighth decade the entire cingulate cortex is damaged to some extent by A ⁇ 42 deposition.
  • transition to diffuse plaques includes lightening of intraneuronal expression and aggressive extrusion contribute to seeding of diffuse plaques in sulcal cortex
  • amyloid- ⁇ peptides in AD and the documented role of A ⁇ 42 in disease etiology, provide important strategies for removing these peptides in depression and possibly for interrupting some or most of the neuron death.
  • the amyloid hypothesis is well established as an etiology of neurodegeneration in AD and strategies for clearing or reducing amyloid-mediated neurotoxicity have been proposed (Hardy and Selkoe, 2002). As noted by these authors, the build-up of amyloid- ⁇ peptides could be reduced by blocking the beta- and gamma-secretases that are responsible for generating the long amyloid- ⁇ peptides such as A ⁇ 42.
  • ⁇ -site APP cleaving enzyme 1 is shown in mice deficient in this enzyme that have no A ⁇ 42 expression (Luo et al, 2001)
  • Another approach to blocking amyloid- ⁇ peptide buildup is to reduce cholesterol levels either through diet and/or with cholesterol lowering drugs.
  • Chronic use of cholesterol lowering drugs such as the statins has been associated with a lower incidence of AD (Wolozin et al., 2000) and high cholesterol diets increase amyloid- ⁇ pathology in experimental animals (Sparks et al., 2002).
  • Direct removal of amyloid- ⁇ peptides has been an important strategy as shown in rodents but there has been no success yet in human vaccination trials.
  • huparizine A stimulates ⁇ APP release and diminishes amyloid- ⁇ generation (Peng et al., 2006).
  • Huparizine A alters APP processing in human neuroblastoma SK-N-SH cells via protein kinase C and MAP kinase pathways (Peng et al., 2007).
  • acetylcholinesterase inhibitors including huparizine A, may be used to shift enzymatic activity toward the non-amyloidogenic pathway to reduce the level of amyloid- ⁇ peptides expressed in depression.
  • Neuron densities are considered in the context of changes in the normal laminar architecture in 50 ⁇ m-thick sections so that changes can be linked to laminar alterations of A ⁇ 42 deposition and neuron shrinkage.
  • the selection process during photography is meant to reflect the common status of a cortical area and is not biased toward the most or least neuron loss and a wide field of view in each photograph assures a good sample from which to draw conclusions, hi the past when drawings of cortical strips were used to assess neuron densities, the perikarya were drawn in three strips that were 160 ⁇ m in width (Vogt et al. ; 1990) providing a narrow sampling window when compared with current digital imaging methods.
  • the field of analysis can reach more than ten times the earlier limits at the current 1,200-2,000 ⁇ m in width.
  • Neurodegeneration is also assessed in terms of A ⁇ 42 deposition with coregistration to thionin-stained sections. This does not mean we consider all or even part of neuron loss a matter of A ⁇ 42 toxicity, although this is a new hypothesis generated by the present sample. Case 12 had no evidence of A ⁇ 42 immunoreactivity yet there was clear evidence of neuron loss as discussed below. Since this patient died at the age of 68, they may have been at a transition point that involved a loss of intraneuronal A ⁇ 42 and a failure or delay in plaque formation. Alternatively, no A ⁇ 42 was ever present in this case and neurodegeneration must be explained by an alternative route. Even when this peptide is present, multiple mechanisms of neuron losses are possible. An overview of cytoarchitectural changes in two BD cases were shown in relation to
  • Case 6 32 year old
  • Figure 25.8 emphasizes some sites of neuron loss with arrows pointing in layer II to two patches of shrunken neurons above which are areas of reduced neuron densities.
  • layer III two large circles emphasize neuron shrinkage and possibly some neuron loss. It appears that neurodegeneration is in an early stage in Case 6 when compared to the other cases. Indeed, Case 7 has somewhat more neuron loss in layers II and III, and cases 8 and 9 have profound loss throughout all of layers II and III. Finally, case 10 has significant neuron shrinkage but overall neuron densities in layers II-III appear closer to that in Case 6.
