Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson’s disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson’s disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson’s disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson’s disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson’s Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson’s disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson’s disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.

We describe nine patients, five women and four men (age at death 58–83 years), who developed isolated progressive frontotemporal dementia over 4 to 12 years. These cases represent nine of the 385 (2.3%) cases from a series of autopsy cases of dementia in a large teaching hospital. One had a mother with a history of frontotemporal dementia and marked frontal lobe atrophy. Another had multiple affected family members with frontotemporal dementia, motor neurone disease or both. None of the nine had clinical evidence of either an upper or lower motor neurone disorder. In each case neuropathological examination revealed cortical pathology identical to that described previously as typical of dementia associated with motor neurone disease. There was variable macroscopic atrophy and neuronal loss in the frontal and temporal lobes. All cases had cortical microvacuolation, in seven limited to cortical layer II, and transcortical in two. There was variable cortical and subcortical gliosis. Intraneuronal ubiquitin-immunoreactive inclusions, characteristic of the extra-motor involvement of motor neurone disease, were found in the hippocampal dentate granule cells and residual neurones in layer II of the frontotemporal cortex of all cases. Similar inclusions were also seen in the nucleus ambiguus of three cases. The hypoglossal nuclei showed no neuronal loss, gliosis or ubiquitin-immunoreactive inclusions. Ubiquitin-immunoreactive dystrophic neurites were detected within affected cortex, being most conspicuous in layer II in areas containing microvacuolation. Dystrophic neurites were not detected in subcortical structures. Spinal cords were unavailable for examination because of limited autopsy consent. The finding of intraneuronal ubiquitin-immunoreactive inclusions characteristic of motor neurone disease in patients with frontotemporal dementia, without clinical or pathological evidence of motor system degeneration, extends the clinical spectrum of diseases associated with such inclusions. We propose the term motor neurone disease-inclusion dementia (MNDID) for these cases.

We would like to clarify details of patients whom we have previously described,1with inclusions characteristic of extramotor involvement in motor neuron disease (MND)—type dementia. Of 11 cases reported, 7 had no evidence of motor weakness while alive. We can now report that of these 7, only 3 showed ubiquitinated inclusions in brain-stem nuclei; because of limited autopsy consent, the spinal cord was not available in these cases. We would therefore like to clarify our discussion: paragraph 2 on page 1014 concerns the "extramotor cortical pathologic features of MND," but the third sentence should have made it clear that these patients have pathologic changesof MND, not ofamyotrophic lateral sclerosis. As spinal cord tissue was not available, we cannot comment on the presence or absence of anterior horn cell inclusions in these cases.

We have studied the brains of 10 patients with clinically and pathologically defined Huntington's disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8. 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C‐terminal hydrolase (PGP 9.5). Dystrophic neurites. immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas. in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin‐immunoreactive neurites were stained with antibodies to β‐amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, αB crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with β‐amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulo‐filamentous material. Granular deposits with a diameter of 40–100 nm were interspersed between randomly orientated ‘fuzzy’ or coated, straight or slightlv curved filaments measuring 10–15 nm in diameter. These structures have not been seen in control brain and differ from age‐related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease. The areal density of these neurites was quantified in 20 microscopic fields in the superior frontal and anterior cingulate sections (Brodmann areas 8 and 24) and did not correlate with the Vonsattel grade, suggesting that they are an independent and possibly primary cortical pathology in Huntington's disease.