Depression in Alzheimer’s disease and other dementias

Much of our current knowledge about depression in Alzheimer’s disease and other dementias is based on the 1991 National Instiute of Health Consensus Development Panel on the Diagnosis and Treatment of Depression in Late Life, and its subsequent 1997 update. However, much research has taken place since these reports. This article summarizes this research, particularly research that has taken place in the past year. Comorbid depression is common in all types of dementia. It may, however, appear to be different from classic depression. Unlike classic depression, the depression found in dementia may result from anatomic damage to the brain. This is most clearly demonstrated in vascular depression. The implications of this are many. Treatments for depression are designed for classic depression. For those with vascular depression (and other depressions associated with dementia) treatments may not be as efficacious. Newer strategies, including agents not commonly thought of as antidepressants, may be needed.     

Neuropsychiatric symptoms and the APOE genotype in Alzheimer’s disease

The study aimed to characterize neuropsychiatric symptomatology in Alzheimer’s disease (AD) and investigate the role of APOE genotype and other clinical variables in the onset of neuropsychiatric disorders. Moreover, an attempt to study the evolution of behavioral and psychiatric symptoms was made. Fifty-three consecutive outpatients with AD were enrolled. Twenty-four were followed longitudinally for 1 year. MMSE was used to evaluate cognitive functions. The neuropsychiatric inventory (NPI) was administered to assess behavioral and psychiatric symptoms. Genotyping was determined through laboratory testing. At baseline, no specific neuropsychiatric disorder was significantly associated with ApoE genotype, but associated with a peculiar neuropsychiatric profile. Patients with ε ₄ allele showed a wider range of neuropsychiatric disturbances when compared to non-carriers and higher scores for hallucinations and aberrant motor behaviors. The longitudinal results suggest different trends in both groups: over time, ε ₄ carriers showed an increase/delayed onset in some symptoms and a parallel decrease in others, while non-carriers presented an undifferentiated worsening of symptomatology. Clear relations with other clinical and demographic variables were also found. APOE ε ₄ allele is associated to a peculiar neuropsychiatric profile characterizing the onset and evolution of Alzheimer’s disease.     

Current application of neurochemical biomarkers in the prediction and differential diagnosis of Alzheimer’s disease and other neurodegenerative dementias

In light of the dramatically increasing prevalence of Alzheimer’s disease (AD) to be expected in the future, the development of novel therapeutics, improved differential and early diagnostics, and means for the identification of individuals at risk are urgently needed. At present, instruments for a reliable differential diagnosis in clinical dementia, mild cognitive impairment, or prodromal stages have direct practical implications for differentiating secondary dementias from neurodegenerative conditions and for treatment decisions. It may also be reasonable to enforce the incorporation of biomarkers into clinical studies as surrogate outcome parameters and as an attempt to optimize recruitment criteria. Recently, revised research criteria increasingly rely on the interpretation of biomarker patterns, including neuroimaging and CSF-based neurochemical dementia diagnosis (NDD) in supporting the clinical diagnosis. Here, we review the performance of current core CSF biomarkers (Aβ₄₂ peptide, total tau protein and phosphorylated tau species) and try to define objectives for prospective markers, also considering blood-based tests, which would increase the acceptance and wide application of NDD. Moreover, we evaluate the role and the limitations of genotyping in the predictive diagnosis of AD.

     

Non-cognitive symptoms and related conditions in the Alzheimer’s disease: a literature review

The Alzheimer’s disease is considered a progressive cognitive disorder; however, several non-cognitive symptoms accompany all stages of the disease, appearing at times before the cognitive symptoms become manifest. This article reviews the literature on non-cognitive symptoms normally related to the Alzheimer’s disease, including gait and balance dysfunction, olfactory dysfunction, diabetes, pain, and psychiatric symptoms.     

Psychiatric symptoms screening in the early stages of Parkinson’s disease

Psychiatric complaints are common in Parkinson’s disease (PD), and have a significant influence in disease outcome and quality of life. Little attention has been paid to psychiatric symptoms at early stage disease. We aimed to screen a population of early stage PD patients for psychiatric symptoms and to study the relation with motor and cognitive function. Thirty-six early stage PD patients underwent motor [Hoehn and Yahr (HY), Unified Parkinson’s Disease Rating Scale] and cognitive [Frontal Assessment Battery, Mini-Mental State Examination (MMSE)] assessment as well as general psychiatric [Symptom Check-List 90 (SCL-90-R)] and psychosis [Brief Psychiatric Rating Scale (BPRS)] screening. Relation between psychiatric domains scores was studied with principal component analysis. Relation between psychiatric, disease related, cognitive and motor function was assessed with bivariate correlation (Pearson). SCL-90-R scores were higher for somatization (significant scores in 66.7% of patients), depression (36.1%), anxiety (27%) and obsessive—compulsive symptoms (OCS) (52.8%). Scores were highly correlated, except for psychosis and phobia. Depression and anxiety were negatively correlated to MMSE score and dopaminergic doses, respectively. BPRS scores were higher for somatic concern, depression, anxiety and hallucinations. There was segregation between depression, anxiety, hallucinations, other positive psychotic symptoms and negative psychotic symptoms. Depression was related to MMSE score. We found a high prevalence of psychiatric complaints in PD patients, mostly related to depression, anxiety, somatization and OCS. Hallucinations were also frequent, but not associated to cognitive function or dopaminergic doses, suggesting a different physiopathological background.     