  • Figure 25.9 emphasizes the following observations. Although all neurons do not shrink and there is no layer with complete neuron loss, there are clearly sites of both in most cases. Case 8 had severe neuron loss in layers II and upper III and the deep layers are more preserved and have only some points of neuron sparcity in layer VL As a rule in these cases, layer Va is least affected with some points of neuron shrinkage but less patent neuron loss. Once again, points of neuron shrinkage increase with age, but the association is not tight as Case 7 also experiences significant shrinkage and neuron loss in the deep layers.
  • Table 24.3 summarizes the laminar changes in neuron densities based on qualitative assessment expressed with a 0-4+ scale. No 4+ values were observed in which severe neuron loss equates to essentially no neurons in a layer (i.e., 76-100% loss). The numbers provide an estimate of neuron loss and the columns and rows are summed to provide perspective on cases and layers with greatest loss. Obviously there are many volumetric issues that must be resolved with a rigorous counting strategy. The shaded values are also meant to draw the eye to the higher levels of neuron loss (about 51-75% loss).
  • PCC has been implicated in depression with a reduction in glucose metabolism observed in unipolar patients that were antidepressant drug responsive (Mayberg et al., 2000; Chapter 24) and volumetric reductions in PCC have been reported early in BD (Kaur et al., 2005). Deposition of A ⁇ 42 shown here also includes PCC, although at a lower level than in sACC in most cases and neuron loss also occurs in PCC.
  • Figure 25.12 shows dorsal area 23b in control (young #2 and old #5), BD and MD cases.
  • neuron densities in each layer were assessed at 500X and the two controls were placed on either side of each strip from a depression case.
  • a single arrow was placed at that point in any layer with observable neuron loss to emphasize points of greatest loss; realizing that in most instances neuron losses are widely distributed beyond these points; indeed, losses are scattered throughout all layers that received an arrow.
  • the 6 cases were selected for the figure based on changes in area s24b; i.e., they were selected on a priori not selected after the analysis shown in Table 25.3 and before photographs were taken or analyzed. The sample selection was based on the following observations.
  • BD Case 6 was the youngest age at death and had least neuron losses in s24b; Case 7 had greatest losses in layers II and III; Case 9 had greatest losses in layer Vb; MD Case 11 was the youngest age at death and had lowest overall losses in area s24b; Case 12 had greatest losses in layers II and V, while Case 15 had greatest losses in layers II, V, and VI and was the oldest of all cases at death.
  • Figure 25.12 shows that losses in Case 6 were mainly in layers II and Vb. Since this is the youngest (suicide) case at death, this is the greatest loss in these layers that might be expected. Interestingly, it is greater than that observed in area s24b; compare this case in Figure 25.12 with Figure 25.8 #6.
  • Case 7 had the greatest overall neuron losses in layers II, Illab, V and VI; however, also reflecting a greater overall degeneration than noted in area s24b.
  • Case 9 had greatest losses in layers II-IIIab and VI with relatively preserved layers in between. Interestingly, in area s24b, the density of neurons in layers II and IIIab were lower than in PCC.
  • neuron loss was greater in dPCC than in s ACC; rather a surprising finding for a disease that supposedly impacts subgenual cingulate cortex to the greatest degree. It is interesting to note that layer IV of dPCC in BD appears to be essentially intact. Finally, in all instances where there are significant neuron losses and there is a commensurate shrinkage of the remaining neurons. In other words, neuron shrinkage is not an independent and unique finding in either category of clinical depression. It is striking that every layer in dPCC in every case of MD experiences substantial neuron loss; including layer IV. This is quite different from BD. The youngest MD case at death had limited overall neuron losses in area s24b, while pronounced changes in area d23 were in all layers.
  • neuron loss in MD are similar to those for BD in that losses are greatest overall in dorsal posterior than sACC.
  • neuron densities in dPCC can be used to differentiate BD and MD with the latter experiencing the earliest and most extensive neurodegeneration that includes layer IV.
