Psychosis in Machado–Joseph Disease: Clinical Correlates, Pathophysiological Discussion, and Functional Brain Imaging. Expanding the Cerebellar Cognitive Affective Syndrome

Abstract

Machado-Joseph disease (MJD) is the most common spinocerebellar ataxia worldwide with a broad range of clinical manifestations, but psychotic symptoms were not previously characterized. We investigated the psychiatric manifestations of a large cohort of Brazilian patients with MJD in an attempt to characterize the presence of psychotic symptoms. We evaluated 112 patients with clinical and molecular diagnosis of MJD from February 2008 to November 2013. Patients with psychotic symptoms were referred to psychiatric evaluation and brain perfusion single-photon emission computed tomography (SPECT) analysis. A specific scale-Positive and Negative Syndrome Scale (PANSS)-was used to characterize psychotic symptoms in MJD patients. We also performed an autopsy from one of the patients with MJD and psychotic symptoms. Five patients presented psychotic symptoms. Patients with psychotic symptoms were older and had a late onset of the disease (p < 0.05). SPECT results showed that MJD patients had significant regional cerebral blood flow (rCBF) decrease in the cerebellum bilaterally and vermis compared with healthy subjects. No significant rCBF differences were found in patients without psychotic symptoms compared to patients with psychotic symptoms. The pathological description of a patient with MJD and psychotic symptoms revealed severe loss of neuron bodies in the dentate nucleus and substantia nigra. MJD patients with a late onset of the disease and older ones are at risk to develop psychotic symptoms during the disease progression. These clinical findings may be markers for an underlying cortical-cerebellar disconnection or degeneration of specific cortical and subcortical regions that may characterize the cerebellar cognitive affective syndrome.

Nosology and Phenomenology of Psychosis in Movement Disorders

“…Among these genetic subtypes, psychosis is more frequent in ATX‐ATXN3, ATX‐TBP, and ATX‐ATN1 in comparison to other subtypes, such as ATX‐ATXN2, ATX‐ATXN8, ATX‐PPP2R2B, or ATX‐ATXN10, in which the presence of psychosis was reported in a few cases . In ATX‐ATXN3 or Machado‐Joseph disease, the most common spinocerebellar ataxia worldwide, a frequency of psychosis of 4.5% was found in a large cohort of 112 patients . Patients with psychotic symptoms were older and presented later onset than those without psychosis .…”

“…In autosomal-dominant cerebellar ataxias, psychosis was reported in different genetic subtypes, such as ATX-ATXN2 (SCA2), ATX-ATXN3 (SCA3), ATX-ATXN7 (SCA7), ATX-ATXN8 (SCA8), ATX-ATXN10 (SCA10), ATX-PPP2R2B (SCA12), ATX-TBP (SCA17), and ATX-ATN1 (dentatorubral-pallidoluysian atrophy), most often after several years of disease course. 120,121,124,125 Among these genetic subtypes, psychosis is more frequent in ATX-ATXN3, ATX-TBP, and ATX-ATN1 in comparison to other subtypes, such as ATX-ATXN2, ATX-ATXN8, ATX-PPP2R2B,…”

“…or ATX-ATXN10, in which the presence of psychosis was reported in a few cases. 120,[124][125][126][127][128][129][130] In ATX-ATXN3 or Machado-Joseph disease, the most common spinocerebellar ataxia worldwide, a frequency of psychosis of 4.5% was found in a large cohort of 112 patients. 120 Patients with psychotic symptoms were older and presented later onset than those without psychosis.…”

“…120,[124][125][126][127][128][129][130] In ATX-ATXN3 or Machado-Joseph disease, the most common spinocerebellar ataxia worldwide, a frequency of psychosis of 4.5% was found in a large cohort of 112 patients. 120 Patients with psychotic symptoms were older and presented later onset than those without psychosis. 120 Anatomopathological studies in 5 patients with psychotic symptoms revealed severe loss of Purkinje cells and also loss of neurons in the dentate nucleus, inferior olives, and SN, but usually with preserved frontal, temporal, and parietal cortex.…”

“…120 Patients with psychotic symptoms were older and presented later onset than those without psychosis. 120 Anatomopathological studies in 5 patients with psychotic symptoms revealed severe loss of Purkinje cells and also loss of neurons in the dentate nucleus, inferior olives, and SN, but usually with preserved frontal, temporal, and parietal cortex. These findings are similar to those found in patients with autosomal-dominant cerebellar ataxias without psychosis.…”