By Harini Sarva, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York Presbyterian Hospital
Dr. Sarva reports no financial relationships relevant to this field of study.
SYNOPSIS: This study compared 18 subjects diagnosed with dementia with Lewy bodies (DLB), 23 with nonsynucleinopathy dementia, and 25 healthy controls and demonstrated that phosphorylated alpha-synuclein was found only in the skin nerve fibers of DLB subjects, helping distinguish this type of dementia from other types.
SOURCE: Donadio V, et al. A new potential biomarker for dementia with Lewy bodies. Neurology 2017;89:318-326.
The authors enrolled 18 subjects who met the criteria consistent with dementia with Lewy bodies (DLB): rapid cognitive decline and parkinsonism developing within one year, rapid eye movement (REM) sleep behavior disorder, fluctuating cognition, visual hallucinations, and neurogenic orthostatic hypotension. Seventeen of the 18 tested positive on DaTscan, suggestive of presynaptic dopaminergic dysfunction, and abnormal cardiac uptake of iodine-123-meta-iodobenzylguanidine, suggestive of cardiac postganglionic sympathetic denervation, both of which supported the diagnosis of DLB clinically. One patient refused both tests, but the clinical picture was consistent with DLB, and the patient was included in the study. This cohort was compared with 23 subjects with dementia of different pathologies (NSD): 13 with Alzheimer’s disease confirmed with appropriate cerebrospinal fluid beta amyloid-42, total tau, and phosphorylated tau; six with frontotemporal dementia associated with C9orf72 repeat expansion (4), progranulin mutation (1), and TDP43 mutation (1); and four with vascular dementia. Peripheral neuropathy was evaluated in these subjects with testing for diabetes; B12 deficiency; and microbiological, autoimmune, paraneoplastic, and thyroid disorders as well as electrophysiological analysis. Twenty-five healthy, age-matched controls also were evaluated.
Those with DLB and NSD had similar disease duration, Mini-Mental State Examination (MMSE) scores, and brief mental deterioration battery (BMDM) scores. Twelve of the DLB subjects had dementia at the onset, whereas six had parkinsonism. Phosphorylated alpha-synuclein (P-syn) was not found in any skin sample in either the NSD group or the healthy controls. Those with DLB showed more P-syn in a proximal to distal distribution, with more found in the cervical region than in the thigh or leg. For example, in one of two sets of samples taken, the abnormal deposits were found in 95%, 89%, and 76% of DLB patients in the cervical region, thigh, and leg, respectively. P-syn also was found more frequently in adrenergic neurons rather than in cholinergic vasoactive intestinal polypeptide-positive fibers, such as those found in the sweat glands. Those with autonomic dysfunction had a higher frequency of P-syn compared to those without autonomic dysfunction (97% vs. 71% of samples analyzed). In addition, those with autonomic dysfunction had homogenous P-syn distribution, whereas those without had the more proximal to distal gradient. The amount of skin samples with P-syn also correlated with Unified Parkinson’s Disease Rating Scale (UPDRS) scores and with leg arrector pilum innervation rate, but not with MMSE score, disease duration, or age of onset. Epidermal and autonomic skin innervation were poor, particularly in the leg in DLB subjects when compared with NSD and healthy controls. When comparing DLB subjects with and without autonomic dysfunction, lower leg autonomic innervation scores were significantly different both for the sweat glands and arrector pilum muscle, but no differences were noted in the cervical region or thigh.
This study highlights three important features of DLB, further adding to our knowledge of the clinical phenotype. First, P-syn staining may assist in accurately diagnosing DLB earlier in the disease course. Second, autonomic neuropathy may be an additional feature of DLB, and third, those with autonomic dysfunction have more widespread P-syn deposition. This observation is important because clinically, DLB can be indistinguishable from Alzheimer’s at times. A skin biopsy also is a safe and easy procedure with few adverse events. Easy access to cutaneous P-syn would enable earlier diagnosis of DLB and potential development of DLB-specific therapies. However, the results of this small study need to be replicated in larger, more diverse cohorts. In addition, the staining procedure for P-syn is challenging, and expert pathological analysis is required to correctly detect its presence.
The most important and challenging underlying issue that can limit the utility of this testing is the suboptimal specificity of the diagnostic criteria of DLB. The presence of autonomic dysfunction in this study can be used to distinguish DLB from NSD but not necessarily from multiple system atrophy (MSA), another synucleinopathy with autonomic dysfunction. MIGB and DaTscan also are positive in MSA; thus, potential therapeutic trials for DLB may incorporate other synucleinopathies. Finally, the authors noted that DLB can have atypical features, such as longer duration of disease and young age of onset (before age of 65), limiting the generalizability of these data.