  • One way to provide a diagnostic perspective is to look at overall neurodegeneration and then consider layer IV. If layer IV is substantially impaired and there is an overall laminar reduction in neuron densities, the case is likely one ofMD.
  • Neuron Shrinkage is to look at overall neurodegeneration and then consider layer IV. If layer IV is substantially impaired and there is an overall laminar reduction in neuron densities, the case is likely one ofMD.
  • Neuron shrinkage has been reported in MD with an 18% reduction in layer VI and a similar trend in layer V, but no changes were observed in BD (Cotter et al., 2001). Chana et al. (2003) observed reductions in somal sizes in BD (-16%) and MD (-9%) in area 24c in the dorsal cingulate sulcus. In contrast, Benes et al. (2000) found no changes in neuron sizes in BD. To the extent that neuron shrinkage is associated with neurodegeneration and there is an age-linked progression in this process; it might be expected that differences in patient ages would influence these interrelated events.
  • Figure 25.14 compares layers II-III and Va in two cases of BD with a control that has an intermediate age between the two depression cases. Layer II in both cases has significant neuron loss and shrinkage, while that in the older Case 9 has substantially more shrinkage in layers III and V. It is possible the process is a progressive one with age.
  • Inflammation may not be a secondary component of neurodegeneration in AD and Rogers et al. (1996) suggested clinical trials of conventional anti-inflammatory medications could slow the onset and progression of AD.
  • An increase in intracellular adhesion molecule- 1 expression was reported for area 24 in depression suggesting an inflammatory response in this disorder as well (Thomas et al., 2004) and the present study showed sites of active neuropil. In these sites there is a buildup in the numbers of glial cells and neuronal shrinkage suggesting there is a link in the inflammatory site between glial proliferation and neurodegeneration.
  • the sACC may be particularly responsive to inflammatory reactions due to its location near to the nasal sinuses and afferent nerves from the olfactory tract.
  • Amygdala- ACC interactions via layer II Amygdala- ACC interactions via layer II:
  • the amygdala has been implicated in fear and anxiety and may contribute in a profound way to the functions of ACC as discussed above in relation to Figure 25.1B.
  • Individuals with a 5HTT polymorphism have enhanced fear responses in the amygdala compared to subjects homozygous for the long 5HTT allele (Hariri et al., 2002).
  • electrical stimulation of areas 25 and 32 in the rat excite neurons in the lateral nucleus of the amygdala and this stimulation blocks neuronal plasticity in the amygdala associated with affective conditioning (Rosenkranz et al., 2003).
  • Chapter 9 reviews the reciprocal functional interactions between the ACC and amygdala.
  • Ramon y Cajal (1922) described large star cells in layer II of entorhinal cortex that had extensive dendritic ramifications throughout layer I as is true of the extraverted pyramidal neurons.
  • a relay from layer II to deeper layers has been proposed in neocortex (Thompson and others, 2002) and may also be the case for ACC.
  • Layer III provides the primary outflow to other cortical areas including dorsolateral prefrontal, orbitofrontal, rostral superior temporal sulcal cortex and ventral PCC (Vogt and Pandya, 1987).
  • the relative importance of amygdala afferents in sACC and the layer II projection to layer III is likely to be much greater than is the case for pACC where layer III is more expanded and the relative significance of amygdala input is reduced.
  • Neurodegeneration in Layer V Impact of Subcortical Motor Systems: Although early ACC stroke cases associated with akinetic mutism were large (Barris and Schuman, 1953), the view that ACC mediates motor activation including speech has been confirmed with human functional imaging and experimental animal studies and its general relevance to the role of ACC in depression cannot be overstated. Indeed, the ACC and MCC have the most extensive projections into autonomic and skeletomotor systems of any cortical region and these are reviewed in Chapter 15 as is he circuit basis for the cingulate vocalization function. Since many of the neurons in layer V project to motor systems, neuron loss in layer V of ACC and MCC, particularly in MD, are expected to inactivate or dysregulate motor output.
