Revisiting a Telencephalic Extent of the Ascending Reticular Activating System.

Is the cerebrum involved in its own activation to states of attention or arousal? "Telencephalon" is a term borrowed from embryology to identify not only the cerebral hemispheres of the forebrain, but also the basal forebrain. We review a generally undercited literature that describes nucleus basalis of Meynert, located within the substantia innominata of the ventrobasal forebrain, as a telencephalic extension of the ascending reticular activating formation. Although that formation's precise anatomical definition and localization have proven elusive over more than 70 years, a careful reading of sources reveals that there are histological features common to certain brainstem neurons and those of the nucleus basalis, and that a largely common dendritic architecture may be a morphological aspect that helps to define non-telencephalic structures of the ascending reticular activating formation (e.g., in brainstem) as well as those parts of the formation that are telencephalic and themselves responsible for cortical activation. We draw attention to a pattern of dendritic arborization described as "isodendritic," a uniform (isos-) branching in which distal dendrite branches are significantly longer than proximal ones. Isodendritic neurons also differ from other morphological types based on their heterogeneous, rather than specific afferentation. References reviewed here are consistent in their descriptions of histology, particularly in studies of locales rich in cholinergic neurons. We discuss the therapeutic implications of a basal forebrain site that may activate cortex. Interventions that specifically target nucleus basalis and, especially, the survival of its constituent neurons may benefit afflictions in which higher cortical function is compromised due to disturbed arousal or attentiveness, including not only coma and related syndromes, but also conditions colloquially described as states of cognitive "fog" or of "long-haul" mental compromise.

Reduced substantia innominata volume mediates contributions of microvascular and macrovascular disease to cognitive deficits in Alzheimer's disease.

The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD.

Structural grey matter changes in the substantia innominata in Alzheimer's disease and dementia with Lewy bodies: a DARTEL-VBM study.

OBJECTIVES: Several cholinergic nuclei, and in particular the nucleus basalis of Meynert, are localised to the substantia innominata in the basal forebrain. These nuclei provide major cholinergic innervation to the cerebral cortex and hippocampus, and have an essential role in cognitive function. The aim of this study was to investigate volumetric grey matter (GM) changes in the substantia innominata from structural T1 images in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy older participants using voxel-based morphometry. METHODS: Participants (41 DLB, 47 AD and 39 controls) underwent 3 T T1 magnetic resonance imaging and cognitive assessments. Voxel-based morphometry analysis used SPM8 with a substantia innominata brain mask to define the subspace for voxel GM analyses. Group differences, and selected behavioural and clinical correlates, were assessed. RESULTS: Compared with that in controls, bilateral GM loss in the substantia innominata was apparent in both AD and DLB. Relative to controls, significant bilateral GM loss in the substantia innominata was observed in DLB and AD. In DLB, significant associations were also observed between substantia innominata GM volume loss, and the levels of cognitive impairment and severity of cognitive fluctuations. CONCLUSIONS: Relative to that controls, atrophy of the substantia innominata was apparent in DLB and AD, and is associated with specific clinical manifestations in DLB. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Is encroachment of the carotid termination into the substantia innominata associated with its atrophy and cognition in Alzheimer's disease?

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD.

Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson's disease.

BACKGROUND: Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial. METHODS: A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups. RESULTS: The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28 ± 0.22 vs 1.41 ± 0.25, p=0.005). CONCLUSIONS: The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators.

Volumetric analysis of the substantia innominata in patients with Parkinson's disease according to cognitive status.

The cholinergic system arising from the substantia innominata (SI) of the basal forebrain has an important role in the cognitive functions of Parkinson's disease (PD). We performed magnetic resonance imaging based volumetric analysis to evaluate the SI volume in patients with PD-intact cognition (PD-IC), PD-mild cognitive impairment (PD-MCI), and PD dementia (PDD). The mean normalized SI volume was significantly decreased in patients with PD-IC (1.54 ± 0.12, p < 0.001), PD-MCI (1.49 ± 0.12, p < 0.001), and PDD (1.39 ± 0.12, p < 0.001) compared with that of control subjects (1.68 ± 0.11). The normalized SI volume did not differ between patients with PD-IC and PD-MCI; however, the normalized SI volume was significantly decreased in patients with PDD compared with that in those with PD-IC (p < 0.001) or PD-MCI (p = 0.016). The normalized SI volume was significantly correlated with general cognitive status (r = 0.51, p < 0.001) as well as with performance in each cognitive subdomain, with a particularly significant independent association with attention (ß = 0.33, p = 0.003) and object naming (ß = 0.26, p = 0.017). The present study demonstrated that the SI volume in PD differs depending on cognitive status and is significantly correlated with cognitive performance.

