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A 60-month follow-up of a naturalistic study of integrative treatment for real-life geriatric patients with depression, dementia and multiple chronic illnesses.


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Background: In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non-pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 60 month follow up. Materials and Methods: The study group consisted of 156 medically ill, physically disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cog-nitive exercises paired with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alpha-lipoic acid, acetyl-L-carnitine, omega-3, and coen-zyme Q-10) and diet modification. Cognitive assessments were performed yearly. Results: After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat-Attention, Cog-nistat-Judgment, and RFFT-Total Unique Designs demonstrated significant improvement. Conclusion: Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment model are warranted .
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Open Journal of Psychiatry, 2012, 2, 129-140 OJPsych
doi:10.4236/ojpsych.2012.22018 Published Online April 2012 (
A 60-month follow-up of a naturalistic study of integrative
treatment for real-life geriatric patients with depression,
dementia and multiple chronic illnesses*
Valentin Bragin1#, Marina Chemodanova1, Ilya Bragin1,2, Narmina Dzhafarova1, Irina Mescher1,
Pavlo Chernyavskyy1, Mark E. Obrenovich3, Hector H. Palacios4, Gjumrakch Aliev1,5,6†
1Stress Relief and Memory Training Center, New York, USA
2Upstate Medical University, Syracuse, USA
3Cleveland State University, Cleveland, USA
4National Institute on Aging, Baltimore, USA
5School of Health Science and Healthcare Administration, University of Atlanta, Atlanta, USA
6“GALLY” International Biomedical Research Institute Inc., San Antonio, USA
Received 28 January 2012; revised 29 February 2012; accepted 17 March 2012
Background: In the past we have shown the preser-
vation and improvement of cognitive tasks in de-
pressed and demented patients after 24 and 36 months
of combined pharmacological and non-pharmacol-
ogical treatment. Here we present the results of our
ongoing, naturalistic study, in the same outpatient
setting, at 60 month follow up. Materials and Meth-
ods: The study group consisted of 156 medically ill,
physically disabled patients with mild to moderate
dementia and depression. Patients were treated with
antidepressants, cholinesterase inhibitors, and NMDA
antagonists, along with their regular medication
regimen. Non-pharmacological intervention was cen-
tered on a home-based program of physical and cog-
nitive exercises paired with vitamins and supplements
(multivitamins, vitamin E, L-methylfolate, alpha-
lipoic acid, acetyl-L-carnitine, omega-3, and coen-
zyme Q-10) and diet modification. Cognitive assess-
ments were performed yearly. Results: After 60 months
of treatment, performance of all tasks remained at or
above baseline. The MMSE, Cognistat-Attention, Cog-
nistat-Judgment, and RFFT-Total Unique Designs
demonstrated significant improvement. Conclusion:
Our results, for the first time, demonstrate arrest in
cognitive decline in demented/depressed patients with
multiple medical co-morbidities for 60 months. Fu-
ture investigations addressing the application of a
combined, integrative treatment model are war-
Keywords: Dementia; Depression; Alzheimer Disease;
Vascular Dementia; Naturalistic Observational Study;
Integrative Treatment; Non Pharmacological
Interventions; Physical Exercises; Memory Training;
Cardiovascular Diseases
There is an ever evolving body of evidence which is re-
shaping our conception of the pathogenesis of Alzheimer
dementia (AD) [1-5]. In addition to the amyloid model of
AD, other models of this disease have been developed
Among many pathophysiological processes, cardio-
vascular abnormalities, and vasculature changes have
been shown to have a strong negative impact on the de-
velopment and progression of AD [3,8]. In this regard
cardiovascular pathology is accompanied by changes in
regional cerebral blood flow (CBF) [9,10], hypoperfu-
sion [11-14], chronic hypoxia [15-17], white matter le-
sions [18], nitrogen oxide and free radical accumulation,
oxidative stress [19], and mitochondrial dysfunction [20].
Theses changes have been shown to be detrimental to en-
ergy metabolism with deleterious effects on protein syn-
thesis, neuronal function, cognitive speed, gait, coordina-
tion, and global cognition. Based on these developments
and emerging neuroplasticity data, novel integrative
treatment approaches for the prevention and therapy of
AD have gained significant attention in recent years [8,
In real life clinical practice, people with dementia,
particularly with AD, generally are given medications
(cholinesterase inhibitors or NMDA receptors antago-
nists) with little to no non-pharmacological intervention.
Treatments that involve solely medication show only a
*Conflicts of Interest: all authors have no conflicts of interest.
#†Corresponding authors.
Published Online April 2012 in SciRes.
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140
transient cognitive improvement with subsequent decline
below baseline levels [28,29].
Research into combining medications with non-phar-
macological interventions for AD is in the fledgling
stages of its development. Recent studies suggest that the
combination of medications alongside non-pharmaco-
logical interventions could be more effective in treating
AD than medication alone. In these studies, medication
treatment was accompanied by one or two non-phar-
macological intervention modalities, including cognitive
rehabilitation [30,31], vitamin or nutriceutical supple-
mentation [32], and physical exercises [33,34].
There have been no comprehensive studies hitherto
which have investigated the long-term (>2 years) effect
of an integrative therapy model with pharmacological
and non-pharmacological treatment modalities imple-
mented simultaneously in a real life clinical setting.
