Balance on the Brain: a randomised controlled trial evaluating the effect of a multimodal exercise programme on physical performance, falls, quality of life and cognition for people with mild cognitive impairment-study protocol.

INTRODUCTION: Exercise and physical activity have been shown to improve cognition for people living with mild cognitive impairment (MCI). There is strong evidence for the benefits of aerobic exercise and medium evidence for participating in regular strength training for people with MCI. However, people living with MCI fall two times as often as those without cognitive impairment and the evidence is currently unknown as to whether balance training for people with MCI is beneficial, as has been demonstrated for older people without cognitive impairment. The aim of this study is to determine whether a balance-focused multimodal exercise intervention improves balance and reduces falls for people with MCI, compared with a control group receiving usual care. METHODS AND ANALYSIS: This single blind randomised controlled trial (Balance on the Brain) will be offered to 396 people with MCI living in the community. The multimodal exercise intervention consists of two balance programmes and a walking programme to be delivered by physiotherapists over a 6-month intervention period. All participants will be followed up over 12 months (for the intervention group, this involves 6-month intervention and 6-month maintenance). The primary outcomes are (1) balance performance and (2) rate of falls. Physical performance, levels of physical activity and sedentary behaviour, quality of life and cognition are secondary outcomes. A health economic analysis will be undertaken to evaluate the cost-effectiveness of the intervention compared with usual care. ETHICS AND DISSEMINATION: Ethics approval has been received from the South Metropolitan Health Service Human Research Ethics Committee (HREC), Curtin University HREC and the Western Australia Department of Health HREC; and approval has been received to obtain data for health costings from Services Australia. The results will be disseminated through peer-review publications, conference presentations and online platforms. TRIAL REGISTRATION NUMBER: ACTRN12620001037998; Australian New Zealand Clinical Trials Registry (ANZCTR).

Efficacy of probucol on cognitive function in Alzheimer's disease: study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study).

INTRODUCTION: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aß) in the peripheral circulation is causally related to the development of Alzheimer's disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aß compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aß moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aß secretion, concomitant with maintaining blood-brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer's study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD. METHODS AND ANALYSIS: The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target sample is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer's Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention. ETHICS AND DISSEMINATION: The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063; Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000726853).

Retinal vascular and structural changes are associated with amyloid burden in the elderly: ophthalmic biomarkers of preclinical Alzheimer's disease.

BACKGROUND: Retinal imaging may serve as an alternative approach to monitor brain pathology in Alzheimer's disease (AD). In this study, we investigated the association between retinal vascular and structural changes and cerebral amyloid-ß (Aß) plaque load in an elderly cohort. METHODS: We studied a total of 101 participants, including 73 elderly subjects (79 ± 5 years, 22 male) with no clinical diagnosis of AD but reporting some subjective memory change and an additional 28 subjects (70 ± 9 years, 16 male) with clinically established AD. Following a complete dilated ocular examination, the amplitude of retinal vascular pulsations and dynamic response, retinal nerve fibre layer thickness and retinal ganglion cell layer (RGCL) thickness were determined in all patients. Systemic blood pressure and carotid-to-femoral pulse wave velocity were measured. The elderly cohort also underwent magnetic resonance imaging and 18F-florbetaben (FBB)-positron emission tomographic amyloid imaging to measure neocortical Aß standardised uptake value ratio (SUVR), and this was used to characterise a 'preclinical' group (SUVR >1.4). RESULTS: The mean FBB neocortical SUVR was 1.35 ± 0.3. The amplitude of retinal venous pulsations correlated negatively with the neocortical Aß scores (p < 0.001), whereas the amplitude of retinal arterial pulsations correlated positively with neocortical Aß scores (p < 0.01). RGCL thickness was significantly lower in the clinical AD group (p < 0.05). CONCLUSIONS: The correlation between retinal vascular changes and Aß plaque load supports the possibility of a vascular component to AD. Dynamic retinal vascular parameters may provide an additional inexpensive tool to aid in the preclinical assessment of AD.