  • the syndrome does not result in an inability to move but rather in an overall paucity of volitional movement and speech.
  • this figure shows the hierarchical clustering analyses of 15 neurotransmitter receptors for postmortem cases with and without these particular four receptors in the analysis.
  • the red highlight shows that with the four receptors sACC area 25 co-segregates with aMCC areas (All Ligands), while without them (Minus 4) it co-segregates with the ACC.
  • aMCC areas All Ligands
  • Minus 4 it co-segregates with the ACC.
  • 5HTergic and anticonvulsant drugs are presently the primary target of treatment for depressed patients, we consider the 5HT1A and GABA A receptors in detail here.
  • GABAergic System This latter finding must eventually meet with the problem of neurodegeneration in the superficial layers and might be explained by up-regulation of receptors as adjacent neurons degenerate. Indeed, it may be critical to determine what the threshold number of remaining neurons needs to be to provide therapeutic sites for drug actions rather than assessing the level of neuron loss per se.
  • Recurrent depression may be associated with decreased GABA levels in ACC (Bhagwager et al., 2007) and two months of SSRI treatment returns it to normal levels in occipital cortex (Sanacora et al., 2002). It is well known that sad memories are stored in s ACC (Chapters 1, 11, 14, 24, 26) and patients with BD have a reduced activation of ACC to facial emotions (Blumberg et al.,2005). The latter study also showed that treatment with anticonvulsants such as GABApentin and valproic acid partially reverse the redced functional ACC activity in BD.
  • GABA B receptors have a presynaptic localization and can regulate GABA release, ligands for this receptor may have efficacy in treating depression.
  • the GABA A receptor is a ligand-gated chloride channel while, GABA B receptors control potassium or calcium conductances via a G-preotin-mediated reduction in adenylyl cyclase activity (review, Pile and Nowak, 2005).
  • the former tend to be posynaptic, while the latter are mostly presynaptic and regulate GABA release.
  • Preclinical studies are underway to develop GABAergic compounds that have antidepressant actions, however, a critical issue in the human brain is that these two receptors have profoundly different distributions in ACC. As shown in Figure 25.15, highest GABA A binding is in sACC where there also is lowest GABA B binding (Chapter 2).
  • GABA B binding is very high in p ACC.
  • One of the difficulties in identifying therapeutic drugs, therefore, is the dissociation of these receptors in ACC rather than their coexpression in particular stuctures as generally assumed in experimental animal studies.
  • the efficacy of drugs acting at GABA A receptors and benzodiazepine regulatory binding actions are likely associated with sACC and could occur in isolation of GABAB actions.
  • each compound with an action on the GABAergic system could produce different levels of relief for symaptoms of depression and anxiety and there is little reason to expect an exact overlap of symptom relief when targeting the ACC.
  • Layers II and III are the prominent sites of SSRI actions based on receptor localization and greatest neuron loss early in BD is in layers II and III. Neurons in layers II- III also have intracellular deposits of A ⁇ 42 early in depression. These observations together suggest that impaired neuronal function in layers II and III may be improved to some extent by SSRI therapy. However, neurodegeneration appears to progress in depression and is not limited to these two layers. In MD, the greatest neuron loss appears to be in layer V and progressive destruction of layer V substantially deafferents subcortical motor systems. One of the reasons that SSRI therapies might loose their efficacy is the progressive and nonreversible loss of neurons throughout sACC and even in PCC.
  • PCC PCC
  • d v posterior cingulate cortex
  • dorsal, ventral parts rCBF regional cerebral blood flow
  • Ballantine HT Cassidy WI, Flannagan NB, Marino R Jr (1967) Stereotaxic anterior cingulotomy for neuropsychiatric illness and intractable pain. J Neurosurg 26:488-495. Barris RW, Schuman HR (1953) Bilateral anterior cingulate gyrus lesions. Neurology 3:44- 52.
  • Schizophrenia In Handbook of Clinical Psychoneuroendocrinology( ⁇ d, Loosen, P.) John Wiley and Sons, New York, pp. 160-194.