MRI-based volumetric measurement of the substantia innominata in amnestic MCI and mild AD.

The substantia innominata (SI) contains the nucleus basalis of Meynert, which provides the major cholinergic innervation to the entire cortical mantel and the amygdala; degeneration of nucleus basalis neurons correlates with cognitive decline in Alzheimer's disease (AD). However, whether SI atrophy occurs in individuals with amnestic mild cognitive impairment (aMCI) has not been examined thoroughly in vivo. In the present study, we developed a new protocol to measure volumetric changes in the SI from magnetic resonance imaging (MRI) scans. Participants consisted of 27 elderly controls with no cognitive impairment (NCI); 33 individuals with aMCI; and 19 patients with mild AD. SI volumes were traced on three consecutive gapless 1mm thick coronal slices. Results showed that SI volume was significantly reduced in the mild AD group compared to both NCI and aMCI participants; however, the NCI and aMCI groups did not differ from each other. Furthermore, a decrease in SI volume was related to impaired performance on declarative memory tasks even when attention was controlled.

Mild cognitive impairment in the elderly is associated with volume loss of the cholinergic basal forebrain region.

BACKGROUND: Cholinergic neurons within the basal forebrain are assumed to be an early (preclinical) manifestation site of pathological changes in Alzheimer's disease (AD). METHODS: We used morphometric magnetic resonance imaging (MRI) to detect and quantify atrophic changes in the basal forebrain of subjects suffering from amnestic mild cognitive impairment (aMCI). Three Tesla magnetic resonance (MR) data of 26 aMCI patients, 46 cognitively normal elderly control subjects (CO), and 12 patients suffering from Alzheimer's dementia were analyzed, including segmentation and quantification of brain tissue as well as a segmentation of basal forebrain structures (substantia innominata [SI]). RESULTS: We found the volume of the SI to be significantly different between groups in that control subjects showed the largest SI volumes, followed by aMCI and AD patients. CONCLUSIONS: These results are in line with the hypothesis that cell loss within the cholinergic basal forebrain regions occurs already in the early (predementia) stage of AD. In vivo quantification of these changes might be of use as a novel neuroimaging marker of cholinergic neurodegeneration in AD.

Prediction of response to donepezil in Alzheimer's disease: combined MRI analysis of the substantia innominata and SPECT measurement of cerebral perfusion.

OBJECTIVE: We performed combined studies of magnetic resonance imaging (MRI) analysis of the substantia innominata and single photon emission CT (SPECT) measurement of cerebral perfusion with the goal of predicting which patients with Alzheimer's disease are most likely to respond to donepezil treatment. METHODS: Ninety-one patients treated with donepezil were divided into responders and non-responders on the basis of changes in their MMSE scores from baseline to study endpoint. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. SPECT data were analysed using three-dimensional stereotactic surface projections. RESULTS: Responders had significantly greater atrophy of the substantia innominata, but less prominent frontal hypoperfusion than non-responders. Receiver operating characteristic analysis revealed that combined MRI and SPECT examination showed an overall discrimination rate of 70% between responders and non-responders. DISCUSSION: Our results suggest that responder patients have more severe damage in the cholinergic system and/or less prominent frontal cortical dysfunction. Combined MRI analysis of the substantia innominata and SPECT measurement of frontal perfusion at baseline may help to predict response to donepezil treatment in patients with Alzheimer's disease.

Atrophy measurement of the anterior commissure and substantia innominata with 3T high-resolution MR imaging: does the measurement differ for patients with frontotemporal lobar degeneration and Alzheimer disease and for healthy subjects?