We have been testing the hypothesis that this type of
integrative therapy could delay the progression of cogni-
tive deficit in demented, depressed and medically ill
seniors in real-life clinical settings. The preservation and,
in some cases, improvement of cognitive functioning
relative to baseline levels in demented patients by 12, 24,
and 36 months of treatment was shown in our previous
work [35,36].
The aim of this study is to investigate the effectiveness
of this integrative treatment model for arresting cognitive
decline in demented, depressed patients in outpatient
settings for duration of 60 months.
2.1. Study Design and Patient Selection
The observational study design was consistent with ac-
tual treatment practices. An informed consent was ob-
tained from each patient. Clinical assessments, organic
work-ups, and evaluation of cognitive functions were
conducted during the first two to three office visits.
These patients underwent yearly cognitive retesting to
assess the progress of the treatment and to make neces-
sary adjustments. The optimal combination of medica-
tions and non-pharmacological interventions were indi-
vidually tailored to every person based on their diseases,
medication profile, cognitive performance, and physical
The study group consisted of 156 geriatric patients (79
male, 77 female) with an average age of 73.7 ± 5.43,
who were afflicted with concomitant mild to moderate
dementia and depression, along with multiple medical
problems (hypertension, coronary artery disease, hyper-
lipidemia, diabetes, arthritis, and others). Their psychiat-
ric diagnoses were probable AD, Vascular Dementia
(VaD), or mixed dementia, and Organic Mood Disorder
with Depressed Mood, Organic Anxiety Disorder and
This ongoing, naturalistic study is based on data that
has been continuously collected from the patients’ medi-
cal records during the period of 2000-2010. All data from
patients who initiated treatment during this time period
and remained in treatment for at least one year was in-
cluded. The data were analyzed for up to 60 months of
treatment. Some patients missed yearly testing and were
tested in subsequent years.
Our integrative treatment protocol was designed as a
combination of medication and non-pharmacological
modalities. The non-pharmacological intervention in-
cluded mild physical activities, cognitive training, sen-
sory stimulation, vitamins, supplements, and dietary
During the course of the study period, newly released
medications (escitalopram, rivastigmine patch and me-
mantine), vitamins and supplements (vitamin D and L-
methylfolate) were added to the treatment regimen.
Medications included antidepressants (sertraline, citalo-
pram, escitalopram, or venlafaxine XR alone or in com-
bination with bupropion XR), cholinesterase inhibitors
(donepezil, rivastigmine, or galantamine alone or in com-
bination with memantine) along with regular medications
for their medical comorbidities. Patients were given me-
dications to manage insomnia (zolpidem, zaleplon, eszopi-
clone), anxiety (lorazepam, oxazepam), neuropathic pain
(gabapentin), and behavioral problems (risperidone,
haloperidol, quetiapine, aripiprazole) when clinically ap-
Non-pharmacological interventions included vitamins
and supplements (multivitamins, vitamin E, vitamin D,
folic acid or L-methylfolate, alpha-lipoic acid, acetyl-l-
carnitine, omega-3 and coenzyme Q-10) and the Bragin
Brain Activation Program™ (B-BAP™).
The B-BAP™ consists of a combination of mild sen-
sory motor exercises and cognitive training presented in
a workbook format [37]. The workbook, comprised of a
description of protocols for home use, was distributed to
each patient. The physical part of the program was spe-
cifically designed for people with extremely limited
physical capacities including but not limited to: problems
with gait and ambulation, movement restrictions due to
osteoarthritis, and low cardiovascular reserve. The cor-
nerstone of the physical activities is a series of hand and
finger movements with tennis balls. A dual task compo-
nent consisted of hand movements coupled with counting
and breathing. Practical demonstration of the exercises
was introduced to the patients and their care-takers on
initial visits. Patients were encouraged to do these exer-
cises at home several times per day, mainly in 10 to 12
minute intervals. Attention and memory training were
performed with simple pen and pencil exercises at home,
and supplemented with cognitive training using our
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140 131
originally designed computer software at our center [38,
2.2. Neuropsychological Test
Our neuropsychological battery consisted of 7 tests:
1) The Folstein Mini Mental Status Exam (MMSE)
with a maximum score of 30. For attention assessment
serial 7’s calculation was used [40].
2) Clock Drawing Test (CDT).
3) Verbal Fluency Tests (VFT)-categories included
animals and letters.
4) Neurobehavioral Cognitive Status Examination (Cog-
nistat), which is used along with MMSE to assess differ-
ent cognitive domains: orientation, attention (digit span),
language abilities (comprehension, repetition, naming),
construction abilities, word memory (four items), calcu-
lations, similarities, and judgment [41].
5) Ruff Figural Fluency Test (RFFT), which provides
information regarding nonverbal capacity of the right
frontal lobe to produce unique designs [42].
6) Ruff 2 & 7 Selective Attention Test (Ruff 2 & 7
SAT), which is used to assess sustained and selective
visual attention [43].
7) Word List Memory Learning Test (WLMLT), which
consists of a learning portion of the test, followed by
5-minute recall and recognition.
Exclusion criteria included patients younger than 65,
those with severe dementia (MMSE < 13), severe depres-
sion, any evidence of psychosis, a history of alcohol or
substance abuse, severe neurological disorders, and re-
cent major stress (e.g. death in the family, surgery).