  • Alzheimer's disease A ⁇ vaccine reduces central nervous system A ⁇ levels in a non-human primate, the Caribbean vervet. Am J Pathol 165:283-297.
  • Huperazine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695. Neuroscience 150:386-395.
  • Pratt GD Bowery NG (1993) Repeated administration of desipramine and a GABAB receptor antagonist, CGP 36742, discretely up-regulates GABAB receptor binding sites in rat frontal cortex. Br J Pharmacol 110:724-735.
  • Thomas AJ, Davis S, Ferrier IN, Kalaria RN, O'Brien JT (2004) Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate cortex in bipolar disorder. Biol Psychiatry, 55:652-5. Thomas AJ, Ferrier IN, Kalaria RN, Davis S, O'Brien JT (2002) Cell adhesion molecule expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in major depression in the elderly. Br J Psychiatry, 181 : 129-34.
  • Todtenkopf MS Vincent SL, Benes FM (2005) A cross-study meta-analysis and three- dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain. Schizophr Res, 73:79-89.
  • Uranova NA Vostrikov VM, Orlovskaya DD, Rachmanova VI (2004) Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res, 67:269-75.
  • Vogt BA (2005) Pain and emotion interactions in subregions of the cingulate gyrus Nat Rev Neurosci, 6:533-44. Vogt BA 5 Hof PR, Vogt, LJ (2004) Cingulate Gyras. In: Paxinos, G. and Mai, JK, eds, The Human Nervous System, second edition, Academic Press, Chapter 24, pp. 915-949.
  • Vogt BA Nimchinsky EA 3 Vogt LJ, Hof PR (1995) Human cingulate cortex: surface features, flat maps, and cytoarchitecture.J Comp Neurol, 359:490-506.

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Abstract

La présente invention concerne une méthode de traitement d'un trouble dépressif par inhibition ou prévention de l'accumulation d'une protéine bêta-amyloïde dans le cerveau. En outre, cette invention concerne une méthode permettant d'inhiber ou empêcher l'accumulation d'une protéine bêta-amyloïde par l'administration d'un ou plusieurs composés parmi un inhibiteur de bêta-secrétase, un inhibiteur de gamma-secrétase, un médicament abaissant la teneur en cholestérol, un agoniste muscarinique, un inhibiteur d'anticholinestérase, un médicament anti-inflammatoire, un antidépresseur, un inhibiteur de réabsorption de sérotonine sélectif, un agoniste de sérotonine, un agoniste d'acide gamma-aminobutyrique, un anticonvulsivant ou un vaccin.
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US10323027B2 (en) 2015-06-26 2019-06-18 Takeda Pharmaceutical Company Limited 2,3-dihydro-4H-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor
US10457670B2 (en) 2014-04-23 2019-10-29 Takeda Pharmaceutical Company Limited Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease
US10548899B2 (en) 2015-10-20 2020-02-04 Takeda Pharmaceutical Company Limited Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

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US20060135403A1 (en) * 2002-12-24 2006-06-22 Francine Gervais Therapeutic formulations for the treatment of beta-amyloid related diseases

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US20060135403A1 (en) * 2002-12-24 2006-06-22 Francine Gervais Therapeutic formulations for the treatment of beta-amyloid related diseases

Cited By (6)

* Cited by examiner, † Cited by third party
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US10457670B2 (en) 2014-04-23 2019-10-29 Takeda Pharmaceutical Company Limited Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease
US10865200B2 (en) 2014-04-23 2020-12-15 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
US10323027B2 (en) 2015-06-26 2019-06-18 Takeda Pharmaceutical Company Limited 2,3-dihydro-4H-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor
US10428056B2 (en) 2015-06-26 2019-10-01 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10899752B2 (en) 2015-06-26 2021-01-26 Takeda Pharmaceutical Company Limited 2,3-dihydro-4H-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor
US10548899B2 (en) 2015-10-20 2020-02-04 Takeda Pharmaceutical Company Limited Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

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