Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.

Frontotemporal dementia (FTD) is one of three neurobehavioural syndromes produced by frontotemporal lobar degeneration. Despite the importance of FTD as a cause of dementia, especially in younger age groups, and a rationale for therapies targeting serotonergic and dopaminergic systems, there have been no large scale treatment trials in FTD. Moreover, there is no consensus on standards to facilitate comparison across therapeutic trials. This paper reviews the literature on therapeutic trials in FTD and outlines general recommendations for standards related to the development of future treatment studies in this disorder. Drugs tested in FTD include trazodone, galantamine, idazoxan, lithium plus fluoxetine, lithium plus paroxetine, SSRIs, l-deprenyl, moclobemide, methylphenidate, piracetam, rivastigmine, donepezil, olanzapine, risperidone, amantadine, guanfacine, allopurinol, and bromocriptine. Improvement has been reported in FTD for all drugs except piracetam, guanfacine and galantamine, although there was improvement on galantamine in primary progressive aphasia. Whereas improvement has been reported for paroxetine and other SSRIs, as well as idazoxan and methylphenidate, paroxetine and idazoxan have also been reported to cause a decline in function, and a marginally significant decline has been reported for methylphenidate. In addition, patients with Pick's disease, which is part of the spectrum of frontotemporal lobar degeneration, showed improvement on calcium EDTA. Six studies are double-blind placebo-controlled trials: two reports of cases using idazoxan and group trials using trazodone, paroxetine, galantamine and methylphenidate. It is recommended that experts in FTD arrive at a consensus to define standards for all clinical trials in FTD. These should include standards for diagnostic criteria, tests of severity, experimental design, and outcome measures.

Vascular dementia (VaD) is a heterogeneous disorder resulting from various cerebrovascular diseases (CVD) causing cognitive impairment that reflects severity and location of damage. Epidemiological studies suggest VaD is the second commonest cause of dementia, but autopsy series report that pure VaD is infrequent, while combined CVD and Alzheimer's Disease(AD) is likely the commonest pathological-dementia correlate. Both diseases share vascular risk factors and benefit from their treatment. The most widely used diagnostic criteria for VaD are highly specific but not sensitive. Vascular Cognitive Impairment (VCI) is a dynamic, evolving concept that embraces VaD, Vascular Cognitive Impairment No Dementia (VCIND) and mixed AD and CVD. Clinical trials to date have focused on probable and possible VaD with beneficial effects evident for different drug classes, including cholinergic agents and NMDA agonists. Limitations have included use of cognitive tools suitable for AD that are insensitive to executive dysfunction. Disease heterogeneity has not been adequately controlled and subtypes require further study. Diagnostic VaD criteria now 13 years old need updating. More homogeneous subgroups need to be defined and therapeutically targeted to improve cognitive-behavioural outcomes including optimal control of vascular risk factors. More sensitive testing of executive function outlined in recent VCI Harmonization criteria and longer trial duration are needed to discern meaningful effects. Imaging criteria must be well-defined, with centralized review and standardized protocols. Serial scanning with quantification of tissue atrophy and lesion burden is becoming feasible, and cognitive interventions, including rehabilitation pharmacotherapy, with drugs strategically coupled to cognitive -behavioural treatments, hold promise and need further development.