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Alzheimer's disease (AD)-related cytoskeletal changes in the supratrochlear (RD ST) and in the interfascicular (RD IF) subnuclei of the dorsal raphe nucleus (100 m m PEG sections) ( a , c , e : Gallyas±silver iodide staining. b , d , f : AT8-immunostaining). Arrows indicate AD-related cytoskeletal changes in the RD ST. Arrowheads point to AD-related cytoskeletal changes in the RD IF. Framed areas in e and f are shown in higher magni®cation in Figure 7 a , b . Scale bar in a also applies to b ± f . For topographical orientation see Figure 3 a . mlf , medial longitudinal fascicle. Initial degree of Gallyas-positive ( a ) and AT8-immunoreactive ( b ) cytoskeletal pathology in the RD ST and RD IF in cortical NFT/NT- stage I (case 2, Table 1). Marked Gallyas-positive ( c ) and AT8-immunoreactive ( d ) cytoskeletal changes in the RD ST and RD IF in a representative case of cortical NFT/NT-stage III (case 11, Table 1). Severe Gallyas-positive ( e ) and AT8-immunoreactive ( f ) cytoskeletal changes are seen in the RD ST and RD IF in cases at the cortical NFT/NT-stage V (case 24, Table 1).
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The cross-sectional analyses currently available show that the Alzheimer's disease (AD)-related cytoskeletal alterations within the human brain affect variously susceptible areas of the cerebral cortex in a uniform sequence with very little interpatient variability. This sequence has been divided for research and comparative purposes into six stage...
Contexts in source publication
Context 1
... these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4a,c,e; Figure 5a,c,e). The severity of the neuro®brillary changes is, indepen- dently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4a,c,e; Figure 5a,c,e; Table 1). ...
Context 2
... distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4a,c,e; Figure 5a,c,e). The severity of the neuro®brillary changes is, indepen- dently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4a,c,e; Figure 5a,c,e; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends sig- ni®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). ...
Context 3
... all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4a; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4a; Figure 6; Table 1). ...
Context 4
... all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4a; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4a; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs ( Figure 6; Table 1). ...
Context 5
... neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II ( Figure 4c; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5a; Figure 6; Table 1). ...
Context 6
... RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs ( Figure 4e; Figure 6; Figure 7a; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5c; Figure 6; Table 1). ...
Context 7
... is the case with the argyrophilic AD-related cytoske- letal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4b,d,f; Figure 5b,d; Figure 7b; Table 1). As with the AD-related neuro®bril- lary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5f; Table 1). ...
Context 8
... distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4b,d,f; Figure 5b,d,f). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). ...
Context 9
... severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immuno- reactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4a±f; Figure 5a±d; Table 2). ...
Context 10
... stage I, the AT8-immunopositive structures con- sistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4b; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). ...
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... severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4c±f; Figure 5a±d; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. ...
Context 12
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 13
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 14
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 15
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 16
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 17
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 18
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 19
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 20
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 21
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
Context 22
