Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample.

BACKGROUND: Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer's disease pathology. RESULTS: Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50-0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals. CONCLUSIONS: M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder.

BACKGROUND: Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples. METHODS: The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2,3-cyclic-nucleotide 3-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting. RESULTS: Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples. LIMITATIONS: Oligodendrocytes were identified using morphological criteria. CONCLUSION: This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.

Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides.

Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression.

Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides.

BACKGROUND: It is hypothesized that mood disorders are accompanied by altered wiring and plasticity in key limbic brain regions such as the anterior cingulate cortex (ACC). To test this hypothesis at the cellular level, we analyzed basilar dendritic arborizations extended by layer VI pyramidal neurons in silver-impregnated postmortem ACC samples from well-characterized depressed suicide subjects (n=12) and matched sudden-death controls (n=7). METHODS: One cm(3) tissue blocks were stained using a Golgi preparation, cut on a microtome, and mounted on slides. Basilar dendritic arbors from 195 neurons were reconstructed, and the number, length, and diameter of branches were determined at each branch order. The size and number of spines borne by these branches were also assessed. RESULTS: Third-order branches were significantly reduced in number (24% fewer; p=0.00262) in depressed suicides compared to controls. The size and average length of these branches, as well as their number of spines/length were unaltered. On average, for each pyramidal neuron analyzed in depressed subjects, the fewer third-order branches resulted in a significant reduction in branch length (28% shorter; p=0.00976) at this branch order. CONCLUSIONS: These results provide the first evidence of altered cortical dendritic branching in mood disorders. Given that proximal dendritic branches grow during perinatal development, and that they are generally less plastic at maturity than distal segments, we speculate that these differences in dendritic branching may reflect a biological predisposition to depression and suicide.

Alcohol dependence-related increase of glial cell density in the anterior cingulate cortex of suicide completers.

BACKGROUND: Suicide is the most serious consequence of major depressive disorder (MDD). Although the anterior cingulate cortex (ACC; Brodmann area [BA] 24) has been increasingly investigated for its role in the etiology of MDD, there is surprisingly very little information about the possible implication of this brain region in suicide. We hypothesized that changes in BA24 cell densities occur in depressed individuals who commit suicide, possibly reflecting an altered state of cortical plasticity that is thought to occur in depression. METHODS: We investigated cell densities and sizes in BA24 among suicide completers and matched sudden-death controls. We examined a 1-cm(3) tissue block from BA24a of the supracallosal ACC in 26 human postmortem brain specimens (13 depressed individuals who committed suicide and 13 controls). We assessed neuronal and glial cell densities as well as neuronal soma sizes in the upper and lower cortical layers using optical fractionator and nucleator 3-dimensional stereological probes. RESULTS: Glial densities, neuronal densities and soma sizes measured in BA24a did not differ significantly between controls and suicide completers. Secondary analyses showed a significant and robust increase in glial cell densities in BA24a of alcohol-dependent depressed suicide completers compared with depressed suicide completers who were not alcohol-dependent (38%) and, to a lesser extent, controls (30%). LIMITATIONS: Our study, conducted with tissue samples from men only, made use of a nonspecific stain that does not distinguish between neuronal or glial cell subtypes. Furthermore, the quantitative analysis concerned upper and lower cortical contours rather than individual cortical layers. CONCLUSION: Our results indicate that in BA24, glial density, neuronal density and soma size are not affected in MDD and suicide. They also suggest that alcohol dependence has an important influence on glial densities in this key limbic structure.

Through the looking glass: examining neuroanatomical evidence for cellular alterations in major depression.

Alterations in brain plasticity are increasingly thought to play important roles in major depressive disorder (MDD) and suicide. To gain a better understanding of the gross structural changes observed in the brains of major depressed and suicide subjects, a number of recent investigations have scrutinized the cellular integrity of brain regions implicated in mood disorders. The purpose of this review is to summarize the current knowledge on the microscopic features of neuronal and glial cell populations in these different brain regions, namely the prefrontal cortex, hippocampus, amygdala, raphe nucleus and locus coeruleus. In general, evidence from this burgeoning field supports the hypothesis of altered cell plasticity in MDD and suicide occurring mainly in key fronto-limbic areas. Interestingly, reported morphometric and cell density alterations are generally region-specific and implicate several neuromodulatory systems, notably GABAergic, serotonergic, noradrenergic and glutamatergic pathways. Cell-specific changes involve reductions in densities of astrocytes and oligodendrocytes, while increases in microglial densities have also been reported. Furthermore, increases in neuronal densities have been found in subcortical regions. The implication of such findings for our understanding of the cellular and molecular underpinnings of MDD and suicide are discussed, and the strengths and weaknesses of morphological approaches used to analyse human postmortem brain tissues are evaluated.