2.3. Statistical Analysis
The Data Analysis was carried out with SPSS for Win-
dows, version 17.0 (SPSS Inc., Chicago, Ill.) [44]. Ana-
lysis included descriptive and non-parametric statistics
(the Wilcoxon signed-rank test, two related samples). All
statistical testing was two-tailed with a p value of <0.05
considered statistically significant.
Demographics and clinical characteristics were charac-
terized in Table 1. The study included 77 women and 79
men with mean age of 73.7 and mean education of 12.7
years. All the participants had depression and memory
problems. The average duration of depression and mem-
ory impairment were over 3 years. Over 80% of the co-
hort suffered from anxiety and insomnia. A majority of
patients suffered from hypertension, dyslipidemia, and
coronary artery disease, while a significant number had
diabetes mellitus, history of head trauma, prior stroke,
osteoarthritis, thyroid dysfunction, cancer and COPD.
Table 1.
profile of
Demographics Patients Percentage
Men 79 50.64
Women 77 49.36
Mean Standard Deviation
Age 73.65 5.43
Education (years) 12.71 2.91
Duration of illnesses (months)
Depression 39.00 22.87
Memory 37.85 3.20
Diagnosis Patients Percentage of group
Anxiety 130 83.33
Insomnia 128 82.05
Hypertension 133 85.26
High Cholesterol 112 71.79
Coronary Artery Disease 91 58.33
Diabetes 56 35.90
Arthritis 53 33.97
Stroke 26 16.67
Head Trauma 29 18.59
Thyroid disorder 18 11.54
Cancer 18 11.54
COPD 15 9.62
Parkinsonism 10 6.41
Renal Insufficiency 10 6.41
Anemia 6 3.85
Radiology Patients Percentage of group
Normal 17 23.9
Abnormal 54 76.1
Neuroimaging data (mainly, non contrast MRI) was
available for nearly half the sample. A “normal” scan
was found in 24% of the imaged group while the re-
maining 76% were found to have cortical atrophy, lacu-
nar infarcts, ventricular dilation, and white matter micro-
vascular changes alone or in combination with each
The patient flow/testing diagram is shown in Figure 1.
The percentage of the patients missing yearly testing
ranged from 20.5% (by 12 months of the treatment) to
42.3% (by 60 months of the observation period). Patient
drop out rate ranged from 21% - 28% between each year
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140
Figure 1. Patient flow/testing diagram*. *Patients tested refers
to those who took the MMSE during that time testing interval.
Patient drop out includes patients who left treatment for any
reason including illness, death, relocation and discontinuation
of therapy.
of testing.
Descriptive statistics are shown in Table 2. The
MMSE score was above the baseline for the whole pe-
riod of treatment with improvement ranging from 2.4%
after the first year to 5.9% after 60 months (Figure 2).
Performance on the CDT increased by 13.6% after 12
months, increasing to 25.0% above baseline for the next
two years and decreased to 17.2% by the end of the ob-
servation period (Figure 3). The VFT (animals) score
increased by a maximal amount, 14.9% above baseline at
36 months of observation and dropped back to baseline
level by 60 months (Figure 4). The VFT (letters) score
showed similar dynamics as the VFT (animals) (Figure
In Cognistat, performance in all subtests for the entire
period of the treatment increased. By the end of 12
months, performances in all subtests of Cognistat were
significantly above the baseline, especially, in attention,
construction and memory (16.7%, 16.4% and 15.3% ac-
cordingly). By the end of 24 months, performances in 9
out of 10 subtests of Cognistat (except for Calculation)
remained significantly above the baseline, especially, in
attention, construction and memory (26.1%, 24.4% and
23.9% respectively). By the end of 36 months, perform-
ances in 7 out of 10 subtests of Cognistat (except for
Naming, Calculation, Similarities) remained significantly
above the baseline, especially, in the same subtests: at-
tention (28.2%), construction (19.6%) and memory (19.3%).
By the end of 48 months, performances in 4 out of 10
subtests of Cognistat (Orientation, Attention, Repetition
and Construction) remained significantly above the base-
line, especially, in attention (25.8%) and construction
(36.4%). By the end of 60 months, performances in 2 out
of 10 subtests of Cognistat (Attention and Judgment)
remained significantly above the baseline, especially, in
attention (27.0%).
The Ruff 2 & 7 SAT (Automatic Detection Speed) did
not show significant decline for the whole period of ob-
The RFFT (Total Unique Designs) increased signifi-
cantly at 12, 36 and 60 months of the treatment (10.1%,
21.1% and 12.5% accordingly). The RFFT (Total Errors)
decrease significantly only by 24 months of the treatment
WLMTL did not show significant changes in per-
formance scores, related to trial one correct, 5 minute
recall and recognition.
