Neuropathological Alzheimer's Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes.

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer's disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer's disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

Septo-optic dysplasia and psychiatric disorders: a case report.

BACKGROUND: Septo-optic dysplasia, a variable combination of abnormalities of cerebral midline structures, is a clinically heterogeneous syndrome in which the midline defects may be implicated in psychiatric disturbances. OBJECTIVE: To describe a case of septo-optic dysplasia associated with depression and psychosis and to discuss the role of these developmental abnormalities in psychiatric disturbances. METHODS: The patient's clinico-anamnestic, neuroradiologic, neuropsychiatric, endocrinologic, ophthalmologic, and genetic profile was evaluated. CONCLUSIONS: Developmental abnormalities due to disruption of the complex neural network linking the septum pellucidum with other limbic structures may have been involved in the affective and psychotic disturbances observed in our patient.

Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes.

Nasu-Hakola disease is a rare, recessively inherited disease characterized by presenile dementia and bone cysts. Until now, no evidence of subclincal pathological changes in individuals heterozygous for the mutations underlying Nasu-Hakola disease has been reported. We performed a functional neuroimaging (99mTc-ECD SPECT) and neuropsychological study of healthy members of an Italian family carrying a mutation in the TREM2 gene. Two healthy subjects heterozygous for one mutated TREM2 allele showed a deficit of visuospatial memory associated with hypoperfusion in the basal ganglia, whereas the homozygotes for the wild-type allele of TREM2 did not show any abnormalities.

Circadian variations of human flexion reflex.

We investigated 8 healthy male volunteers, evaluating RII and RIII thresholds every 6 h starting from noon, for a 24-h period. Both reflex responses exhibited a circadian rhythmicity: the lowest values were found in the early morning (9.1 +/- 3.0 and 13.1 +/- 4.4 mA, respectively), while the highest values were observed at midnight (13.1 +/- 3.5 and 18.5 +/- 5.3 mA). Also mean cosinor analysis indicated the existence of a significant rhythm with acrophase at 20:12 for RII and 22:29 for RIII. In 4 subjects, beta-endorphin plasma (beta-EP) level was tested during the day. No correlation was observed between circadian changes of beta-EP and RIII threshold. Other factors are likely to be involved in the circadian variation of nociceptive flexion reflex in man.

Nasu-Hakola disease: a rare entity in Italy. Critical review of the literature.

Nasu-Hakola disease (NHD, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile dementia associated with sclerosing encephalopathy. The disease has a worldwide distribution, but most patients have been reported in Finland and in Japan; in Italy there are anecdotal reports. The combination of neuropsychiatric symptoms and bone cysts is unique to this disease, which we believe to be underestimated in Italy. The molecular defect has been identified in loss-of-function mutations in the TYROBP gene in Finnish and in Japanese patients, and in the TREM2 gene in other families of different ethnic origins. We reviewed the international literature to define better the diagnostic steps and to draw the attention of neurologists and orthopaedic specialists to the disease. The identification of new cases followed by appropriate genetic counselling, genetic analysis, and study of the territorial distribution of affected patients could be a good strategy to follow in order to improve understanding of the disease.

Proteomic analysis of lymphoblastoid cells from Nasu-Hakola patients: a step forward in our understanding of this neurodegenerative disorder.

Nasu-Hakola disease (NHD) is a recessively inherited rare disorder characterized by a combination of neuropsychiatric and bone symptoms which, while being unique to this disease, do not provide a rationale for the unambiguous identification of patients. These individuals, in fact, are likely to go unrecognized either because they are considered to be affected by other kinds of dementia or by fibrous dysplasia of bone. Given that dementia in NHD has much in common with Alzheimer's disease and other neurodegenerative disorders, it cannot be expected to achieve the differential diagnosis of this disease without performing a genetic analysis. Under this scenario, the availability of protein biomarkers would indeed provide a novel context to facilitate interpretation of symptoms and to make the precise identification of this disease possible. The work here reported was designed to generate, for the first time, protein profiles of lymphoblastoid cells from NHD patients. Two-dimensional electrophoresis (2-DE) and nano liquid chromatography-tandem mass spectrometry (nLC-MS/MS) have been applied to all components of an Italian family (seven subjects) and to five healthy subjects included as controls. Comparative analyses revealed differences in the expression profile of 21 proteins involved in glucose metabolism and information pathways as well as in stress responses.