Concomitant LATE-NC in Alzheimer's disease is not associated with increased tau or amyloid-ß pathological burden.

AIMS: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. METHODS: A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-ß in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. RESULTS: LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P = 0.009). CONCLUSION: The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or Aß pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.

Cholinergic deficits and galaninergic hyperinnervation of the nucleus basalis of Meynert in Alzheimer's disease and Lewy body disorders.

AIMS: Galanin is a highly inducible neuroprotective neuropeptide and in Alzheimer's disease (AD), a network of galaninergic fibres has been reported to hypertrophy and hyperinnervate the surviving cholinergic neurons in the basal forebrain. We aimed to determine (i) the extent of galanin hyperinnervation in patients with AD and Lewy body disease and (ii) whether galanin expression relates to the neuropathological burden and cholinergic losses. METHODS: Galanin immunohistochemistry was carried out in the anterior nucleus basalis of Meynert of 27 Parkinson's disease (PD) cases without cognitive impairment (mild cognitive impairment [MCI]), 15 with PD with MCI, 42 with Parkinson's disease dementia (PDD), 12 with Dementia with Lewy bodies (DLB), 19 with AD, 12 mixed AD/DLB and 16 controls. Galaninergic innervation of cholinergic neurons was scored semiquantitatively. For a subgroup of cases (n = 60), cholinergic losses were determined from maximum densities of choline acetyltransferase positive (ChAT+ve) neurons and their projection fibres. Quantitative data for α-synuclein, amyloid beta and tau pathology were obtained from tissue microarrays covering cortical/subcortical regions. RESULTS: Significant losses of cholinergic neurons and their projection fibres were observed across all diseases. Galaninergic hyperinnervation was infrequent and particularly uncommon in established AD and DLB. We found that hyperinnervation frequencies are significantly higher in the transition between PD without MCI to PDD and that higher burdens of co-existent AD pathology impair this galaninergic response. CONCLUSIONS: Our results suggest that galanin upregulation represents an intrinsic response early in Lewy body diseases but which fails with increasing burdens of AD related pathology.

Magnetic resonance imaging of fixed post mortem brains reliably reflects subcortical vascular pathology of frontal, parietal and occipital white matter.

AIMS: Subcortical vascular pathology of the white and deep grey matter (WM and DGM) is associated with cognitive impairment. Routine neuropathological assessment of subcortical vascular pathology is based on semiquantitative scoring of characteristic lesions in a limited number of histological slides from selected WM and DGM areas. Clinically, WM and DGM lesions are visualized as hyper-intensities on magnetic resonance imaging (MRI). The aim of this study was to evaluate the feasibility of MRI on fixed post mortem brain hemispheres to complement routine neuropathological assessment of subcortical vascular pathology. METHODS: We assessed subcortical vascular pathology in 40 post mortem brain hemispheres from demented (n = 26) and nondemented (n = 14) individuals (mean age 83.2 ± 14.8 years; 62.5% female) using (i) routine histological assessment; (ii) extensive histological assessment of the entire hemisphere at 7-mm intervals; and (iii) full T2-weighted MRI performed on fixed post mortem brain hemispheres. RESULTS: In both WM and DGM routine histological scores for subcortical vascular pathology were significantly lower (P < 0.01) than the corresponding scores obtained by extensive histological assessment. In contrast, no significant differences were seen between scores obtained by MRI and extensive histological assessment in frontal, parietal and occipital lobes while MRI scores were significantly lower in the temporal WM and DGM (P < 0.01). CONCLUSIONS: The results of our study indicate that routine histological assessment underrates subcortical vascular pathology and we conclude that MRI could be used in addition to complement neuropathological post mortem assessment of subcortical vascular pathology of the WM.