The preservation of cognitive function in demented pa-
tients including AD becomes visible based on intensive
basic and clinical dementia research, which expands our
understanding of AD pathophysiology [45,46]. Among
different pathophysiological factors, a reduction of brain
blood flow with subsequent development of a chronic
hypoxic state, oxidative stress, mitochondria failure, en-
ergy deprivation, and increased inflammation are seen [4,
Prospective animal studies presented positive data re-
lated to the possible modification of the natural course of
dementia. The combination of acetyl-L-carnitine and
lipoic acid (ALCAR + LA) ameliorated mitochondrial
dysfunction in aging rats [49] and improved learning
abilities in aging beagles [50]. An antioxidant-enriched
diet partially reversed mitochondrial dysfunction in ag-
ing canines [51]. In addition, the combination of an an-
tioxidant-fortified diet and behavioral enrichment (phy-
sical exercises, social interaction, and cognitive training)
improved cognitive performance in aging dogs and re-
duced beta amyloid (Aβ) deposition [52]. An adaptation
to hypobaric intermittent hypoxia in rats with experi-
mental AD prevented Nitrogen Oxide (NO) overproduc-
tion and ameliorated oxidative stress [53]. Moreover,
recently we’ve demonstrated, for the first time, the age-
dependent effects of human Apolipoprotein E4 (ApoE4)
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140
Copyright © 2012 SciRes.
*P Value between baseline and 12 months; **P Value between baseline and 24 months; ***P Value between baseline and 36 months; *****P Value between baseline and 48 months; ******P Value between baseline
and 60 months.
Table 2. Cognitive tests results.
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140
Baseline 12 Months 24 Months 36 Months 48 Months 60 Months
MMSE Score
Figure 2. MMSE (Mini mental status exam). Data are presented as MEAN ± SEM.
Baseline 12 Months 24 Months 36 Months 48 Months 60 Months
CDT Score
Figure 3. CDT (Clock drawing test). Data are presented as MEAN ± SEM.
on CBF using ApoE4 transgenic mice compared to
age-matched wild-type (WT) mice by use of [(14) C]
iodoantipyrene autoradiography. ApoE4 associated fac-
tors reduced CBF gradually to create brain hypoperfu-
sion relative to WT animals [54]. The differences in CBF
are greatest in animals of age from 6-weeks to 12-months.
Furthermore, transmission electron microscopy with
colloidal gold immunocytochemistry showed that struc-
tural damage in young and aged endothelium microves-
sels of ApoE4 animals extended to the cytoplasm of
perivascular cells, perivascular nerve terminals, hippo-
campal neurons, and glial cells. These abnormalities co-
existed with mitochondrial structural alteration and mi-
tochondrial DNA overproliferation and/or deletion in all
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140 135
Baseline 12 Months 24 Months 36 Months 48 Months 60 Months
Number of Unique Responses
Figure 4. VFT (Animals). Data are presented as MEAN ± SEM.
Baseline 12 Months 24 Months 36 Months 48 Months 60 Months
Number of Unique Responses
Figure 5. VFT (Letters). Data are presented as MEAN ± SEM.
brain cellular compartments. Spatial and temporal mem-
ory tests showed a trend in improving cognitive function
of ApoE4 mice fed selective mitochondrial antioxidants,
acetyl-l-carnitine, and alpha-lipoic acid, which may have
practical application in humans as well [47,49,54].
Studies in rodents have shown that mental exercise
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140
enhances cerebrovasculature [55], induces neurogenesis
[56] and synaptogenesis, increases hippocampal synaptic
reactivity, and reduces brain Aβ deposition [57]. This
basic research has served as the foundation for clinical
implementation of an integrative treatment model: a
combination of medication therapy and non-pharmaco-
logical modalities.
Clinical data related to the integrative treatment of AD
is growing. A recent report by Chan et al. [32] showed an
improvement in multiple domains of the neuropsychiat-
ric inventory and maintenance of ADL in people in early
stages of AD, who were taking donepezil and a vitamin/
nutriceutical formulation for 12 months. Another report
by Bottino et al. [30] indicated a positive treatment ef-
fects on the MMSE and the backward digit span as a
result of a combined therapy (cognitive rehabilitation and
rivastigmine) in AD patients for 5 months. A study by
Rozzini et al. [31] demonstrated an improvement in
memory, abstract reasoning, and depression in a longitu-
dinal, 12 month, combined therapy (cognitive rehabilita-
tion and cholinesterase inhibitors) study. Reguena et al.
[58] used a combination therapy model (medication and
cognitive training) and showed an improvement in cog-
nitive functions by the end of 12 months of therapy. By
the end of 24 months of the treatment, this effect dimin-
ished. Chapman et al. [59] studied the slowing rates of
verbal and functional decline in AD patients, after 8
weeks of cognitive-communication stimulation and do-
nepezil treatment. Erkroth-Bucher and Siberski [60] pre-
sented an improvement on the Dementia Rating Scale in
mild AD patients after 6 weeks of cognitive training.
Some of these patients were taking medications at the
same time. There is no data to our knowledge related to
the implementation of a multi-modal, integrative treat-
ment in which many pharmacological and non-pharma-
cological modalities were used concurrently.
Our goal was to incorporate a set of non-pharmaco-
logical modalities to use simultaneously with standard
pharmacological therapy. There was no consensus about
non-pharmacological intervention modalities in literature.