BACKGROUND AND PURPOSE: The anterior commissure (AC) and substantia innominata (SI) can be clearly demonstrated at 3T high-resolution MR imaging. Our aim was to investigate if atrophy of the AC and SI on 3T MR imaging differs among patients with frontotemporal lobar degeneration (FTLD) and Alzheimer dementia (AD) and healthy subjects. MATERIALS AND METHODS: Seven consecutive patients with FTLD, 20 patients with AD, and 16 age-matched control subjects were enrolled. MR imaging was performed at 3T. The AC thickness as well as the SI thickness was measured on a thin-section coronal T2-weighted image, and the AC area was measured on a sagittal T1-weighted image. The measurement differences among the participants were analyzed with the Kruskal-Wallis test. A correlation of the measurement with the Mini-Mental State Examination (MMSE) score was obtained with the Spearman rank correlation test. RESULTS: Thinning of the AC was significantly more prominent in FTLD than in AD (P < .001). Although the right SI thickness was significantly decreased in patients with AD as compared with control subjects (P < .05), there was no significant difference, with a substantial overlap of the average SI thickness among the 3 groups. The thickness and the area of the AC were positively correlated with the MMSE score (rho = 0.612, P < .001, and rho = 0.659, P < .001, respectively). In contrast, the average SI thickness showed a weak positive correlation with the MMSE score (rho = 0.325, P < .05). CONCLUSION: Measurement of AC atrophy with 3T MR imaging may provide additional diagnostic clues for FTLD and AD. Conversely, SI atrophy measurement does not provide an additional benefit in the evaluation of FTLD and AD, owing to a considerable overlap in the average thickness of bilateral SI.

Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer's disease.

Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease. However, unlike the latter, the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it with the pattern found in Alzheimer's disease. Seventy-two patients that fulfilled clinical criteria for probable DLB were age- and gender-matched to 72 patients with probable Alzheimer's disease and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter (GM) atrophy in the two patient groups, relative to controls, after correction for multiple comparisons (P < 0.05). Study-specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional GM loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the Alzheimer's disease group showed a widespread pattern of GM loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in Alzheimer's disease; however, they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the Alzheimer's disease group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain GM in both patient groups, with a trend for more reduction of SI GM in Alzheimer's disease than DLB, and more reduction of midbrain in DLB than Alzheimer's disease. Significantly greater loss in the hippocampus and temporo-parietal cortex was observed in the Alzheimer's disease patients when the two patient groups were compared. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex is, therefore, suggestive of DLB and this may aid in the differentiation of DLB from Alzheimer's disease. These findings support recent pathological studies showing an ascending pattern of Lewy body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.

MR features of the substantia innominata and therapeutic implications in dementias.

We measured the thickness of the substantia innominata using magnetic resonance imaging in 122 patients with Alzheimer's disease (AD), 31 patients with dementia with Lewy bodies (DLB) and 34 patients with vascular dementia (VaD), and examined the correlates of cognitive response to donepezil. Although all dementia groups showed significant atrophy of the substantia innominata compared to 28 age-matched controls, atrophy was greater in the DLB group, but less in the VaD group than the AD group. Mini-Mental State Examination score changes at 12 weeks after donepezil administration inversely and significantly correlated with the thickness of the substantia innominata in patients with AD (n=103, r=-0.43, p<0.0001) and in patients with DLB (n=24, r=-0.57, p<0.01), but not in patients with VaD (n=12, r=-0.22, p>0.1). There may be some differences in cholinergic impairment among AD, DLB and VaD, reflecting cholinergic neuropathology. Clinical response to cholinergic therapy may be partly attributable to damaged cholinergic neurons in AD and DLB, but not in VaD, suggesting differences in the therapeutic implication of cholinergic system degeneration.

Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior.

Previous research has suggested that cholinergic neurons in the nucleus basalis magnocellularis and substantia innominata (NBM/SI) may be important in mediating aversive states. The authors investigated the effect of NBM/SI cholinergic lesions, induced with 192 IgG saporin, on behavioral measures of aversive states in rats. Behavior in the elevated plus maze and behavioral suppression induced by 2 fear-conditioned stimuli, a tone and a light, were evaluated. Lesions had no effect on any measures in the elevated plus maze but attenuated operant suppression induced by the light and attenuated freezing induced by the tone, though this last effect was not statistically significant. The results of the study suggest that NBM/SI cholinergic neurons may be important in mediating selective aspects of aversive states.

Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.

In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Measurement of basal forebrain atrophy in Alzheimer's disease using MRI.

