Longitudinal dopamine D2 receptor changes and cerebrovascular health in aging

BACKGROUND AND OBJECTIVES: Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates. METHODS: We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity. RESULTS: Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion. DISCUSSION: These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline

Differentiation of Pre- and Postganglionic Nerve Injury Using MRI of the Spinal Cord.

Brachial plexus injury (BPI) is a devastating type of nerve injury, potentially causing loss of motor and sensory function. Principally, BPI is either categorized as preganglionic or postganglionic, with the early establishment of injury level being crucial for choosing the correct treatment strategy. Despite diagnostic advances, the need for a reliable, non-invasive method for establishing the injury level remains. We studied the usefulness of in vivo magnetic resonance imaging (MRI) of the spinal cord for determination of injury level. The findings were related to neuronal and glial changes. Rats underwent unilateral L4 & L5 ventral roots avulsion or sciatic nerve axotomy. The injuries served as models for pre- and postganglionic BPI, respectively. MRI of the L4/L5 spinal cord segments 4 weeks after avulsion showed ventral horn (VH) shrinkage on the injured side compared to the uninjured side. Axotomy induced no change in the VH size on MRI. Following avulsion, histological sections of L4/L5 revealed shrinkage in the VH grey matter area occupied by NeuN-positive neurons, loss of microtubular-associated protein-2 positive dendritic branches (MAP2), pan-neurofilament positive axons (PanNF), synaptophysin-positive synapses (SYN) and increase in immunoreactivity for the microglial OX42 and astroglial GFAP markers. Axotomy induced no changes in NeuN-reactivity, modest decrease of MAP2 immunoreactivity, no changes in SYN and PanNF labelling, and a modest increase in OX42 and SYN labeling. Histological and radiological findings were congruent when assessing changes after axotomy, while MRI somewhat underestimated the shrinkage. This study indicates a potential diagnostic value of structural spinal cord MRI following BPI

Assessment of ventral horn size on MRI & histological measurements of the ventral horn neuron pool size.

<p>Axial image of the L4/L5 spinal cord segment following ventral root avulsion, with the spinal cord divided in a right and a left side (yellow line), and the ventral horn separated from the dorsal horn (black line). The ventral horn area is outlined on the injured (red line) and uninjured side (blue) (A). The equivalent measurement was performed in histological preparations of the spinal cord sections stained with NeuN after axotomy (B) and ventral root avulsion (C). The histogram shows the relative area ratios obtained by measurements of the ventral horn area in MRI images (D) and histological preparations (E) after ventral root avulsion (VRA) and axotomy (AXO). Error bars show S.E.M. P<0.001 is indicated by ***.</p

Expression of microtubule-associated protein-2 and synaptophysin.

<p>Horizontal sections through the ventral horn of L4–L5 segments showing immunostaining for microtubular-associated protein-2 (MAP2; dendritic branches, left column) and synaptophysin (SYN; synaptic boutons, middle column) of a control animal (A–C; CONT), at 4 weeks after spinal cord injury (D–F; SCI) and following treatment with N-acetyl cysteine (G–I; NAC) or acetyl-L-carnitine (J–L; ALC). Note that synaptic boutons around motoneuron cell bodies are not recovered after NAC or ALC treatment (right column). Scale bar, 50 µm (left and middle columns) and 20 µm (right column).</p

Quantification of dendrites, synapses & axons.

<p>Histogram showing the relative tissue area occupied by MAP2-positive dendritic branches (A), synaptophysin-positive synaptic boutons (B) and neurofilament-positive nerve fibers (C) in the L4-L5 segments of the spinal cord 4 weeks after ventral root avulsion (VRA) or axotomy (AXO) on the injured (inj.) and uninjured side (uninj.). Error bars show S.E.M. P<0.05 is indicated by *, p<0.01 is indicated by ** and p<0.001 is indicated by ***.</p

Quantification of the glial response and assessment of correlation between MRI and histological data.

<p>Histogram showing the relative tissue area occupied by OX42-positive microglial cells (A) and and GFAP-positive astroglial (B) in the L4-L5 segments of the spinal cord 4 weeks after ventral root avulsion (VRA) or axotomy (AXO) on the injured (Inj.) and uninjured side (Uninj.). Histogram showing the comparison between the relative area ratio following axotomy (C) and ventral root avulsion (D), as measured on MRI images (MRI) and histological preprations stained with NeuN (HISTO). Error bars show S.E.M. p<0.01 is indicated by **, p<0.001 is indicated by *** and ns. indicates lack of statistical significance.</p

Quantification of neuronal degeneration and reaction of glial cells.

<p>Histogram showing survival of Fast Blue-labeled tibial motoneurons (A) and relative tissue area occupied by MAP2-positive dendritic branches (B), synaptophysin-positive synaptic boutons (C), neurofilament-positive nerve fibers (D), GFAP-positive astrocytes (E) and OX42-positive microglial cells (F) in the L5 ventral horn of uninjured control rats (CONT), at 4 weeks after spinal cord injury (SCI) and following treatment with N-acetyl cysteine (NAC) or acetyl-L-carnitine (ALC). Error bars show S.E.M. P<0.05 is indicated by*, P<0.01 is indicated by** and P<0.001 is indicated by*** (SCI vs. CONT, NAC, ALC in A–D and F; CONT vs. SCI, NAC, ALC in E).</p

Experimental groups and numbers of animals.

<p>Experimental groups and numbers of animals.</p

Expression of neurofilament proteins, glial fibrillary acidic protein and microglial complement C3bi receptor.

<p>Horizontal sections through the ventral horn of L4–L5 segments showing immunostaining for neurofilaments (NF; nerve fibers; left column), glial fibrillary acidic protein (GFAP; astrocytes, middle column) and microglial complement C3bi receptor (OX42; microglial cells; right column) of a control animals (A–C; CONT), at 4 weeks after spinal cord injury (D–F; SCI) and following treatment with N-acetyl cysteine (G–I; NAC) or acetyl-L-carnitine (J–L; ALC). Note that NAC and ALC did not change GFAP immunoreactivity but significantly decreased OX42 immunostaining. Scale bar, 50 µm.</p