Journal of Alzheimer's Disease - Volume 33, issue 2

Authors: Olazarán, Javier | Hernández-Tamames, Juan Antonio | Molina, Elena | García-Polo, Pablo | Dobato, José Luis | Álvarez-Linera, Juan | Martínez-Martín, Pablo | AD Research Unit Investigators

Article Type: Research Article

Abstract: We conducted a cross-sectional study to investigate the clinical and anatomical correlates of gait dysfunction in advanced Alzheimer's disease (AD). A comprehensive clinical protocol that included cognitive, functional, behavioral, and motor variables was administered to patients with probable AD (n = 100), possible AD (n = 17), and AD with cerebrovascular disease (AD + CVD) (n = 27). Gait dysfunction was evaluated with the Rating Scale for Gait Evaluation in Cognitive Deterioration and magnetic resonance imaging was analyzed in 94 patients (volumetry study) and 78 patients (diffusion tensor imaging study). Univariate correlations, multivariate regression, and statistical parametric mapping analyses were …conducted in the total sample and in the subsample of patients with probable AD. Mean age was 82.5 (SD 6.3, range 56 to 98), 83.3% were female patients, and 95.1% displayed moderate to severe dementia. Parkinsonism, patient setting (nursing home), dementia severity, apathy, and (worse) cognitive performance significantly predicted gait dysfunction in the total sample (p < 0.05, R2 = 0.58), whereas parkinsonism, patient setting, and limb weakness due to non-AD conditions predicted gait dysfunction in probable AD (p < 0.05, R2 = 0.57). Gait dysfunction was related to atrophy in the motor cortex, the middle cingulate, the anterior insula, the right caudate (total sample only), and the anterior lobe of the cerebellum (p < 0.01, corrected). Significant correlations were also observed between gait dysfunction and damage in several white matter locations (p < 0.001, uncorrected). The present results are congruent with a model of multi-system gray matter degeneration, with progressive damage to critical regions (i.e., motor cortex, cingulate, insula, and cerebellum) producing gait dysfunction and, eventually, gait loss in AD. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging, gait dysfunction, inpatients, nursing homes, outpatients, primary senile degenerative dementia, volumetry

DOI: 10.3233/JAD-2012-121207

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 495-505, 2013

Authors: Xu, Wei-Li | Caracciolo, Barbara | Wang, Hui-Xin | Santoni, Giola | Winblad, Bengt | Fratiglioni, Laura

Article Type: Research Article

Abstract: The impact of APOE ε4 on mild cognitive impairment (MCI) and its progression to dementia remain controversial. We aimed to examine the association of APOE ε4 with MCI, and to verify the hypothesis that ε4 accelerates progression from MCI to dementia. In the Kungsholmen project, 756 cognitively healthy participants and 212 people with MCI aged ≥75 years were identified at baseline. Amnestic MCI (aMCI) and other cognitive impairment no dementia (oCIND) as two subtypes of MCI were assessed based on standard definitions. The two cohorts were followed for 9 years to detect incident cases of MCI and dementia following international …criteria. APOE genotypes were assessed at baseline. Data were analyzed using Cox models. During the follow-up, in the cognitively healthy cohort, 165 people developed MCI (40 aMCI and 125 oCIND) and 176 developed dementia; in the MCI cohort, 118 persons progressed to dementia. Compared with APOE ε3ε3, the hazard ratios (HRs) (95% CIs) of ε2ε4/ε3ε4 were 2.24 (1.10–4.57) for aMCI and 1.78 (1.15–2.75) for oCIND, while the ε4ε4 was related to dementia with a HR of 4.35 (1.97–9.63) in the cognitively healthy cohort. In the MCI cohort, the ε4ε4 genotype led to a multi-adjusted HR of 2.89 (1.12–7.48) for dementia and accelerated the progression to dementia by 3.36 years. The APOE ε4 heterozygotes are associated with an increased risk of aMCI and oCIND. The ε4 homozygote substantially accelerates progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. Show more

Keywords: Amnestic mild cognitive impairment, APOE ε4, dementia, longitudinal study, mild cognitive impairment, other cognitive impairment no dementia, hazard ratio