Based on emerging data related to hypoperfusion in the
brain of demented individuals and its contribution to
brain hypoxia, oxidative stress, and mitochondria failure,
we developed the B-BAP™. At the heart of the program
are hand and finger exercises, which increase regional
CBF [61-65]. This fact has been well described in the
literature but has not been seen in widespread clinical
practice. Cognitive training has also been shown to in-
crease CBF in healthy subjects [66]. To our knowledge,
this program is the first attempt to use hand exercises for
possible restoration of brain blood flow in chronic neu-
rodegenerative disease, such as AD.
The present material is a part of this ongoing, natura-
listic treatment study. A comparison with similar studies
could not be done due to the lack of literature of any
study with a similar objective, except our previous 24-
and 36-month studies [35,36].
These studies have demonstrated the preservation and
improvement of cognitive functions in people who have
actively participated in the treatment. The maximum
cognitive function improvements were seen after the first
6 months of treatment in the 24 month study (first co-
hort), and by 24 months of treatment in the 36 month
study (second cohort). One possible explanation for the
difference between the two cohorts is that patients from
the first cohort had a younger average age and less car-
diovascular pathology enabling them to respond to
treatment earlier.
In the present study (third cohort), the maximum cog-
nitive improvements were observed by 24 months on the
treatment. The performance on all tasks did not decline
but improved significantly (MMSE, Cognistat-Attention,
Cognistat-Judgment, and RFFT-Total Unique Designs).
It was noted through performance, that brief cognitive
tasks (MMSE, CDT, Cognistat, and VFT) demonstrated
significant improvement for the first 36 months of the
treatment. At the same time, the continuous performance
tasks (Ruff 2 & 7 SAT, WLMLT and RFFT) remained
around the baseline. We suggest that brief cognitive tasks
had a shorter administration time, and most likely acti-
vated a limited amount of networks that were less de-
pendent on already compromised cerebral blood circula-
tion. The continuous performance tasks had a longer ad-
ministration time, and probably activated an extended
numbers of networks which may have more heavily re-
lied on an already limited supply of blood and oxygen
going into the brain. This suggestion may warrant a sepa-
rate investigation.
4.1. Strengths of the Study
There are several important strengths of this study. First,
the primary strength of this ongoing, self-controlled, natu-
ralistic study is that it is a real life outcome study whose
longitudinal design closely reflects actual clinical prac-
tices. In our study, cognitive performance was tested
every year during regular office visits for the entire pe-
riod of 60 months.
Second, our study is unique in its simultaneous usage
of the combination of pharmacological treatment with a
set of comprehensive non-pharmacological interventions
impacting brain function.
Third, the non-pharmacological part of the program
was designed with fragile patients in mind, for long term,
indefinite usage in the office and at home.
4.2. Limitations of the Study
Our study has certain limitations. First, depression was
Copyright © 2012 SciRes. OJPsych
V. Bragin et al. / Open Journal of Psychiatry 2 (2012) 129-140 137
only clinically diagnosed, without using any psychologi-
cal scales, such as Beck or Zung Depression and Anxiety
scales or the Activities of Daily Living questionnaires.
Secondly, there were some patients (approximately 30%)
who missed yearly retesting procedures and were tested
in the following year. The third limitation is that there is
no reliable information about the patients’ compliance
with medications, vitamins, physical exercises, and
memory training. Fourth, data about concomitant medi-
cations were not always available. Fifth, the test results
raters were non-blinded, and therefore there is the possi-
bility that the raters were unintentionally biased to see
positive results. Finally, a control group was not present
as this would be practically impossible because of ethical,
social, and personal issues related to the standards of the
care for the treatment of the selected demented and de-
pressed patients for this duration of time.
Despite these limitations, the data in this study dem-
onstrates the effectiveness of a combined, multifaceted
treatment approach and supports the notion that even
today, there are many available venues in routine outpa-
tient practice to prevent cognitive decline in medically ill,
clinically depressed/demented patients over a long period
of the time (60 months). The results of this observational
study are encouraging. The cognitive function stabiliza-
tion in this group was demonstrated consistently year by
year, during the entire observation period. At this point, it
is not possible to separate the role of each integrative
treatment modality in preservation of cognitive decline in
dementia/depression [67-69].
Based on this study, combination therapy can have an
effect on disease progression and stabilization of cogni-
tive function in mild to moderate dementia patients, even
in severely medically ill patients with depression. One of
the plausible explanations is a partial restoration of brain
blood circulation, oxygen/nutrient flow, and the removal
of oxidative stress products via the activation of a NO
dependent pathway. Functional imaging studies, quanti-
tative EEG, and NO assays would help to confirm these
suggestions in the future.
The integrative treatment model described here has been
effective in the preservation of cognitive functions in
severely medically ill, demented, depressed seniors for
period of 60 months.
As a new practical framework for treatment of patients
with dementia and depression, it is important to include
medical office visits, coupled with lifelong home based
activities. Late age interventions appear to have positive
effects in the treatment of the elderly. Going forward,
prospective studies with combined therapy for “real life”
patients with AD/dementia are necessary [67-69].
This study was supported by the Stress Relief and Memory Training
Center, Brooklyn, New York, NY USA and “GALLY” International
Biomedical Research Institute, Inc., San Antonio, TX, USA. We are
very grateful for Ms. Galina Alieva for her editorial work throughout
the preparation of this manuscript.
