Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation

Abstract

Sirs, PSEN1 mutations are the most common cause of autosomal dominant early-onset familial Alzheimer disease (EO-FAD) in diverse ethnic groups [1–3]. Cognitive decline is a cardinal clinical feature in patients with PSEN1 mutations; however, various accompanying clinical manifestations have been reported [4]. We report a family with a novel PSEN1 mutation who developed depression and psychiatric symptoms preceding the onset of dementia. The first patient (Patient 1, III-1 in Fig. 1a) has suffered from depression and has undergone antidepressant treatment from the age of 29. She gradually became apathetic at the age of 47. At the age of 48, she developed visual and auditory hallucinations and personality change. She was referred to us for neurological evaluation. Her cognition was impaired as determined using the revised version of the Hasegawa dementia scale (HDS-R) [5] of 11/30. Neurological examination revealed rigidity of the left upper limb and postural instability, suggesting the presence of parkinsonism. Brain MRI showed atrophy of the medial temporal lobe with right predominance. 99mTc-ECD SPECT revealed hypoperfusion in the posterior cingulate gyri as well as in the frontal and parietotemporal cortices with right hemisphere predominance. The younger sister of Patient 1 (Patient 2, III-2 in Fig. 1a) was diagnosed as having depression when she was in high school. Since then, she has experienced repeated manic and depressive bipolar episodes. Because hallucinations, abnormal cravings, and spatial disorientation were noted at the age of 40, she was admitted to a psychiatric hospital. She was examined by us at the age of 42 and found to exhibit parkinsonian gait, stooped posture, rigidity of limbs, and severe cognitive decline as determined by HDS-R (0/30). Brain MRI showed predominant medial temporal atrophy. 99mTc-ECD SPECT revealed severe hypoperfusion in the posterior cingulated gyri and bilateral parietal area. On the basis of clinical and imaging findings, we clinically suspected them as having EO-FAD, although they exhibited unusual accompanying symptoms. Their mother, uncles, and grandfather were demented according to an interview with family members (Fig. 1a). A genetic screening of mutations in APP, PSEN1, PSEN2, and MAPT was performed after obtaining written, informed consent from the patients and their caregivers. We identified a heterozygous G to C transition in exon 6 of PSEN1 in the patients, which resulted in a previously undescribed Leu173Phe mutation. This mutation was absent in 110 healthy controls from the same population, as determined by allele-specific PCR methods (Fig. 1b). Codon 173 leucine is located in the third transmembrane domain of PSEN1 and is highly conserved among species. The APOE genotype was 3/4 in both patients. To examine the pathological characteristics of the PSEN1 mutation, we established neuroblastoma-derived K. Kasuga T. Ishihara O. Onodera T. Ikeuchi (&) Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Chuo-ku, Niigata 951-8585, Japan e-mail: ikeuchi@bri.niigata-u.ac.jp