Risk factors for dementia with Lewy bodies: a case-control study.

OBJECTIVE: To determine the risk factors associated with dementia with Lewy bodies (DLB). METHODS: We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort. RESULTS: Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5-16; p < 0.0001), depression (6.0; 3.7-9.5; p < 0.0001), stroke (2.8; 1.3-6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5-8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5-3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27-0.70; p = 0.0006) or use caffeine (0.29; 0.14-0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42-1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3-8.5; p < 0.0001), have a history of depression (4.3; 2.4-7.5; p < 0.0001), be more educated (2.5; 1.1-5.6; p = 0.031), have a positive family history of PD (5.0; 2.4-10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40-0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5-39; p = 0.015). CONCLUSION: DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.

Clinical characterization of a kindred with a novel 12-octapeptide repeat insertion in the prion protein gene.

OBJECTIVE: To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene, PRNP. DESIGN: Clinical description of a kindred. SETTING: Mayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota). SUBJECTS: Two pathologically confirmed cases and their relatives. MAIN OUTCOME MEASURES: Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses, and neuropathologic features. RESULTS: The proband was a woman with clinical and neuroimaging features of atypical frontotemporal dementia and ataxia. Generalized tonic-clonic seizures developed later in the disease course, and electroencephalography revealed spike and wave discharges but no periodic sharp-wave complexes. Her affected sister and father also exhibited frontotemporal dementia-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in the disease course. Genetic analyses in the proband identified a novel defect in PRNP, with 1 mutated allele carrying a 288-base pair insertion consisting of 12 octapeptide repeats. Neuropathologic examination of the proband and her sister revealed prion protein-positive plaques and widespread tau-positive tangles. CONCLUSIONS: This kindred has a unique combination of clinical and neuropathologic features associated with the largest base pair insertion identified to date in PRNP and underscores the need to consider familial prion disease in the differential diagnosis of a familial frontotemporal dementia-like syndrome.

Frequency, characteristics, and risk factors for amiodarone neurotoxicity.

OBJECTIVE: To assess the incidence, severity, and spectrum of neurologic toxic effects associated with administration of amiodarone hydrochloride. DESIGN: Retrospective medical record analysis of cardiac patients treated with amiodarone between January 1, 1996, and July 31, 2008. SETTING: Residents of Olmsted County, Minnesota, treated at the Mayo Clinic. PATIENTS: The Mayo Clinic medical records of all adult Olmsted County residents prescribed amiodarone between January 1, 1996, and July 31, 2008, were reviewed and all possible neurologic adverse effects that might be attributable to amiodarone were tabulated. MAIN OUTCOME MEASURES: Risk factors and clinical characteristics of patients developing neurologic problems were compared with those who did not. RESULTS: Over the 151 months of analysis, 707 patients were treated with amiodarone. Among these patients, the cumulative incidence of likely amiodarone neurotoxic effects was 2.8%; 1.6% of all amiodarone-treated patients were referred to Neurology for a neurotoxic reaction. Neurologic problems included tremor, gait ataxia, peripheral neuropathy, and cognitive impairment. The primary risk factor for amiodarone neurotoxic effects was duration of treatment, not age, drug dose, sex, or indication for therapy. Where this could be assessed, the adverse effects were usually but not always reversible. CONCLUSIONS: Amiodarone infrequently causes clinically significant neurologic toxic effects. Substantially higher estimates of neurotoxic effects in the early amiodarone era may be related to a much higher daily dose.

A possible role for humoral immunity in the pathogenesis of Parkinson's disease.

The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with alpha-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue samples from the substantia nigra and primary visual cortex for comparison were stained for alpha-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1-4 and IgG receptors FcgammaR I-III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = -0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 +/- 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = -0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcgammaRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcgammaRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcgammaRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.