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... In animal and cell models of AD, herbal extracts appear to have fewer adverse effects than beneficial effects on cognitive functions because of their antioxidant and anti-inflammatory properties [140]. Recen tly , we presented the results of our ongoing naturalistic study in the same outpatient setting at 60 month follow up [141]. The study group consisted of 156 medically ill, physically disabled patients with mild to moderate dementia and depression. ...
... Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises as well as with vitamins and supplements (multivitamins, vitamin E, Lmethylfolate, a-lipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification [141]. Cognitive assessments were performed yearly [141]. ...
... Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises as well as with vitamins and supplements (multivitamins, vitamin E, Lmethylfolate, a-lipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification [141]. Cognitive assessments were performed yearly [141]. After 60 months of treatment, performance of all tasks remained at or above baseline. ...
Full-text available
Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) that leads to Alzheimer disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase enzymes (NOSs), which further exasperates the formation of the reactive oxygen and reactive nitrogen species (ROS/RNS). The ROS and RNS collectively contribute to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.
... 7 Nutrition and other nonpharmacological interventions, especially physical and cognitive activities, have shown promising results in delaying the onset of dementia and could significantly improve the outcome of dementia and/or depression treatment. 8,9 The main driving force for this hypothesis is that combined therapy has an unique influence on brain functions in patients with AD or other dementia/depression, and potentially exerts a synergistic effect, by controlling the rate of cognitive decline and improving the quality of life, thus delaying nursing home placement. Existing clinical research observations have focused on the potential implementation of one of the several modifying factors, with or without medication. ...
... The goal of this review is to highlight the recent clinical and animal studies concerning the possibility of modifying the course of dementia and potentially improving the cognitive functioning through simultaneous implementation of pharmacological and nonpharmacological treatment regimes in the real-life clinically ill patients with dementia and/or depression. 8,9 The Influence of the Vascular Hemodynamics Failure in the Context of Dementia Effects of CBF in Initiation and Progression of Dementia. The fact that cardio-and cerebrovascular pathology goes along with neurodegenerative processes in dementia is well documented. ...
... Outcome of this effectiveness explores improvement in the mental and cognitive performance. 3,[8][9][10] Influence of the Physical Activities on CBF and Cognitive Performance. The relationship between physical activities and rCBF have been extensively studied in humans (healthy seniors and patients with MCI) as well as animal models that mimic human MCI or mental retardation. ...
Full-text available
It has been postulated that Alzheimer disease (AD) is a systemic process, which involves multiple pathophysiological factors. A combination of pharmacotherapy and nonpharmacological interventions has been proposed to treat AD and other dementia. The nonpharmacological interventions include but are not limited to increasing sensory input through physical and mental activities, in order to modify cerebral blood flow and implementing nutritional interventions such as diet modification and vitamins and nutraceuticals therapy to vitalize brain functioning. This article highlights the recent research findings regarding novel treatment strategies aimed at modifying natural course of the disease and delaying cognitive decline through simultaneous implementation of pharmacological and nonpharmacological modulators as standardized treatment protocols.
... So- called 'naturalistic' studies, which follow a group of patients in an outpatient clinic over many months are relevant and informative to clinical practice. Bragin et al. (2012) showed arrest in cognitive decline for 60 months for patients with depression, dementia, physical disability and medical illnesses. Patients were treated with a multimodal intervention specific to their needs, including anti-depressants, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, vitamins and supplements as well as physical and cognitive exercises. ...
... This example strengthens the evidence base, informs clinical practice and is rele- vant to people living with dementia who (1) would routinely be prescribed a dementia drug, and (2) often have comorbidities. Such a patient consequently may benefit from a combined, integrative treatment model, as Bragin et al. (2012) aptly demonstrated. ...
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Objective Multimodal non-pharmacological interventions have been argued to have the potential to complement current pharmacological approaches to improving quality of life for people living with dementia. The aim of this review was to identify, synthesise and appraise the evidence for the effectiveness of multimodal non-pharmacological interventions for improving cognitive function specifically. Method After a comprehensive search strategy including grey literature, 26 studies were reviewed. The inclusion criteria concerned adults with a primary diagnosis of dementia. Studies used two or more different modes of intervention, and measured a cognitive outcome. Due to differences in the conceptualisations of the term ‘multimodal’, a typology of modes and methods was developed to facilitate classification of candidate studies. Results Twenty-one group studies and five case studies were found. Group studies used two or three modes of intervention and multiple methods to implement them. Interventions utilised were cognitive, physical, psychological and psychosocial, nutrition, fasting, gut health, sleep hygiene, stress reduction, detoxification, hormonal health and oxygen therapy. Five individual case studies were found in two separate papers. Each personalised patient treatment utilised in-depth assessments and prescribed up to nine different modes. In 19 (90%) of the 21 group comparisons, participants were reported to have cognitive improvements, stability with their dementia or a delay in their decline. The extent of these improvements in terms of meaningful clinical change was variable. Conclusion Multimodal non-pharmacological interventions have the potential to complement singular therapeutic approaches by addressing multiple modifiable risk factors currently understood to contribute towards cognitive decline.
... nd cognitive exercises). The optimal combinations of pharmacological and non-pharmacological modalities were individually tailored to every patient. Yearly cognitive retesting was implemented to assess the level of cognitive functions. The exclusion criteria for this group were moderate-to-severe dementia (MMSE less than 18), and severe depression. [9] ResultsTable 2. ...
