Human brain pathology in myotonic dystrophy type 1: A systematic review

Abstract

Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974–2017) and MEDLINE (index period 1887–2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full‐text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1

“…During neurodegenerative disease, astrocytes become reactive and gain abnormal roles that include enhanced GFAP expression ( 18 , 36 ). Histopathological findings in DM1 brain tissue also shows evidence of gliosis ( 34 ). Our findings may reflect temporally dynamic changes in GFAP over the course of DM1 progression.…”

“…The kit is sensitive to the fetal isoform that is overexpressed in DM1 patients ( 32 ); however, the detection antibody does not recognize the epitope when tyrosine 18 is phosphorylated. Immunohistochemistry studies have identified that tau proteins are hyperphosphorylated in DM1 ( 32 , 33 ), and NFTs that have been found in the DM1 brain are the result of aggregation of hyper-phosphorylated tau ( 34 ). Further, Peric and colleagues reported evidence of increased phosphorylated tau levels in patients with adult-onset DM1 relative to juvenile-onset DM1 and controls ( 16 ).…”

DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

“…Brain structural abnormalities include prevalent white matter lesions [ 7 ], some of which may denote focal demyelination [ 8 ]. Reduced grey matter volume has also been reported in cortical brain regions and in the hippocampus of DM1 patients [ 7 , 9 , 10 ], corroborating histopathological evidence of diffusing cerebral atrophy and neuronal loss [ 11 , 12 ]. It is conceivable that brain structural abnormalities in DM1 result in alterations in the connectivity of functional brain networks [ 13 , 14 ].…”

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

“…Other than Tau pathology, several kinds of protein and nucleotide deposits have also been observed in the brain of DM1 patients ( Weijs et al, 2021 ), including Lewy bodies (LBs), neuronal intranuclear eosinophilic inclusion bodies, intracytoplasmic inclusion bodies, increased Marinesco bodies, gliosis ( Itoh et al, 2010 ; Jinnai et al, 2013 ), skein-like ubiquitin-positive inclusions and granulovacuolar degeneration (GVD), which suggest neurodegeneration in the DM1 brain ( Itoh et al, 2010 ; Yamazaki et al, 2011 ; Nakamori et al, 2012 ).…”