DOI: 10.3233/JAD-2012-121369

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 507-515, 2013

Authors: Szigeti, Kinga | Lal, Deepika | Li, Yanchun | Doody, Rachelle S. | Wilhelmsen, Kirk | Yan, Li | Liu, Song | Ma, Changxing | The Texas Alzheimer Research and Care Consortium

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60–80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the …heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings. Show more

Keywords: Age at onset, Alzheimer's disease, copy number variation

DOI: 10.3233/JAD-2012-121285

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 517-523, 2013

Authors: Bonnì, Sonia | Lupo, Federica | Lo Gerfo, Emanuele | Martorana, Alessandro | Perri, Roberta | Caltagirone, Carlo | Koch, Giacomo

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by altered functional cortico-cortical connectivity likely due to loss of afferent and efferent connections between different cortical areas. Here we explored parieto-frontal functional connectivity in 15 AD patients and 12 healthy control subjects by means of bifocal transcranial magnetic stimulation (TMS). Conditioning stimuli were applied over the right posterior parietal cortex (PPC) at different intensities (90% and 110% of resting motor threshold, RMT). Motor evoked potentials (MEPs) were then recorded from the ipsilateral primary motor cortex at different interstimulus intervals (ISIs) ranging between 2 and 15 ms. Results showed that in healthy subjects, a conditioning …TMS pulse applied over the ipsilateral PPC at 90%, but not at 110%, of RMT intensity was able to increase the excitability of the right M1. This functional interaction peaked at ISI = 6 ms. Conversely, in AD patients the facilitatory pattern of parieto-motor connections was evident only when TMS was delivered at an intensity of 110% of RMT with a peak at ISI = 8 ms. Moreover in AD patients, treatment with cholinesterase inhibitors did not induce any significant modification in the strength of the connection. In subsequent analyses, we found that, in AD patients, the effects induced by PPC conditioning at 110% RMT correlated with neuropsychological measures of episodic memory and executive functions, implying that patients with better cognitive performance had less impaired connectivity. Our findings reveal that parieto-frontal cortico-cortical functional connectivity is altered in AD patients, providing further evidence for a disconnection-based interpretation of AD symptoms. Show more

Keywords: Alzheimer's disease, connectivity, parietal cortex, transcranial magnetic stimulation

DOI: 10.3233/JAD-2012-121144

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 525-533, 2013

Authors: Vilalta-Franch, Joan | Calvó-Perxas, Laia | Garre-Olmo, Josep | Turró-Garriga, Oriol | López-Pousa, Secundino

Article Type: Research Article

Abstract: The objective of this paper was to assess the prevalence, incidence, persistence, and risk and mortality factors for Apathy Syndrome in Alzheimer's disease (ASAD) in a clinical sample. This was a cohort study of 491 patients with probable Alzheimer's disease (AD). The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX), the Neuropsychiatric Inventory (NPI), the Rapid Disability Rating Scale (RDRS-2), and the Zarit Burden Interview (ZBI) were administered, and all patients were reevaluated after 12 months. Baseline ASAD diagnosis was made using specific diagnostic criteria. ASAD prevalence and incidence/year were 21.0% and 10.6%, respectively. After one year, ASAD persisted …in 61.2% of patients. At baseline, patients with ASAD scored lower on the CAMCOG and higher on the Blessed, RDRS-2, and ZBI. Antipsychotic use was the only risk factor for ASAD (RR = 3.159; 95% CI: 1.247–8.003). ASAD was related to an increased functional disability, but no relationship with cognitive impairment or increased caregiver burden was detected. Finally, ASAD was associated with an increased risk of mortality (HR = 1.987; 95% CI: 1.145–3.450; p = 0.014). ASAD suggests a more severe AD clinical profile, with poorer functional progression and increased mortality risk. Antipsychotic use seems to be the only risk factor for ASAD. Show more

Keywords: Alzheimer's disease, apathy, epidemiology, incidence, prevalence

DOI: 10.3233/JAD-2012-120913

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 535-543, 2013

Article Type: Other

DOI: 10.3233/JAD-2012-120914B

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 545-546, 2013