... The limitation of the study is an absence of a control group, which does not seem feasible for 72 months of treatment. The fairly high annual drop out rate (24 %) reflects real life office practice [9]. The cohort itself is always evolving as more individuals who started treatment later are included into analysis as their treatment reaches a certain time, while some individuals from prior studies have dropped from treatment for a variety of causes. ...
Integrative Treatment Postpones Cognitive Decline in Patients with Dementia and Depression: A 72 Month Follow up Observational Study Valentin Bragin, M.D., PhD, Gary Shereshevsky PhD, Arina Gorskaya, Elena Dorfman, MS, Ilya Bragin M.D., Frank Copeli BA, Kevin Vinokur. Stress Relief and Memory Training Center, Brooklyn, New York, NY USA Background: Alzheimer’s disease (AD) is a multi-faceted, whole brain and body illness. Given the complexity of the pathogenesis of AD, a multi-faceted approach to therapy makes practical sense for real-life, patient care. In the past several years, we have been testing the hypothesis that integrative treatment could delay the progression of cognitive decline in demented, depressed, and medically ill seniors. The preservation of cognitive performance was demonstrated in demented and depressed patients after 60 months of integrated therapy (Bragin V et al., 2012). Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 72 months of treatment. Methods: 70 Patients (43 females, 27 males, mean age of 71.4 ± 5.94, education – 13.00 ± 2.69 with mild to moderate dementia and depression, with multiple chronic medical co-morbidities (hypertension, coronary artery disease, hyperlipidemia, diabetes, arthritis etc.) underwent integrative treatment which consisted of pharmacological therapy (cholinesterase inhibitors, NMDA antagonists, antidepressants, along with their regular medication regimen) and non-pharmacological interventions. The non-pharmacological modalities included office and home-based physical and cognitive exercises aimed at the modification of regional cerebral blood flow. Diet modifications, vitamins, and nutritional supplements were incorporated as well. Cognitive testing was performed annually and included the MMSE, clock drawing test, verbal fluency tasks, and the Neurobehavioral Cognitive Status Examination (Cognistat), Ruff 2 & 7 Selective Attention and Ruff Figural Fluency tests. Descriptive and non-parametric statistical analysis (Wilcoxon signed-rank test) was performed on SPSS for Windows, version 21.0. Results Performance on all cognitive tests remained at or improved from their baseline for a period of 72 months. The baseline MMSE was 26.8 ± 7.09 and by 72 months of the treatment, MMSE was 27.6 ± 6.50 (p > 0.05). Significant improvement (p < 0.05) was observed on Cognistat orientation, attention, construction and memory subtests. Conclusion: The integrative treatment approach postponed cognitive decline in demented and depressed patients with multiple medical co-morbidities for 72 months. Future investigations addressing integrated treatment in AD are warranted.
... 51 rational design aimed at exploring the possibility of developing compounds that possessed the ability to inhibit AChE, A processing and aggregation, and the capacity to neutralize oxidative stress. Among the possible carriers of radical scavenger activity, attention was focused on the benzoquinone fragment of coenzyme Q10 (CoQ10) since this natural antioxidant has the potential to be a beneficial agent in neurodegenerative diseases in which there is mitochondrial function and/or excessive oxidative damage [210][211][212][213]. From a medicinal chemistry point of view, 51 is a bivalent ligand, with a symmetrical structure composed of two 2-methoxybenzyldiamino moieties connected by a benzoquinone spacer. ...
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Alzheimer`s disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Aβ aggregation in AD. Though there are still many enigmatic aspects of the Aβ cascade, none of the gaps invalidate the hypothesis. The amyloid hypothesis determines that the production, aggregation and accumulation of Aβ in the brain gives rise to a cascade of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding, oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Aβ plaques, the intracellular neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others. The observations supporting the development of multifunctional compounds in association with the perception that several dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy, the multi-target-directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses which would enable the treatment of multi-factorial diseases. This review summarizes a few current therapeutic trends on MTDL strategy intended to halt or revert the progression of the disease.
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Neurodegeneration and cancer are fast becoming one of the leading causes of age-associated disability, dementia, and death worldwide. Although oxidative stress biosynthesis has been intensely studied, little analysis has been done in chronic oxidative stress-induced mitochondrial models. In this regard, DNA overproliferation and/or deletion of the organ and/or tissues initiates the mitochondrial energy failures, which have been implicated in the pathogenesis of Alzheimer disease (AD), tumor growth, and metastasis. In this regard, decline in mitochondrial normal homeostasis during the development and maturation of the neurodegeneration, tumor growth, and/or metastases is known to be characterized by tissue and cellular oxygen deficiency, which can lead to subcellular energy defects that are well compensated by vital cellular components and regulators. In addition, the overexpression of the cascades that initiates the formation and releases of the large amount of free radicals [mainly nitric oxide (NO) via the overexpression of NO synthases] and their intermediate products cause the oxidative stress, cellular alterations, and particularly the concomitant mitochondrial lesions and decline in normal organ function. The present study explores the intimate, i.e. direct relationship between chronic oxidative stress and mitochondrial damage as a vital life-supporter for cells and/or the microcirculatory systems whose damage occurs before the development of human AD. Our study highlights the pattern of chronic oxidative stress induced mitochondrial DNA overproliferation and/or deletion and mitochondrial enzyme activities during the development of human AD. In this regard, human AD, colorectal cancer in liver metastasis, and malignant brain cancers appeared to be primary pathogenic factors during the development of these conditions. Our conclusion is that mitochondrial lesions, especially mitochondrial DNA abnormalities, are responsible for cell viability which can be used as new diagnostic tools and/or criteria for the earlier detection of diseases and future considerations for this approach will enable us to open new pathways, not only for the better understanding of the blood brain barrier (BBB) homeostasis which most likely plays a key role in the development of AD and some of forms of the cancer, but also for the development of new and more specific treatment strategies that will be more powerful and effective in bringing a cure for these devastating disease.