... become involved early on ± is on the rise ( Figure 1; Table 1). In these ®nal stages, isolated neuro®brillary lesions also are seen in the caudal raphe nuclei (Table 1). The distribution of the NFTs/NTs is nearly bilaterally symmetrical in all of the affected nuclei of the raphe system in all of the stages (Figure 4 a , c , e ; Figure 5 a , c , e ). The severity of the neuro®brillary changes is, independently of the level of staging from I±VI, highest in the RD, followed by the RC, RL, and the caudal raphe nuclei, the latter of which are only mildly affected (Figure 4 a , c , e ; Figure 5 a , c , e ; Table 1). In all of the nuclei studied, the severity of the neuro®brillary pathology depends signi®cantly upon the level of staging from I±VI and varies only slightly for all nuclei within a given stage (Tables 1,2). The trend analyses show that the association between the severity of the neuro®brillary lesions and the staging levels I±VI is characterized by a linear trend (Table 2). In all of the cases investigated, the RD ST, RD IF, and RD CC display the AD-related cytoskeletal lesions (Figure 4 a ; Figure 6; Table 1). In the majority of cases, the extent of the damage to these three subnuclei is still light (Figure 4 a ; Figure 6; Table 1). At these earliest stages, the RD CL, RC, RL, and the caudal raphe nuclei are still completely untouched by NFTs/NTs (Figure 6; Table 1). The neuro®brillary pathology in the RD ST, RD IF, and RD CC is now more pronounced than in stages I and II (Figure 4 c ; Figure 6; Table 1). The lesions consistently appear in the RD CL of the dorsal raphe nucleus, in both subnuclei of the central raphe nucleus (RC A and RC P), and in the RL (Figure 5 a ; Figure 6; Table 1). The severity, however, of the intraneuronal damage in these four nuclei is for the time being relatively light (Figure 5 a ; Figure 6; Table 1). The caudal raphe nuclei remain more or less intact (Table 1). The RD ST, RD IF, and RD CC are literally strewn with NFTs/NTs (Figure 4 e ; Figure 6; Figure 7 a ; Table 1). In the RD CL, in both of the subnuclei of the central raphe nucleus (RC A, RC P), and in the RL the lesions are now more pronounced than in the previous stages III and IV (Figure 5 c ; Figure 6; Table 1). In the ®nal two stages, the neuro®brillary pathology also is routinely demonstrable in the caudal raphe nuclei. These lesions appear solely within the con®nes of the RMG and ROB and occur infrequently in both nuclei (Figure 5 e ; Table 1). As is the case with the argyrophilic AD-related cytoskeletal lesions, there exist ± independently of the level of staging from I±VI ± distinct differences among the nuclei of the raphe system regarding the density of neuronal perikarya and cellular processes that react immunoposi- tively with the antibody AT8 (Table 1). The severity of the AT8-immunoreactive cytoskeletal pathology is highest in the dorsal raphe subnuclei, followed by the central raphe subnuclei and the RL (Figure 4 b , d , f ; Figure 5 b , d ; Figure 7 b ; Table 1). As with the AD-related neuro®brillary material, the caudal raphe nuclei, of all the nuclei in the human raphe system, register the lowest density of AT8-immunopositive nerve cell somata and cellular processes (Figure 5 f ; Table 1). The distribution of the AT8-immunoreative material in the affected raphe nuclei is bilaterally symmetrical in every stage (Figure 4 b , d , f ; Figure 5 b , d , f ). The severity of the AT8-immunoreactive cytoskeletal pathology varied only slightly from one individual to another, similarly to that of the NFTs/NTs within a given stage in one and the same nucleus (Table 1). The density of the AT8-immunoreactive material increased linearly in all of the nuclei investigated with the growing severity of the AD-related neuro®brillary lesions ± and this in correlation with stages I±VI of the cortical neuro®brillary lesions (Figure 4 a ± f ; Figure 5 a ± d ; Table 2). In stage I, the AT8-immunopositive structures consistently appear in the RD ST, RD IF, and RD CC of the dorsal raphe nucleus (Figure 4 b ; Table 1). In stage II, the RD CL of the dorsal raphe nucleus, the two subnuclei of the central raphe nucleus (RC A and RC P), and the RL routinely show the presence of the immunoreactive material (Table 1). The severity of the immunoreactive cytoskeletal pathology is clearly higher in the dorsal raphe subnuclei in stage II than in the central raphe nuclei and RL (Table 1). With respect to the density of the AT8-immunopositive structures in stages III±VI, the same graduated difference ± as in the case of the AD- related NFTs/NTs ± can be detected between the dorsal raphe subnuclei, on the one hand, and the central raphe subnuclei and the RL, on the other (Figure 4 c ± f ; Figure 5 a ± d ; Table 1). The situation in the caudal raphe nuclei also resembles that of the AD-related neuro®brillary lesions in that their immunoreactive neuronal somata and cellular processes are the last to become involved within the raphe system. This immunoreactive material consistently appears in the caudal raphe nuclei for the ®rst time in stage IV. Moreover, it is con®ned solely to the RMG and ROB. (Figure 5 f ; Table 1). The oral raphe nuclei constitute the source of the ascending serotonergic system projecting to numerous cortical and subcortical regions of the forebrain [4,56]. This system is crucial to the regulation of waking and sleeping patterns as well as sleep architectonics. Furthermore, it plays a signi®cant role in modulating a person's emotional wellbeing and emotional self-control [4,28,49]. Dysfunctions within this system have ...