Association between fatigue and other motor and non-motor symptoms in Parkinson’s disease patients

Although fatigue is a common non-motor symptom in patients affected by Parkinson’s disease (PD), its association with motor and other non-motor symptoms is still largely unclear. We assessed fatigue in PD patients studying the possible association with motor and non-motor symptoms. Eighty-one PD patients were included in the study. The PD Fatigue Scale (PFS) and the Fatigue Severity Scale (FSS) scale were used to measure fatigue. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS). Motor impairment was assessed using the modified Hoehn and Yahr (HY) staging and the Unified PD Rating Scale (UPDRS) part-III and IV. Bivariate tests comparing all independent variables between patients with our without fatigue were used. Significant predictors of presence and severity of fatigue were determined with different models of logistic regression analyses. Fatigue severity was significantly higher in female patients. Bivariate test showed significant higher NMSS score in fatigued patients according to PFS (p < 0.00001) and FFS (p < 0.001), while HY was higher only in fatigued patients according to FSS (p < 0.022). Significant correlations between severity of fatigue and HY stage (p < 0.002) and UPDRS-III score (p < 0.001) were found, while, among specific non-motor symptoms, anhedonia presented with the most significant correlation (p < 0.003). Binary logistic regression confirmed NMSS as the main variable predicting presence of fatigue, while HY was significant as predicting variable only in the FSS model. Strongest non-motor symptoms predictors of severity were those included in Domain 3 (mood/anxiety) and Domain 2 (sleep disorders) of the NMSS. A significant increase in severity of fatigue related to the burden of non-motor symptoms (mainly affective and sleep disorders) was observed. Our findings indicate a moderate discrepancy in the ratings of the two fatigue scales, with PFS principally directed towards the burden of non-motor symptoms. Finally, the accurate individuation of the factors underlying fatigue, assessed with the systematic administration of holistic evaluation scales such as the NMSS, might improve current strategies used in the treatment of this disabling condition.     

Sleep and non-motor symptoms in Parkinson’s disease

Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson’s disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under-recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients’ quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson’s disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management.     

Diet and Alzheimer’s disease

Alzheimer’s disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homocysteinerelated vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B₆, B₁₂, and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B₁₂, B₆, and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.     

Astrocyte and Alzheimer’s disease

The past several decades have given rise to more insights into the role of astrocytes in normal brain function and diseases. Astrocytes elicit an effect which may be neuroprotective or deleterious in the process of Alzheimer’s disease (AD). Impairments in astrocytes and their other functions, as well as physiological reactions of astrocytes to external injury, can trigger or exacerbate hyperphosphorylated tau and amyloid-beta (Aβ) pathologies, leading to the formation of both amyloid plaques and neurofibrillary tangles (NFTs), as well as neuronal dysfunction. This review addresses the involvement of astrocytes in the Aβ pathology, where the main mechanisms include the generation and clearance of Aβ, and the formation of NFTs. It is also discussed that metabolic dysfunction from astrocytes acts as an initiating factor in the pathogenesis of AD and a contributor to the onset and development of clinical presentation in AD.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies

Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer’s disease (AD), tangle-predominant dementia, Guam Parkinson dementia complex, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies.     

Amyloid metabolism and secretases in Alzheimer’s disease

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid beta-protein (A beta) in senile plaques. A beta is derived from the beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavages. beta-secretase was recently identified to be a membrane-anchored aspartyl protease that is widely distributed in subcellular compartments, including Golgi, trans-Golgi network, and endosomes. Although definitive identification of gamma-secretase will require reconstituting its activity in vitro, mounting evidence suggests that gamma-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for A beta generation. Three classes of gamma-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PSI as gamma-secretase. These results provide the molecular basis for therapeutic interventions that reduce A beta accumulation in AD patients by inhibiting beta- or gamma-secretase.     

Total recognition discriminability in Huntington’s and Alzheimer’s disease

Both the original and second editions of the California Verbal Learning Test (CVLT) provide an index of total recognition discriminability (TRD) but respectively utilize nonparametric and parametric formulas to compute the index. However, the degree to which population differences in TRD may vary across applications of these nonparametric and parametric formulas has not been explored. We evaluated individuals with Huntington’s disease (HD), individuals with Alzheimer’s disease (AD), healthy middle-aged adults, and healthy older adults who were administered the CVLT–II. Yes/no recognition memory indices were generated, including raw nonparametric TRD scores (as used in CVLT–I) and raw and standardized parametric TRD scores (as used in CVLT–II), as well as false positive (FP) rates. Overall, the patient groups had significantly lower TRD scores than their comparison groups. The application of nonparametric and parametric formulas resulted in comparable effect sizes for all group comparisons on raw TRD scores. Relative to the HD group, the AD group showed comparable standardized parametric TRD scores (despite lower raw nonparametric and parametric TRD scores), whereas the previous CVLT literature has shown that standardized TRD scores are lower in AD than in HD. Possible explanations for the similarity in standardized parametric TRD scores in the HD and AD groups in the present study are discussed, with an emphasis on the importance of evaluating TRD scores in the context of other indices such as FP rates in an effort to fully capture recognition memory function using the CVLT–II.