Alzheimer's disease is characterized by the degeneration and loss of cholinergic neurones in the nucleus basalis Meynert, located within the substantia innominata at the ventral surface of the basal forebrain. An in vivo measure of morphological changes in the nucleus basalis Meynert would be of high relevance to better understand the structural correlate of cholinergic dysfunction in Alzheimer's disease. In this study, we applied a newly developed automated technique of image regression analysis, implemented through code written in Matlab 5.3 (MathWorks, Natick, MA), to the analysis of proton density weighted structural MRI of the basal forebrain from 13 patients with Alzheimer's disease (mean age = 77.5 years, SD = 4.4 years, 8 women) and 12 healthy elderly subjects (mean age = 62.3 years, SD = 5.6 years, 6 women). This technique allows searching a large portion of the substantia innominata for signal changes. We used corresponding MRI and histological sections of a post mortem brain to map the locations of basal forebrain cholinergic nuclei into the MRI standard space. Additionally, we used voxel-based morphometry, implemented in SPM2 (Wellcome Department of Imaging Neuroscience, London, UK) to determine correlations between signal changes in the substantia innominata and cortical grey matter atrophy in the patients with Alzheimer's disease. When matching the locations of signal reductions in the in vivo MRI to the template of basal nuclei based on the postmortem brain, signal intensity was decreased in areas corresponding to anterior lateral and anterior medial nucleus basalis Meynert and increased in the third ventricle, the transverse fissure and the optic tract in patients with Alzheimer's disease compared with controls. The reduction of the signal intensity in an area corresponding to the anterior lateral nucleus basalis Meynert was significantly correlated with reduced grey matter concentration in the bilateral prefrontal cortex, inferior parietal lobule and cingulate gyrus. Our findings suggest that signal changes occur in patients with Alzheimer's disease in the substantia innominata which may be related to the loss or degeneration of cholinergic neurones and correspond to regional cortical grey matter atrophy. If replicated in an independent sample, our technique may be useful to detect degeneration of basal forebrain cholinergic neurones in vivo.

Substantia innominata: MR findings in Parkinson's disease.

To elucidate MR imaging changes of the substantia innominata in Parkinson's disease (PD), using a 1.5-T superconductive MR unit, the thickness of the substantia innominata was measured on coronal thin-section images in 44 PD patients and 20 age-matched control subjects. We also evaluated the correlation between the thickness of the substantia innominata and mental status in PD patients. Mean thickness of the substantia innominata was 2.3 mm in PD patients, and 2.5 mm in control subjects. Thinning of the substantia innominata was statistically significant in PD patients compared with control subjects, although there were large overlaps. Among the PD patients, thinning was remarkable in cases with dementia. A positive correlation between thickness of substantia innominata and score of Mini-Mental-Status-Examination was also observed in PD patients. Atrophy of the substantia innominata was demonstrated, especially in PD patients with cognitive impairment, on coronal MR images, and this is compatible with the previous pathological reports.

Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer's disease patients.

To investigate whether atrophy of the substantia innominata as shown on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, predicts response to donepezil treatment in patients with Alzheimer's disease (AD), we studied correlations between the thickness of the substantia innominata and clinical efficacy. Eighty-two patients were divided into responders, including transiently and continuously responding groups, and nonresponders, based on the changes in the Mini-Mental State Examination (MMSE) score from baseline at 3 months and at 12 months. Atrophy of the substantia innominata was more pronounced in transiently and continuously responding groups than nonresponders, but no significant change in the thickness between transiently and continuously responding groups was found. The MMSE score changes from baseline at 3 months and at 12 months significantly inversely correlated with the thickness of the substantia innominata. Logistic regression analysis revealed that the overall discrimination rate with the thickness of the substantia innominata was 70% between responders and nonresponders. We conclude that atrophy of the substantia innominata on MRI helps to predict response to donepezil treatment in patients with AD.

MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia.

BACKGROUND AND PURPOSE: The substantia innominata can be visualized on coronal thin-section T2-weighted MR images. The purpose of this study was to investigate the morphologic changes of the substantia innominata in normal aging by using MR imaging and to determine whether the changes in this structure on MR images were specific to Alzheimer disease (AD). METHODS: The thickness of the substantia innominata was measured on the coronal T2-weighted image obtained through the anterior commissure in 39 healthy control subjects (age range, 25-86 y; mean age, 62 y); 39 patients with AD; and 36 patients with non-AD dementia, including vascular dementia, frontotemporal dementia, and Parkinson disease with dementia. RESULTS: In the control subjects, the thickness of the substantia innominata significantly decreased with age. Compared with age-matched control subjects, both patients with AD and patients with non-AD dementia had significant atrophy of the substantia innominata. The thickness of the substantia innominata significantly correlated with scores from the Mini-Mental State Examination in patients with AD but not in patients with non-AD dementia. CONCLUSION: MR analysis reveals age-related shrinkage of the substantia innominata. Atrophy of the substantia innominata, which reflects degeneration in the nucleus basalis of Meynert, is pronounced both in patients with AD and in those with non-AD dementia. MR imaging features in this structure may not be specific to AD.