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... 7. Alzheimer's disease (AD)-related cytoskeletal changes in the supratrochlear and interfascicular subnuclei of the dorsal raphe nucleus ( a ) Gallyas±silver-iodide staining. ( b ) AT8-immunostaining). For orientation see framed areas in Figure 4 e , f ). Inset in a : Gallyas-positive NFT shown at higher magni®cation.
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Background: Tau pathology is characterized by hyperphosphorylation of the microtubule-associated protein tau, which leads to aggregated tau in neurons and glial cells, and characterizes a group of neurodegenerative diseases termed tauopathies. Granulovacuolar degeneration (GVD) is a neurodegenerative change that has been shown to be associated with...
Citations
... As suggested in the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD), it is reasonable to hypothesize that the progression of SCA2 may traverse the brain in a stepwise manner from one anatomical region to the next [122][123][124]. Neurodegeneration in SCA2 has been proposed to occur in anatomically interconnected brain areas, following the neuronal fibers outlined by tracing studies in non-human primates [122][123][124][125]. ...
A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.
... The IC retains its sensitivity to growth and plasticity factors throughout life (not just during neurodevelopment) and is selectively vulnerable to the early neurodegenerative processes in AD [212,219]. NFTs are found across brainstem nuclei in AD [122,220], including in the LC, SN, dorsal raphe nucleus (DRN) and basal forebrain in post mortem samples of patients with early-stage AD and MCI [221][222][223][224][225][226][227]. Critically, IC pathology appears before that of other AD-associated brain regions; the LC shows evidence of NFTs in the absence of Aβ ten years before the onset of cognitive changes [123,[228][229][230][231]. The same is true for the DRN, where lesions were observed in all Braak stage I (BB I) patients, and even in 20% of BB 0 individuals [223,232]. ...
... NFTs are found across brainstem nuclei in AD [122,220], including in the LC, SN, dorsal raphe nucleus (DRN) and basal forebrain in post mortem samples of patients with early-stage AD and MCI [221][222][223][224][225][226][227]. Critically, IC pathology appears before that of other AD-associated brain regions; the LC shows evidence of NFTs in the absence of Aβ ten years before the onset of cognitive changes [123,[228][229][230][231]. The same is true for the DRN, where lesions were observed in all Braak stage I (BB I) patients, and even in 20% of BB 0 individuals [223,232]. ...
... A greater number of NFTs in the LC was associated with lower cognitive (Mini-Mental State Exam, MMSE) scores, indicating more advanced degeneration [224]. DRN pathology and serotonergic denervation of the cortex also correlated with behavioural changes in patients, such as altered emotionality and psychosis [223,240,241], further linking IC damage to the precognitive symptoms of AD. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson’s disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, ‘the isodendritic core’, which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.
... IdC nuclei comprise some of the earliest known sites of tauopathy in Alzheimer's disease (AD), the leading cause of dementia worldwide. Tauopathy is evident in the IdC decades before cognitive decline, and prior to degeneration of cortical regions including entorhinal cortex, as revealed by histopathological [8][9][10][11][12][13][14][15][16][17] and neuroimaging studies 9,18-27 . Braak staging describes pretangle stages a-c, characterized by IdC tauopathy, prior to the stage I neurofibrillary tangle formation 12 . ...
The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout the brain’s white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.
... Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly individuals, characterized by progressive dementia and neurodegeneration. The neurodegeneration in AD is thought to start with the loss of synaptic integrity in the forebrain and the subsequent loss of various neuronal populations, including the cholinergic (Ach) systems in the basal forebrain and monoaminergic (MAergic) systems in the brainstem [1][2][3][4]. The combined findings of current studies indicate that the production of β-amyloid (Aβ) and subsequent formation of senile plaques/Aβ deposits are believed to be the early pathogenic event in AD [5]. ...