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Oxidative stress in the cardiovascular system, including brain microvessels and/or parenchymal cells results in an accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) compounds thus promoting leukocyte adhesion and increasing endothelial permeability. The resulting chronic injury stimulus results in progressive cellular hypometabolism. We propose that hypometabolism, coupled with oxidative stressors, is responsible for most Alzheimer disease (AD) and cerebrovascular accidents (CVAs) and appears to be a central initiating factor for vascular abnormalities, mitochondrial damage and an imbalance in the activity of vasoactive substances, such as different isoforms of nitric oxide synthase (NOS), endothelin-1 (ET-1), oxidative stress markers, mtDNA and mitochondrial enzymes in the vascular wall and in brain parenchymal cells. At higher concentrations, ROS induces cell injury and death, which occurs during the aging process, where accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms, especially in the mitochondria. Vascular endothelial and neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, which can cause a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondrial DNA abnormalities such as overproliferation and or deletion can be used as a key marker for diseases differentiation and effectiveness of the treatment. We speculate that specific antioxidants such as acetyl-L-carnitine and R-alpha lipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and restore the normal cellular function, making these antioxidants very powerful alternate strategies for the treatment of cardiovascular cerebrovascular as well as neurodegenerative diseases including AD. Future potential exploration using mtDNA markers can be considered more accurate hallmarks for diagnosis and monitoring treatment of human diseases. The present article discusses some of the patents regarding the oxidative stress.
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Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.
The Neurobehavioral Cognitive Status Examination: a brief but quantitative approach to cognitive assessment. Meetinstrument Neurobehavioral Cognitive Status Examination Afkorting NCSE / COGNISTAT Auteurs Kiernan & al. Onderwerp Beoordeling van cognitieve functies Doelstelling Meetinstrument voor stoornissen die verbonden zijn met verwardheid Populatie Psychiatrische patiënten boven de 12 jaar Gebruikers Alle professionals uit de gezondheidszorg Aantal items Niet gespecificeerd Deelname van de patiënt Deelname van de patiënt is noodzakelijk Meetinstrument te vinden Niet beschikbaar Doelstelling De Neurobehavioral Cognitive Status Exam (NCSE) is een meetinstrument dat werd ontwikkeld om snel symptomen die samenhangen met verwardheid en stoornissen in het CZS meten. Met dit instrument kan men cognitieve functiestoornissen opsporen en duiden. Doelpubliek De NCSE richt zich tot psychiatrische patiënten boven de 12 jaar en niet tot psychogeriatrische patiënten. Beschrijving De cognitieve domeinen die de NCSE/ Cognistat meet zijn (Doninger et al.2000):  oriëntatie,  aandacht,  taal (3 domeinen: begrijpen, herhaling van zinnen, benoemen van voorwerpen),  verbaal geheugen,  constructie-capaciteit,  mentaal rekenen en redeneervermogen. De beoordelaar noteert eveneens het bewustzijnsniveau van de patiënt. De NCSE/Cognistat gebruikt een metrisch benaderingssysteem: een eerste item dient als vertrekpunt voor elk domein, behalve voor de domein oriëntatie en geheugen. Als de patiënt het eerste item succesvol afwerkt, worden de fundamentele capaciteiten die men nodig acht om over de uitvoering te onderhandelen als zijnde normaal beschouwd, het maximum aantal punten wordt toegekend en er zijn niet meer vragen. Als het patiënt er niet in slaagt, krijgt hij bijkomende metrische items om zijn prestatieniveau vast te stellen. De NCSE meet onafhankelijk de verschillende cognitieve domeinen voor men tot de totale score komt.
Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-β (Aβ) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Aβ deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain—effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Aβ is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Aβ. Failure of perivascular drainage of Aβ and deposition of Aβ in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Aβ-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Aβ and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Aβ and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.
The majority cases of Alzheimer's disease (AD) are sporadic late-onset form not being linked to APP and PS1 gene mutations. It is believed that the environmental risk factors play an important role in the onset and development of AD. Patients suffering from cerebral ischemia and stroke in which hypoxic conditions occur are much more susceptible to AD. Increasing evidence suggests that hypoxia facilitates the pathogenesis of AD through accelerating the accumulation of Aβ, increasing the hyperphosphorylation of tau, impairing the normal functions of blood–brain barrier, and promoting the degeneration of neurons. Further investigations into the relationship between hypoxia and AD may open the avenue for effective preservation and pharmacological treatments of this neurodegenerative disease.