Alzheimer’s disease (AD) is characterized by a loss of neurons in the cortex and subcortical regions. Previously, we showed that the progressive degeneration of subcortical monoaminergic (MAergic) neurons seen in human AD is recapitulated in the APPswe/PS1ΔE9 (APP/PS) transgenic mouse model. Because degeneration of cholinergic (Ach) neurons is also a prominent feature of AD, we examined the integrity of the Ach system in the APP/PS model. The overall density of Ach fibers is reduced in APP/PS1 mice at 12 and 18 months of age but not at 4 months of age. Analysis of basal forebrain Ach neurons shows no loss of Ach neurons in the APP/PS model. Thus, since MAergic systems show overt cell loss at 18 months of age, the Ach system is less vulnerable to neurodegeneration in the APP/PS1 model. We also examined whether the proximity to Aβ deposition affected the degeneration of Ach and 5-HT afferents. We found that the areas closer to the edges of compact Aβ deposits exhibit a more severe loss of afferents than the areas that are more distal to Aβ deposits. Collectively, the results indicate that the APP/PS model recapitulates the degeneration of multiple subcortical neurotransmitter systems, including the Ach system. In addition, the results indicate that Aβ deposits cause global as well as local toxicity to subcortical afferents.
... 17 The DRN has been identified as one of the key subcortical regions that shows tau-related cytoskeletal impairments and NFT pathology at these preclinical stages. 13,15 Our data suggest that the presence of pathological tau in 5-HT neurons in the DRN is sufficient to induce anxiety, suggesting a potential mechanism for the onset of early-stage NPS. Importantly, DRN 5-HT neurons project to a variety of postsynaptic regions that modulate anxiety-like behavior and anxiety states, including but not limited to the basal 32 and extended amygdala 33 while amygdala is among the earlier regions to exhibit tau deposition in AD. 34,35 Future studies focused on the effect of tau pathology on DRN-amygdala circuits will offer further insight into anxiety states exacerbated earlier in the disease progress. ...
... Damage to the monoamine-producing nuclei, including dorsal raphe, is evident pathologically early in AD [3]. Clinical pathologic correlations consistently link NPS with dorsal raphe degeneration [4][5][6][7][8][9][10][11]. Available (modestly) effective therapies for psychosis and agitation are medications that target the dopamine and serotonin systems, such as atypical antipsychotics, SSRIs, or psychostimulants [3]. ...
... Damage to the monoamine-producing nuclei, including dorsal raphe, is evident pathologically early in AD [3]. Clinical pathologic correlations consistently link NPS with dorsal raphe degeneration [4][5][6][7][8][9][10][11]. Available (modestly) effective therapies for psychosis and agitation are medications that target the dopamine and serotonin systems, such as atypical antipsychotics, SSRIs, or psychostimulants [3]. ...
Agitation is one of the most eminent characteristics of neuropsychiatric symptoms (NPS) affecting people living with Alzheimer's and Dementia and has serious consequences for patients and caregivers. The current consensus is that agitation results, in part, from the disruption of ascending monoamine regulators of cortical circuits, especially the loss of serotonergic activity. It is believed that the first line of treatment for these conditions is selective serotonin reuptake inhibitors (SSRIs), but these are effective in only about 40% of patients. Person-specific biomarkers, for example, ones based on in vitro iPSC-derived models of serotonin activity, which predict who with Agitation responds to an SSRI, are a major clinical priority. Here, we report the generation of human-induced pluripotent stem cells (iPSCs) from a 74-year-old AD patient, the homozygous APOE ε4/ε4 carrier, who developed Agitation. His iPSCs were reprogrammed from peripheral blood mononuclear cells (PBMCs) using the transient expression of pluripotency genes. These display typical iPSC characteristics that are karyotypically normal and attain the capacity to differentiate into three germ layers. The newly patient-derived iPSC line offers a unique resource to investigate the underlying mechanisms associated with neuropsychiatric symptom progression in AD.
... However, in our study, depression was an exclusion criterion. Hence, loss of serotonergic neurons in the rostral nuclear complex of the raphe is believed to be secondary to pathological changes taking place in the target areas of these projections [32,33]. ...
Background
Multiple sclerosis (MS) is widely known to cause brain atrophy due to neurodegeneration. Neuroimaging investigations revealed a direct link between brain atrophy detected by MRI and impairment. Transcranial sonography is a safe, feasible and cost-effective imaging technique. In this study, we aimed to validate B-mode transcranial sonography (TCS) as a marker of neurodegeneration in MS. This study is the first study directed to set cut-off point for brain parenchyma measurement in Egyptian population. An observational, case–control study, conducted on 125 subjects; divided into 2 groups: first group, 71 healthy volunteers and patients’ group (54 patients) with relapsing–remitting multiple sclerosis (RRMS). All studied subjects were assessed using B-mode TCS. Transcranial sonography findings were categorized into: first, assessment of brain atrophy parameters by measuring diameter (cm) of third ventricle and both frontal horns of lateral ventricles. Then, the echogenicity of thalamus and brainstem structures (substantia nigra (SN), red nucleus) planimetric surface area (cm ² ) were assessed along with their abnormal echogenicity (cm ² ), while brainstem raphe was assessed semi-quantitatively for its echogenicity (intact or interrupted).
Results
Quantitative measures of brain atrophy: in normal control group the third ventricle diameter mean was 0.2 cm (± 0.08), right and left frontal horn diameter were 0.3 cm (± 0.13) and 0.28 cm (± 0.1), respectively, brain atrophy parameters could differentiate between MS patients and normal control group as a statistically significant (p< 0.001) larger ventricular diameter was found in MS patients. On the other hand, assessment of brain stem structures and thalamus showed no statistical significance between MS patients and normal control except in surface area of both red nuclei.
Conclusions
Brain parenchymal sonography may be used as a tool in assessment of neurodegeneration in MS patients.
... In addition to the cellular changes, gross hallmark morphological changes occur in the DRN of the AD brain. The DRN is among the first brain regions affected by cytoskeletal changes associated with NFTs in AD, with NFTs first appearing in the DRN in early stages of AD 81,83,88,89 . Taken together, the cellular and morphological changes suggest that neurodegeneration of the DRN affects AD progression and pathology. ...
Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited therapeutic options. Cellular transplantation of healthy exogenic neurons to replace and restore neuronal cell function has previously been explored in AD animal models, yet most of these transplantation methods have utilized primary cell cultures or donor grafts. Blastocyst complementation offers a novel approach to generate a renewable exogenic source of neurons. These exogenic neurons derived from stem cells would develop with the in vivo context of the inductive cues within a host, thus recapitulating the neuron-specific characteristics and physiology. AD affects many different cell types including hippocampal neurons and limbic projection neurons, cholinergic nucleus basis and medial septal neurons, noradrenergic locus coeruleus neurons, serotonergic raphe neurons, and limbic and cortical interneurons. Blastocyst complementation can be adapted to generate these specific neuronal cells afflicted by AD pathology, by ablating important cell type and brain region-specific developmental genes. This review discusses the current state of neuronal transplantation to replace specific neural cell types affected by AD, and the developmental biology to identify candidate genes for knockout in embryos for creating niches to generate exogenic neurons via blastocyst complementation.
... During the early stages of AD pathology (Braak stage I-II), the DRN is heavily affected by tau tangles (Rüb et al., 2000) and exhibits marked neurodegeneration, with estimates of up to 77% neuronal cells lost depending on disease stage . As a consequence of the degeneration in the DRN, lower cortical serotonin, serotonin metabolites (5-hydroxyindoleacetic acid) and reduced serotonin transporter levels (Smith et al., 2017) have been reported in AD and other dementia syndromes (van der Zande et al., 2019). ...
Depression in dementia is common, disabling and causes significant distress to patients and carers. Despite widespread use of antidepressants for depression in dementia, there is no evidence of therapeutic efficacy, and their use is potentially harmful in this patient group. Depression in dementia has poor outcomes and effective treatments are urgently needed. Understanding why antidepressants are ineffective in depression in dementia could provide insight into their mechanism of action and aid identification of new therapeutic targets. In this review we discuss why depression in dementia may be a distinct entity, current theories of how antidepressants work and how these mechanisms of action may be affected by disease processes in dementia. We also consider why clinicians continue to prescribe antidepressants in dementia, and novel approaches to understand and identify effective treatments for patients living with depression and dementia.
